Tumor immune evasion is a lineament of cancer. Endothelial monocyte activating polypeptide-II (EMAP II) has been assumed to impact tumor immune escape significantly. EMAP II was first reported in the murine methylcholanthrene A-induced fibrosarcoma supernatant and identified as a tumor-derived cytokine. This study evaluated EMAP II expression in peripheral blood cells and its association with treatment outcome, lactate dehydrogenase (LDH) levels, and clinical criteria in non-Hodgkin’s lymphoma (NHL) patients. EMAP II expression on different blood cells obtained from the peripheral blood of 80 NHL patients was evaluated by two-color flow cytometry. The study reported that EMAP II expression was significantly increased in peripheral blood cells in patients with NHL compared to normal volunteers (P < 0.001). Additionally, EMAP II expression levels on blood cells decreased in complete remission (CR) while they increased in relapse. This study showed coexpression of EMAP II and CD36 on peripheral lymphocytes in NHL patients but not in healthy controls (P < 0.001). EMAP II expression on blood cells was associated with increased serum LDH levels. Furthermore, the percentages of EMAP II+/CD36+ peripheral lymphocytes were significantly higher in relapse than in CR and healthy controls. Analyses revealed that higher percentages of EMAP II+CD36+ cells were positively correlated with hepatomegaly, splenomegaly, and an advanced (intermediate and high risk) NHL stage. The results assume that EMAP II might be involved in NHL development and pathogenesis.

1. Introduction

Non-Hodgkin’s lymphomas (NHL) are malignant lymphoproliferative diseases characterized by heterogeneous clinical and histological criteria [1, 2]. NHL is manifested by the abnormal accumulation or proliferation of B, T, and natural killer (NK) cells that infiltrate hematopoietic and lymphoid tissues and extend to different organs [3, 4]. Follicular lymphoma (about 10%) and diffuse large B-cell lymphoma (approximately 30%) are the most frequent NHL subtypes, while the frequency of all other NHL subtypes is less than 10% [5]. For the treatment of NHL patients, a slew of new therapeutic protocols based on a cocktail of multidrug chemotherapy has been developed [6]. In aggressive NHL, multidrug treatment results in a five-year overall survival rate of 50–60% [7]. However, many patients relapsed, either due to failure after lengthy treatment, referred to as a refractory disease, or due to relapse after an initial response, referred to as relapsing disease [8]. Thus, the search for reliable markers in NHL might usher in a new era of cancer immunotherapy.

Endothelial monocyte activating polypeptide-II (EMAP II), which is produced from its precursor aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1), is expressed as a 34 kDa intracellular peptide [9]. EMAP II mRNA and the corresponding precursor protein, proEMAP, have been found in normal and malignant tissue [10–15]. Full-length cDNAs encoding human and murine EMAP II were isolated from normal peripheral blood cells [12]. AIMP1 enhanced normal macrophages and dendritic cells to release IL-12 and initiate Th1 responses [16, 17]. On the cell surface, the C terminus of pro-EMAP II undergoes proteolytic cleavage by apoptosis and protease inhibitors [18–20] to generate the extracellular 22 kDa C-terminal peptide [21–23] that acts as an antiangiogenic protein [9, 24].

EMAP II is classified as a part of the aminoacyl-tRNA synthetase (ARS) family due to a high degree of similarity between it and ARS p43 [20]. EMAP II and p43 have a high degree of similarity in amino acid sequence, and the human homologs of p43 and EMAP II are congruent. p43’s extracellular function is identical to that of EMAP II in terms of its angiogenic properties [25].

EMAP II was first reported in the murine methylcholanthrene A-induced fibrosarcoma supernatant and identified as a tumor-derived cytokine based on its propensity to enhance procoagulant activity in the cultured endothelial cells [21]. It has various activities against neutrophils, macrophages, and endothelial cells [26, 27]. As a result, EMAP II has antiangiogenic and proinflammatory properties [28, 29]. EMAP II is a 169-amino-acid cytokine that plays a role in inflammation, apoptosis, and angiogenesis [30, 31]. Endothelial apoptosis, hypoxia, and cellular stress were observed to induce the processing and release of EMAP II [14, 32–34].

EMAP II not only promotes cancer formation by increasing tumor autophagy, sensitizing tumor cells to tumor necrosis factor- (TNF-) alpha, blocking angiogenesis, and increasing brain tumor barrier permeability [35–44], but also promotes cancer formation by causing lymphocyte death [31, 45–47]. EMAP II expression induced lymphocyte apoptosis, suggesting an immunosuppressive role in cancer [48]. Previous data indicated that serum EMAP II might be a potential biomarker in patients with NHL and lung cancer [49, 50]. Some reports have examined EMAP II expression in tumors and its correlation with prognosis [33, 50, 51].

CD36 (cluster of differentiation 36), a scavenger receptor, is a protein encoded by the CD36 gene and expressed in different human immune cells [52]. CD36 promotes the association of lipid rafts with receptors, adapter molecules, and signaling [53]. It is expressed in tumor cells, where it binds, initiates internalization, and regulates long-chain FAS transport [54, 55]. CD36 has a significant role in cancer progression, spread, and metastasis [56–58]. CD36 expression has been explored in different types of NHL [59, 60].

Different immune checkpoint molecules regulate immunity against cancer. EMAP II is one of the molecules expressed on tumor cells and provides a negative signal by inducing lymphocyte apoptosis in cancer. Some reports have examined EMAP II expression in tumors and its correlation with prognosis. However, EMAP II expression on peripheral blood cells of cancer patients, especially in NHL, has not been studied. This paper analyzed EMAP II expression on peripheral blood cells in NHL patients and revealed some association with prognosis in NHL.

2. Subjects and Methods

2.1. Subjects

The study was done at the Oncology Department, Minia Oncology Centre, Minia, Egypt, and at the Clinical Pathology Department, Minia University, Faculty of Medicine, Egypt, Minia. Thirty healthy controls were involved in this study and 80 NHL patients. Blood was withdrawn from healthy volunteers without autoimmunity, immunosuppression, or malignancy. NHL subjects were divided into three groups: group I: newly diagnosed NHL subjects and not started therapy, group II: NHL subjects who achieved complete remission (CR), and group III: NHL subjects with relapse. NHL diagnosis was confirmed by histopathology and immunophenotyping. The responses of NHL patients have been evaluated regarding the response criteria of Cheson et al. [61]. CR is recognised by free laboratory data and the absence of radiographic symptoms and signs of the disease. Relapse was identified as disease return within five months of complete remission, lymphoma progression during the first treatment, and failure to have complete or partial remission after therapy [61]. NHL patients and normal controls gave informed written consent.

2.2. Clinical Characteristics and Samples Collection

Clinical examination, lymph node biopsy, and bone marrow aspiration defined NHL’s stage, type, and clinical evaluation. Three experienced pathologists performed the validation of the pathological specimens according to WHO classifications [62]. A flow cytometer was used to perform immunophenotyping for NHL patients. The individuals were also subjected to an X-ray and a pelviabdominal ultrasound. The status of NHL was evaluated on the Eastern Cooperative Oncology Group scale [63]. The Ann Arbor system was used to determine the NHL stage [64]. NHL subjects with incomplete pathological or clinical information did not participate in this study. The controls with chronic infections or autoimmune diseases were excluded from the study. For flow cytometric analysis, 2 mL of blood was placed in a sterile K3EDTA tube. In addition, 3 mL of blood was centrifuged in a plain tube, and the produced serum was used to measure lactate dehydrogenase (LDH) levels using an automated clinical chemistry analyzer (Schiapparelli Biosystems, Inc.).

2.3. NHL Treatment

Twenty newly diagnosed NHL patients have not received treatment yet. 60 NHL patients received CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone) therapy [65].

2.4. Antibodies

Flow cytometry analysis with a verified EMAP II antibody was used to examine EMAP II expression in peripheral blood cells: 546-2, monoclonal antibody (Santa Cruz; catalog no. 32723); CD3 antibody, UCHT1, monoclonal antibody (BioLegend; catalog no. 300406); CD4 antibody, RPA-T4, monoclonal antibody (BioLegend; catalog no. 300506); CD4 Antibody; RPA-T4, monoclonal antibody (BioLegend; catalog no. 300530); CD8 antibody, SK1, monoclonal antibody (BioLegend; catalog no. 344704); CD16 antibody, 3G8, monoclonal antibody (BioLegend; catalog no. 302006); CD20 antibody, 2H7, monoclonal antibody (BioLegend; catalog no. 302304); CD22 antibody, S-HCL-1, monoclonal antibody (BioLegend; catalog no. 363508); HLA-DR antibody, L243, monoclonal antibody (BioLegend; catalog no. 980402); and CD36 antibody, 5-271, monoclonal antibody (BioLegend; catalog No. 336204). For the negative controls is PE mouse IgG2b (k) antibody, 27-35, isotype control antibody (BioLegend; catalog no. 402203). Blocking, immunoprecipitation, and immunohistochemistry (IHC) were used to confirm each antibody for flow cytometric analysis.

2.5. Flow Cytometry Analysis

Flow cytometry analysis was assessed by having the following antibodies: CD4-FITC, CD4-PerCP-Cy5.5, CD3-FITC, CD8-FITC, CD16-FITC, CD20-FITC, CD22-FITC, CD5-FITC, CD7-FITC, CD36-FITC, HLA-DR-FITC, EMAP II-PE, and PE isotype control. Antibodies’ staining was assessed according to the instructions of the manufacturer. 5 μL of fluorescently conjugated antibodies were mixed with 100 μL of blood and incubated at room temperature for fifteen minutes in the dark. Subsequently, 2 mL red cell lysis buffer was added (BD FACS lysing solution), vortexed, and then was made to sit for fifteen minutes at room temperature in the dark. Sample centrifugation was performed for about 5 min at 1200 rpm. The supernatant was taken out, and 1 mL of phosphate-buffered saline (PBS) solution was put into each tube and mixed thoroughly. The tubes were centrifuged for five minutes at 1200 rpm, and the supernatant was taken out. To resuspend the cells for flow cytometry analysis, 300 μL PBS was added.

A minimum of ten thousand total events were collected and analyzed [66–68]. Two-color immunofluorescence analysis was performed on BD FACSCanto II (Becton Dickinson, San Diego, CA, USA). The analysis of the data was performed by FACSDiva. To exclude cell aggregates and debris, lymphocytes were gated using the scatter forward (size) vs. side scatter (granularity) technique (FSC/SSC) [69–74]. The percentage of cells stained with antibodies was used to represent the results. The percentages of positive cells were assessed from the lymphocyte gate. According to the isotypic controls, the percentage of positive cells was determined. An isotype-matched control was used to assess background fluorescence. For each subject, unstained cells were used as a negative control.

2.6. Statistical Analyses

All statistical analyses were conducted using IBM SPSS Statistics, version 24 (IBM; Armonk, New York, USA). The Shapiro-Wilk test checks normality. Continuous variables were expressed as the mean and standard deviation (SD) if normally distributed or the median and interquartile range (IQR) if not normally distributed. Numbers and percentages were used to present categorical variables. Student’s t-test or Mann–Whitney U test was used to compare two independent groups’ variables, as applicable. Kruskal-Wallis was used to compare independent groups for nonparametric data, followed by Dunn’s test with Bonferroni correction to assess intergroup differences. The strength of the linear link between two continuous variables was estimated using Spearman’s correlation. A P value of less than 0.05 was considered significant, and values less than 0.001 were regarded as highly significant.

3. Results

3.1. Patients’ Criteria

NHL patients’ criteria are illustrated in Table 1. For 20 NHL patients, peripheral blood samples were taken at early NHL diagnosis. Thirty NHL patients had complete remission of the disease. Thirty patients experienced a relapse. The mean age of NHL subjects was 45.3 ± 15.7 years, while it was 44.5 ± 15 for healthy controls. 80 NHL patients (38 female, 42 male) and 30 normal controls (12 female, 18 male) were involved. Regarding gender and age, healthy individuals and NHL subjects did not reveal any difference (P > 0.05) (Supplementary Table 1).

1. Clinical characteristics of non-Hodgkin’s lymphoma (NHL) patients.

	N (%)
Group
Group I (newly diagnosed)	20 (25.0%)
Group II (complete remission)	30 (37.5%)
Group III (relapse)	30 (37.5%)

Subtype
DLBCL	59 (73.8%)
CLL	10 (12.5%)
FCL	7 (8.8%)
SCL	1 (1.2%)
MALT	2 (2.5%)
Missing	1 (1.2%)

B/T
B	74 (92.5%)
T	3 (3.8%)
Mixed	2 (2.5%)
Plasma cell differentiation	1 (1.2%)

Hepatomegaly
Positive	39 (48.8%)
Negative	41 (51.2%)

Splenomegaly
Positive	49 (61.2%)
Negative	31 (38.8%)

Stage
I	9 (11.3%)
II	26 (32.5%)
III	21 (26.2%)
IV	24 (30.0%)

N: number; DLBCL: diffuse large B-cell lymphoma; SCL: small lymphocytic lymphoma; CLL: chronic lymphocytic leukemia; FCL: follicular cell lymphoma; MALT: mucosa-associated lymphoid tissue lymphoma.

3.2. EMAP II Expression on Peripheral Blood Cells from NHL Subjects

High differences were identified between all NHL subjects and normal controls regarding the percentage of EMAP II+CD4+, EMAP II+CD16+, EMAP II+CD20+, and EMAP II+CD22+ (P < 0.001). However, no differences were found between NHL subjects and normal volunteers regarding EMAP II+CD8+ percentages (P = 0.911) (Supplementary Table 2).

EMAP II expression was examined in blood cells obtained from patients before and after therapy. In NHL, EMAP II was expressed dimly by peripheral blood cells. Newly diagnosed NHL subjects had a higher EMAP II+CD4+% than patients with CR [median: 7.4% (range 6.8-8.1) vs. 2.3% (range 1.5-2.7); P = 0.001] as well as a higher percentage of EMAP II+CD8+ [median: 4% (range 4-5) vs. 0.6 (range 0.4-0.7); P = 0.001]. The median percentage of EMAP II+CD16+ cells in newly diagnosed patients was 2.8% (range: 2.5-3.0) vs. 1.1% (range: 1.0-1.4) in patients with complete remission, P = 0.023. Measuring EMAP II expression in peripheral blood cells showed that EMAP II+CD20+% was higher in newly diagnosed patients than in patients with CR [median: 6% (range 5-6) vs. 1% (range 0.8-1.2%); P = 0.001]. Similarly, EMAP II+CD22+% was also increased in newly diagnosed patients compared to patients with CR [median 6.1: (5.9-6.6%) vs. 2.4: (2-3.5%); P = 0.001] (Figure 1 and Table 2). Gating of peripheral immune cells was shown in Supplementary Figure 1.

Details are in the caption following the image — Open in figure viewer PowerPoint

2. Percentage of EMAP II in peripheral blood cells in non-Hodgkin’s lymphoma (NHL) patients.

	(n = 20)	(n = 30)	(n = 30)	P value
	Group I (newly diagnosed)	Group II (complete remission)	Group III (relapse)	P value
EMAP II+CD4+% Median (IQR)	7.4 (6.8-8.1)	2.3 (1.5-2.7)	0.7 (0.6-1)	<0.001 ^∗∗
				I vs. II	I vs. III	II vs. III
				0.001 ^∗	0.001 ^∗	0.004 ^∗

EMAP II+CD8+% Median (IQR)	4 (4-5)	0.6 (0.4-0.7)	0.2 (0.1-0.3)	<0.001 ^∗∗
				I vs. II	I vs. III	II vs. III
				0.001 ^∗	0.001 ^∗	0.005 ^∗

EMAP II+CD16+% Median (IQR)	2.8 (2.5-3)	1.1 (1-1.4)	8 (6.2-8.8)	<0.001 ^∗∗
				I vs. II	I vs. III	II vs. III
				0.023 ^∗	0.003 ^∗	<0.001 ^∗∗

EMAP II+CD20+% Median (IQR)	6 (5-6)	1 (0.8-1.2)	1.1 (1-1.3)	<0.001 ^∗∗
				I vs. II	I vs. III	II vs. III
				0.001 ^∗	0.001 ^∗	0.786

EMAP II+CD22+% Median (IQR)	6.1 (5.9-6.6)	2.4 (2-3.5)	6.8 (6-7.3)	<0.001 ^∗∗
				I vs. II	I vs. III	II vs. III
				0.001 ^∗	>0.99	<0.001 ^∗∗

N: number; IQR: interquartile range. Significance (P < 0.05) is identified with ^∗. High statistical significance (P < 0.001) is identified with ^∗∗. Total events are 10,000 events. The percentages of positive cells were assessed from the lymphocyte gate. Kruskal-Wallis test was used, followed by Dunn’s test with Bonferroni correction.

In relapse, patients had a higher percentage of EMAP II+CD16+ cells compared to pretherapy patients [median: 8% (range 6.2–8) vs. 2.8% (range: 2.5–3.0); P = 0.003]. Also, there was an increase in EMAP II+CD22+% within relapse group III compared to newly diagnosed group I but without significance (P > 0.05). Furthermore, when compared to pretherapy NHL subjects, EMAP II+CD4+%, EMAP II+CD8+%, and EMAP II+CD20+% were lower in NHL patients with recurrence (P = 0.001) (Figure 1 and Table 2).

EMAP II expression was examined in blood cells obtained from patients with relapse and CR. NHL subjects with relapse had a lower EMAP II+CD4+% than patients with CR [median: 0.7% (range 0.6–1.0) vs. 2.3% (range 1.5–2.7); P = 0.004] as well as a lower percentage of EMAP II+CD8+ in patients with disease recurrence than in CR [median: 0.2% (range 0.1–0.3) vs. 0.6 (range 0.4–0.7); P = 0.005]. The median percentage of EMAP II+CD16+ cells in relapsed patients was 8% (range: 6.2-8.8) compared to 1.1% in complete remission patients (range: 1.0-1.4), P < 0.001. Furthermore, the proportion of EMAP II+CD22+ was higher in patients with disease relapse than in patients with CR [median: 6.8% (range 6-7.3%) vs. 2.4% (range 2.0-3.5%); P < 0.001]. No differences were identified between NHL subjects with recurrence and patients with CR with regard to EMAP II+CD20+% (P > 0.05) (Table 2 and Figure 1).

EMAP II expression on CD3, CD5+, CD7+, and HLA-DR+ cells in 5 T-NHL patients was investigated. EMAP II was dimly positive in T-NHL, with a percentage of EMAP II+CD3+ positive cells above 20%. A high increase in EMAP+CD3+% was observed in newly diagnosed NHL patients compared to healthy volunteers [median: 24.3% (range: 24-26) and 1.3% (range: 1.3-1.4); P < 0.001, respectively]. The percentages of EMAP+CD5+ and EMAP II+CD7+ cells were higher in new T-NHL patients than in healthy controls (median = 2.9% vs. 0.2%; 3.5% vs. 0.3%; P < 0.001). However, no statistical significance was observed regarding EMAP II+HLADR+ percentages in this small group when compared to normal controls [median = 0.3% (range: 0.3-0.4) vs. 0.2% (range: 0.2-0.3); P > 0.05] (Figure 2, Supplementary Table 3).

3.3. EMAP II– and CD36–Coexpressing Cells in NHL

The coexpression of EMAP II+ and CD36+ on peripheral lymphocytes was analyzed in patients with NHL and peripheral lymphocytes from healthy controls. In newly diagnosed patients, nearly all peripheral EMAP II+ lymphocytes coexpressed CD36, whereas in healthy controls, EMAP II+CD36+ expression was minimal [median 28.4% (range: 26.7-29.3) vs. 0.5% (range: 0.4-0.6); P < 0.001]. In complete remission, the median EMAP II+CD36+% was 2.2% (range: 2-2.47). Coexpression of CD36 and EMAP II was also higher in NHL subjects with relapse compared with patients with CR and healthy controls [median: 28.5% (range: 21.5-30.25); P < 0.001] (Figure 3).

3.4. EMAP II Expression Status (%) and LDH

All patients had their serum LDH levels checked, which is an important traditional prognostic sign for NHL. Regarding LDH levels, there was a high increase in LDH levels in NHL patients compared to healthy controls (P < 0.001). Contrary, there was a significant decrease in LDH among patients with CR compared to newly diagnosed NHL patients (P = 0.03). However, there were nonsignificant differences between NHL patients with relapse compared to newly diagnosed patients and patients with CR. The comparison of LDH levels between NHL subgroups is shown in Supplementary Table 4.

Table 3 shows that the percentage of EMAP II+CD16+, EMAP II+CD20+, and EMAP II+CD22+ cells was associated with LDH levels (P = 0.007, P = 0.025, and P = 0.042, respectively).

3. Correlation of EMAP II expression in different blood cells and LDH levels in NHL patients.

	Rho	P
	LDH (U/L)
EMAP II+CD4+%	-0.03	0.793
EMAP II+CD8+%	-0.026	0.818
EMAP II+CD16+%	0.299	0.007 ^∗
EMAP II+CD20+%	0.250	0.025 ^∗
EMAP II+CD22+%	0.227	0.042 ^∗

NHL: non-Hodgkin’s lymphoma; LDH: lactate dehydrogenase. Statistically, significance (P < 0.05) is identified with ^∗.

3.5. EMAP II Expression Status (%) and Clinical Criteria

Hepatomegaly and splenomegaly were associated with an increase in EMAP II+CD16+% (P = 0.002 and P = 0.003, respectively). Subjects with advanced high-risk disease (stages III and IV) had a higher EMAP II+CD16+% of cells than subjects with intermediate-risk disease (stage I-II) [median: 3.4% (range: 2-8) vs. 1.6% (range: 1.1-3.2); P = 0.004] Table 4. The results revealed that EMAP II+CD22+% cells in NHL subjects with advanced stage (stages III and IV) were higher compared with patients with intermediate-risk disease but with no significance [median: 6.3% (range: 3.6-7) % vs. 5.5% (range: 2.2-7) %; P = 0.218] (Table 4).

4. Correlation between percentages of EMAP II+CD4+, EMAP II+CD8+, EMAP II+CD16+, EMAP II+CD20+, and EMAP II+CD22+ and clinical characteristics of NHL patients.

	N	Median (IQR)	Median (IQR)	Median (IQR)	Median (IQR)	Median (IQR)
	N	EMAP II+CD4+%	EMAP II+CD8+%	EMAP II+CD16+%	EMAP II+CD20+%	EMAP II+CD22+%
Hepatomegaly
Positive	39	1.6 (0.7-7.3)	0.5 (0.1-4)	3.4 (2.4-8)	1.3 (1-5)	6.3 (4.5-7)
Negative	41	2.4 (1.1-3.9)	0.6 (0.4-1)	1.5 (1.1-3.2)	1.1 (0.9-1.3)	3.7 (2.2-7)
P value		0.689	0.615	0.002 ^∗	0.062	0.067
Splenomegaly
Positive	49	2 (0.8-6.4)	0.5 (0.2-3)	3.1 (2-8)	1.2 (1-1.5)	6.1 (3.5-7)
Negative	31	2.5 (1.4-6.1)	0.6 (0.4-3)	1.6 (1.1-3.2)	1.2 (0.9-5)	5 (2.4-6.7)
P value		0.335	0.264	0.003 ^∗	0.662	0.201
Stage
Stage I/II	35	2.5 (1.4-6.1)	0.7 (0.4-3)	1.6 (1.1-3.2)	1.2 (0.9-5)	5.5 (2.2-7)
Stage III/IV	45	1.8 (0.7-6.4)	0.4 (0.1-3)	3.4 (2-8)	1.2 (1-1.5)	6.3 (3.6-7)
P value		0.098	0.076	0.004 ^∗	0.438	0.218

NHL: non-Hodgkin’s lymphoma; IQR: interquartile range. Significant statistical differences (P < 0.05) are identified with asterisks ( ^∗).

The correlation between EMAP II+ cells in NHL patients (Figure 4) was further investigated. EMAP II+CD4+% was positively associated with EMAP II+CD8+% and EMAP II+CD20+% of cells (r = 0.659, P < 0.001; r = 0.510, P < 0.001) but negatively associated with EMAP II levels on CD16+ and CD22+ cells (r = 0.445, P < 0.001; r = 0.284, P = 0.011). EMAP II+CD8+ percentages also had a negative relationship with EMAP II+CD16+ (r = 0.026, P = 0.02) and a positive relationship with EMAP II+CD20 (r = 0.453, P < 0.001). EMAP II+CD16+% had a significant positive association with EMAP II+CD22+ cell percentages (P < 0.001) (Figure 4).

3.6. Diagnostic Efficacy of EMAP II for NHL

Receiver operating characteristic (ROC) curve analysis was performed for discriminating patients with recurrence, as shown in (Figure 5(a)). ROC curve analysis showed that the area under the ROC curve (AUC) of EMAP II+CD4+%, EMAP II+CD8+%, EMAP II+CD16+%, EMAP II+CD20+%, and EMAP II+CD22+% in peripheral blood was 0.980, 0.649, 0.964, 0.521, and 0.947 with cut-off value of ≤1.1, ≤0.3, >3.9, >1, and >4.8 being the most approximate index, respectively. In addition, based on the cut-off values, the specificity and sensitivity of EMAP II+CD4+% were 91.2% and 100%, respectively, while EMAP II+CD16+% were 100% and 96.2%, respectively. The specificity and sensitivity of EMAP II+CD22+% were 94.1% and 96.2%, respectively (Figure 5(b)).

Furthermore, ROC curves for differentiating patients with complete remission were determined. EMAP II+CD4+% AUC was 0.789 (P < 0.001). In addition, EMAP II+CD8+% showed an AUC of 0.855 (P < 0.001). EMAP II+CD16+% AUC was 0.921, while EMAP+CD22+% AUC was 0.854 (P < 0.001) (Figure 6(a)). These ROC curves indicated that EMAP II+CD16+% value of ≤1.3 and EMAP II+CD22+% value of ≤2.5 yielded a specificity and sensitivity of 100% and 73%, respectively, for discriminating patients with CR. For EMAP II+CD4+%, the cut-off with the maximum specificity and sensitivity for identifying CR was >1.1. Additionally, the specificity and sensitivity of EMAP II+CD8+% were 80% and 90%, respectively, while applying a cut-off level of >0.3 (Figure 6(b)).

4. Discussion

EMAP II expression has been demonstrated to affect tumor immune suppression and regulation [33, 46–48]. Serum EMAP II levels were elevated in NHL, suggesting EMAP II’s role in NHL [49]. However, EMAP II expression on peripheral lymphocytes in tumors has not been evaluated, and its predictive and prognostic values are still not thoroughly investigated. The study assessed EMAP II expression on peripheral blood cells in NHL and further explored its association with disease outcomes and clinical data. The data revealed direct evidence that EMAP II was involved in the progression and development of NHL.

The results concur that newly diagnosed NHL patients had dim EMAP II expression in peripheral blood cells in NHL patients using flow cytometry. Flow cytometry analysis, especially when utilizing a strong fluorochrome like phycoerythrin, is a very sensitive approach for detecting dim antigen expression than immunohistochemistry. Using unstained cells and isotype controls clarified that the dim expression and low frequency of EMAP II might not be an artifact. Negligible EMAP II expression was detected in healthy controls, thus assuming a significant role for EMAP II in NHL pathogenesis. This study expanded the results of the previous study [49]. Overexpression of EMAP II/P43 was confirmed in patients with mantle cell lymphoma compared to normal cells [75]. Thus, EMAP II could potentially play a role in NHL pathogenesis.

EMAP II’s role in cancer is not known. Some reports have shown that EMAP II is a tumor suppressor [27, 30, 76–78]. On the other hand, previous studies have indicated that EMAP II protein expression was identified in tumor cells [32, 33, 45, 47]. EMAP II transcripts have been found in a variety of human tissues as well as normal and malignant cell lines [11, 25]. However, there was no information regarding EMAP II expression in peripheral blood cells in tumors.

Subsequently, the results demonstrated EMAP II expression in peripheral blood cells in NHL subjects and normal volunteers. This is in line with the theory that all human normal and malignant cells express the intracellular 34 kDa form of EMAP II as a multisynthetase complex part in p43 form [12, 15]. EMAP II is released and processed under different circumstances, one of which is malignant transformation [11, 32, 33].

The mechanism by which EMAP II is subsequently present in peripheral blood cells is poorly understood. A previous report implied high serum EMAP II levels in subjects with NHL [49]. It is, therefore, possible that lymphoma cells express and release EMAP II and are subsequently found in the blood of NHL patients. EMAP II might act against normal lymphocytes. In Jurkat cells and peripheral blood mononuclear cells (PBMCs), EMAP II inhibited cell proliferation and DNA synthesis, inducing cell death. Native EMAP II expressed activated caspase 8 in Jurkats, causing cell apoptosis [45, 46]. It is presumed that lymphoma cells released EMAP II, facilitating EMAP II-induced apoptosis of lymphocytes. Future experiments are needed to confirm this theory.

Another scenario of increased EMAP II expression in blood cells is due to membrane translocation rather than increased EMAP II synthesis. EMAP II is translocated from inside the cell to the cell membrane through an unknown mechanism. The EMAP II 34 kDa form lacks a signal peptide required for translocation nor is it subjected to being glycosyl phosphatidyl inositol-anchored. Hypoxia increased EMAP II expression on the cell surface. The expression and release of plasminogen activator-1 and matrix metalloproteinases from tumor cells were upregulated by hypoxia [79, 80]. These enzymes might be engaged in EMAP II processing at the cell surface. Future experiments are needed to detect EMAP II expression in lymphoma cells and to explain these theories.

The previous study had shown that serum EMAP II could be positively associated with NHL progression [49]. This study demonstrated high EMAP II expression was observed in peripheral cells before treatment and decreased significantly after therapy. EMAP II may suppress antitumor immunity in newly diagnosed NHL, while treatment could induce a disruption in EMAP II signaling and expression. Another possibility is that the therapy induced the recruitment of EMAP II+ lymphocytes into the tumor area, leading to a decrease in the percentage of peripheral EMAP II+ cells. These results could be explained by the fact that EMAP II might have a part in the pathogenesis and progression of NHL. Future studies are required to describe the dysfunction of these cells.

EMAP II expression on CD16 and CD22 cells was significantly higher in a relapse in the current subject. NHL patients with relapse had lower EMAP II expression on CD4, CD8, and CD20 cells. Previous reports have demonstrated the correlation between high EMAP II expression and poor clinical outcomes or tumor metastasis [50]. This is concluded by using EMAP II to detect relapse, assuming longer endurance and earlier therapy.

This study analyzed EMAP II expression on peripheral CD3+, CD5+, CD7+, and HLA-DR+ in 5 T-NHL patients. EMAP II was identified on CD3+ cells in NHL patients. The high EMAP II expression on CD3+ cells in newly diagnosed NHL patients has clinically significant implications as it might provide a potential biomarker for NHL patients. Moreover, EMAP II was also present on CD5+ and CD7+ cells. EMAP was frequently expressed on CD3+ cells but was weak on CD5+ and CD7+ cells. Aberrant lack or dim expression of one or more pan-T antigens is required for T cell tumor diagnosis [81–86]. Previous studies reported the lack of CD5 and CD7 expression in T-NHL [85, 87]. In addition, the patients had decreased expression of HLA-DR on EMAP II+ cells compared to results in normal controls. Previously, it was shown that reduced HLA-DR expression is a powerful tool for tumor immune evasion [88]. It is possible that EMAP II could participate in suppressing host immunity in cancer. However, the group is too small to represent valuable statistical data.

CD36 is upregulated in patients with NHL [59, 60]. Studies of the EMAP II gene illustrated that EMAP II was associated with immune suppression in tumors [45, 47, 48]. However, no direct results were found to show whether EMAP II was upregulated on immune cells in NHL or whether EMAP II expression was related to CD36 expression. The results suggested that both CD36 and EMAP II were upregulated on peripheral blood cells in NHL patients and that more than 90% of EMAP II+ peripheral lymphocytes were CD36+, while there was no expression compared to peripheral lymphocytes from healthy controls. CD36 was found on less than 2% of normal CD8+ and CD4+ cells, 3% of normal CD19+ cells, and 4% of normal NK cells [61]. Circulating lymphocytes might express low levels of CD36 mRNA [89].

CD36 has a crucial role in immune suppression in cancer by enhancing T cell dysfunction and cancer progression [90, 91]. CD36 is found in various cell types and is thought to play a role in lipid transport in malignancies [92]. The differentiation and functioning of different types of T cells and the maintenance of immunological tolerance are all influenced by lipid metabolism [93]. Interestingly, a preceding study revealed that CD36-mediated cell death impairs CD8+ T antitumor activity and inhibits its functions [94]. Moreover, cell apoptosis was observed in CD8+ T cells with high CD36 expression. High CD36 expression in Treg cells initiates their survival and disables CD8+ T cell antitumor response [95]. EMAP II and CD36, which function as inhibitory molecules in T cell proliferation, could be linked to NHL pathogenesis. The roles of EMAP II and CD36 in the pathogenesis of NHL need further evaluation.

The study investigated an association between the percentages of EMAP II+ cells in NHL patients. Data revealed a significantly positive association of EMAP II expression on different cells, suggesting that EMAP II regulation was not cell-specific in NHL. As EMAP II is expressed on other cells like macrophages, monocytes, and dendritic cells, the level of EMAP II on these cells will be evaluated in future studies.

Further, the study revealed significant differences between LDH levels when NHL patients were compared to normal controls. The study demonstrated that percentages of EMAP II+CD16+, EMAPII+CD20+, and EMAP II+CD22+ cells had a significant positive association with elevated LDH levels, which implies the value of EMAP II expression on peripheral blood cells in NHL as a potential biomarker. The reported associations in these data support the correlation between higher levels of EMAP II expression and bad prognosis as elevated LDH levels, which are considered risk factors for poor performance and inferior overall survival [96].

The study also examined EMAP II expression on peripheral blood cells and the prognosis of NHL by evaluating EMAP II expression clinical data and identified that percentages of EMAP II+CD16+ were elevated in NHL patients with hepatomegaly or splenomegaly. Increased percentages of EMAP+CD16+ cells are linked to NHL stages 3 and 4, implying that EMAP II may play an important role in advanced tumor stages. High EMAP II levels were correlated with a worse prognosis in tumors [33, 49–51]. These findings suggest a potential poor prognostic influence of EMAP II in NHL and that high EMAP II expression might be associated with more aggressive or advanced disease. However, it is unknown how EMAP II might influence NHL progression and development. EMAP II might inhibit the activation and proliferation of lymphocytes. Future studies are required.

To the best of our knowledge, no previous reports analyzed ROC curves to assess EMAP II diagnostic performance in different peripheral blood cells in NHL. Previous reports investigated the diagnostic performance of different markers other than EMAP II in NHL [97]. According to the data, EMAP II+ cell percentages could be a valuable diagnostic for diagnosing NHL-related relapse and identifying individuals in complete remission. Hence, future studies with many patients might be helpful for the investigation of EMAP II expression.

The data revealed that the AUC of percentages of EMAP II+CD4+ cells for distinguishing NHL patients with recurrence was 0.98, and a cut-off for EMAP II + CD4 + % ≤ 1.1. The specificity and sensitivity of EMAP II+CD4+% for differentiating relapse in NHL were 91.2% and 100%, respectively. The AUC value of EMAP II+CD16+% for detecting patients with relapse was 0.964, which was higher than EMAP II+CD22+% (AUC = 0.947) and with a cut-off for EMAP II + CD16 + % > 3.9 and for EMAP II + CD122 + % > 4.8. The specificity and sensitivity of EMAP II + CD16 + % for differentiating relapse were 100% and 96.2%, respectively, while 94.1% and 96.2%, respectively, for EMAP II+CD22+%. These findings assume that EMAP II+CD16+% diagnostic performance might be superior to EMAP II+CD22+% in identifying NHL patients with recurrence.

In this study, the AUC of EMAP II+CD16+% for distinguishing NHL patients with complete remission from normal individuals was 0.921. It was higher than the EMAP II+CD22+% (AUC = 0.854) percentage, with a cut-off for EMAP II+CD16+% = 1.3%. The specificity and sensitivity of EMAP II+CD16+% and EMAP II+CD22+% for differentiating this subgroup were 100% and 73%, respectively. The AUC of EMAP II+CD4+% for identifying NHL with complete remission was higher than EMAP II+CD8+ (AUC = 0.855 and 0.789, respectively). Percentages of EMAP II+CD16+ had the best diagnostic performance for diagnosing complete remission in NHL.

Several limitations should be noted. The overall sample size of NHL cases, especially T-NHL cases, is relatively small; thus, further larger prospective longitudinal studies are required. Another limitation is the lack of EMAP II assessment on lymphoma cells. Future experiments are required to assess tumoral EMAP II expression in patients with lymphoma. Further studies are required to investigate the mechanistic insights of EMAP II expression in peripheral blood cells. Two-color staining might be considered a limitation of the study. Multicolor protocols will be followed in future experiments.

5. Conclusion

In conclusion, this study provides the first evidence of EMAP II expression on peripheral blood cells and highlights its prognostic value in NHL. Peripheral CD36 and EMAP II coexpression in NHL patients suggests that EMAP II expression might regulate tumor dissemination and identify NHL patients with more aggressive diseases. The data highlight and inform about the pathogenesis of NHL.

Abbreviations

AIMP1:: Aminoacyl-tRNA synthetase-interacting multifunctional protein 1
ARS:: Aminoacyl-tRNA synthetase
AUC:: Area under the ROC curve
CD36:: Cluster of differentiation 36
CHOP:: Cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone
CR:: Complete remission
EMAP II:: Endothelial monocyte activating polypeptide-II
LDH:: Lactate dehydrogenase
NHL:: Non-Hodgkin lymphomas
PBMCs:: Peripheral blood mononuclear cells
PBS:: Phosphate-buffered solution
ROC curve:: Receiver operating characteristic curve
TNF-alpha:: TNF-alpha.

Ethical Approval

The research was carried out in accordance with the Declaration of Helsinki’s principles. Minia University, Faculty of Medicine Ethics Committee approved the study and gave informed consent to the study protocol, which was authorized by the faculty (Ref No.: 252).

Consent

All subjects who took part in this study gave their informed written consent.

Conflicts of Interest

The author declares no financial or commercial conflicts of interest.

Acknowledgments

The author expresses gratitude to all the study’s participants and technicians.

Open Research

Data Availability

The datasets for this study are available from the corresponding authors upon reasonable request.

Supporting Information

References

1 Singh R., Shaik S., Negi B. S., Rajguru J. P., Patil P. B., Parihar A. S., and Sharma U., Non-Hodgkin's lymphoma: a review, Journal of Family Medicine and Primary Care. (2020) 9, no. 4, 1834–1840.
10.4103/jfmpc.jfmpc_1037_19
CAS PubMed Google Scholar
2 Swerdlow S. H., Campo E., Harris N. L., Jaffe E. S., Pileri S. A., Stein H., Thiele J., and Vardiman J. W., Tumors of Hematopoietic and Lymphoid Tissues, 2008, WHO Press, Geneva, Switzerland.
Google Scholar
3 Al-Naeeb A. B., Ajithkumar T., Behan S., and Hodson D. J., Non-Hodgkin lymphoma, British Medical Journal. (2018) 362, article k3204, https://doi.org/10.1136/bmj.k3204, 2-s2.0-85052395100.
10.1136/bmj.k3204
Google Scholar
4 Siegel R. L., Miller K. D., and Jemal A., Cancer statistics, 2012, CA: A Cancer Journal for Clinicians. (2015) 65, no. 1, 5–29, https://doi.org/10.3322/caac.21254, 2-s2.0-84920837701.
10.3322/caac.21254
PubMed Web of Science® Google Scholar
5 Ekstrom-Smedby K., Epidemiology and etiology of non-Hodgkin lymphoma-a review, Acta Oncologica. (2006) 45, no. 3, 258–271, https://doi.org/10.1080/02841860500531682, 2-s2.0-33646434804.
10.1080/02841860500531682
PubMed Web of Science® Google Scholar
6 Witzig T. E., Nowakowski G. S., Habermann T. M., Goy A., Hernandez-Ilizaliturri F. J., Chiappella A., Vitolo U., Fowler N., and Czuczman M. S., A comprehensive review of lenalidomide therapy for B-cell non-Hodgkin lymphoma, Annals of Oncology. (2015) 26, no. 8, 1667–1677, https://doi.org/10.1093/annonc/mdv102, 2-s2.0-84937708862, 25712458.
10.1093/annonc/mdv102
CAS PubMed Web of Science® Google Scholar
7 Seshadri T., Kuruvilla J., Crump M., and Keating A., Salvage therapy for relapsed/refractory diffuse large B cell lymphoma, Biology of Blood and Marrow Transplantation. (2008) 14, no. 3, 259–267, https://doi.org/10.1016/j.bbmt.2007.11.013, 2-s2.0-38949115531.
10.1016/j.bbmt.2007.11.013
CAS PubMed Web of Science® Google Scholar
8 Moccia A. A., Hitz F., Hoskins P., Klasa R., Power M. M., Savage K. J., Shenkier T., Shepherd J. D., Slack G. W., Song K. W., Gascoyne R. D., Connors J. M., and Sehn L. H., Gemcitabine, dexamethasone, and cisplatin (GDP) is an effective and well-tolerated salvage therapy for relapsed/refractory diffuse large B-cell lymphoma and Hodgkin lymphoma, Leukemia & Lymphoma. (2017) 58, no. 2, 324–332, https://doi.org/10.1080/10428194.2016.1193852, 2-s2.0-84976293827, 27347845.
10.1080/10428194.2016.1193852
CAS PubMed Web of Science® Google Scholar
9 Schwarz M. A., Kandel J., Brett J., Li J., Hayward J., Schwarz R. E., Chappey O., Wautier J. L., Chabot J., Gerfo P. L., and Stern D., Endothelial-monocyte activating polypeptide II, a novel antitumor cytokine that suppresses primary and metastatic tumor growth, and induces apoptosis in growing endothelial cells, Journal of Experimental Medicine. (1999) 190, no. 3, 341–354, https://doi.org/10.1084/jem.190.3.341, 2-s2.0-0033517112, 10430623.
10.1084/jem.190.3.341
CAS PubMed Web of Science® Google Scholar
10 Schwarz M., Lee M., Zhang F., Zhao J., Jin Y., Smith S., Bhuva J., Stern D., Warburton D., and Starnes V., EMAP II: a modulator of neovascularization in the developing lung, American Journal of Physiology. (1999) 276, no. 2, L365–L375, https://doi.org/10.1152/ajplung.1999.276.2.L365, 9950900.
10.1152/ajplung.1999.276.2.L365
CAS PubMed Web of Science® Google Scholar
11 Knies U. E., Behrensdorf H. A., Mitchell C. A., Deutsch U., Risau W., Drexler H. C. A., and Clauss M., Regulation of endothelial monocyte-activating polypeptide II release by apoptosis, Proceedings of the National Academy of Sciences of United States of America. (1998) 95, no. 21, 12322–12327, https://doi.org/10.1073/pnas.95.21.12322, 9770485.
10.1073/pnas.95.21.12322
CAS PubMed Web of Science® Google Scholar
12 Tas M. P. R., Houghton J., Jakobsen A. M., Tolmachova T., Carmichael J., and Murray J. C., Cloning and expression of human endothelial-monocyte-activating polypeptide 2 (emap-2) and identification of its putative precursor, Cytokine. (1997) 9, no. 8, 535–539, https://doi.org/10.1006/cyto.1997.0198, 2-s2.0-0031214350, 9245479.
10.1006/cyto.1997.0198
CAS PubMed Web of Science® Google Scholar
13 Marvin M. R., Libutti S. K., Kayton M., Kao J., Hayward J., Grikscheit T., Fan Y., Brett J., Weinberg A., Nowygrod R., LoGerfo P., Feind C., Hansen K. S., Schwarz M., Stern D., and Chabot J., A novel tumor-derived mediator that sensitizes cytokine-resistant tumors to tumor necrosis factor, Journal of Surgical Research. (1996) 63, no. 1, 248–255, https://doi.org/10.1006/jsre.1996.0256, 2-s2.0-0029948526, 8661206.
10.1006/jsre.1996.0256
CAS PubMed Web of Science® Google Scholar
14 Gao W., An C., Xue X., Zheng X., Niu M., Zhang Y., Liu H., Zhang C., Lu Y., Cui J., and Zhao Q., Mass spectrometric analysis identifies AIMP1 and LTA4H as FSCN1-binding proteins in laryngeal squamous cell carcinoma, Proteomics. (2019) 19, article e1900059, 21–22.
Web of Science® Google Scholar
15 Murray J. C., Barnett G., Tas M. P. R., Jakobsen A., Brown J., Powe D., and Clelland C., Immunohistochemical analysis of endothelial-monocyte-activating polypeptide-II expression in vivo, American Journal of Pathology. (2000) 157, no. 6, 2045–2053, https://doi.org/10.1016/S0002-9440(10)64843-2, 2-s2.0-0033636256, 11106577.
10.1016/S0002-9440(10)64843-2
CAS PubMed Web of Science® Google Scholar
16 Kim E., Kim S. H., Kim S., and Kim T. S., The novel cytokine p43 induces IL-12 production in macrophages via NF-κB activation, leading to enhanced IFN-γ production in CD4+T cells, Journal of Immunology. (2006) 176, no. 1, 256–264, https://doi.org/10.4049/jimmunol.176.1.256, 16365417.
10.4049/jimmunol.176.1.256
CAS PubMed Web of Science® Google Scholar
17 Kim E., Kim S. H., Kim S., Cho D., and Kim T. S., AIMP1/p 43 protein induces the maturation of bone marrow-derived dendritic cells with T helper type 1-polarizing ability, Journal of Immunology. (2008) 180, no. 5, 2894–2902, https://doi.org/10.4049/jimmunol.180.5.2894, 2-s2.0-48749115388, 18292511.
10.4049/jimmunol.180.5.2894
CAS PubMed Web of Science® Google Scholar
18 Liu J. and Schwarz M. A., Identification of protease-sensitive sites in human endothelial-monocyte activating polypeptide II protein, Experimental Cell Research. (2006) 312, no. 12, 2231–2237, https://doi.org/10.1016/j.yexcr.2006.03.024, 2-s2.0-33745262526, 16674941.
10.1016/j.yexcr.2006.03.024
CAS PubMed Web of Science® Google Scholar
19 Zhang F. R. and Schwarz M. A., Pro-EMAP II is not primarily cleaved by caspase-3 and -7, American Journal of Physiology Lung Cellular and Molecular Physiology. (2002) 282, L1239–L1244.
10.1152/ajplung.00141.2001
CAS PubMed Web of Science® Google Scholar
20 Quevillon S., Agou F., Robinson J. C., and Mirande M., The p43 component of the mammalian multi-synthetase complex is likely to be the precursor of the endothelial monocyte-activating polypeptide II cytokine, Journal of Biological Chemistry. (1997) 272, no. 51, 32573–32579, https://doi.org/10.1074/jbc.272.51.32573, 2-s2.0-0031464187, 9405472.
10.1074/jbc.272.51.32573
CAS PubMed Web of Science® Google Scholar
21 Kao J., Ryan J., Brett G., Chen J., Shen H., Fan Y. G., Godman G., Familletti P. C., Wang F., and Pan Y. C., Endothelial monocyte-activating polypeptide II. A novel tumor-derived polypeptide that activates host-response mechanisms, Journal of Biological Chemistry. (1992) 267, no. 28, 20239–20247, https://doi.org/10.1016/S0021-9258(19)88692-1.
10.1016/S0021-9258(19)88692-1
CAS PubMed Web of Science® Google Scholar
22 Kao J., Fan Y. G., Haehnel I., Clauss M., and Stern D., Endothelial-monocyte activating polypeptides (EMAPs): tumor derived mediators which activate the host inflammatory response, Behring Institute Mitteilungen. (1993) 92, 92–106.
CAS PubMed Web of Science® Google Scholar
23 Kao J., Houck K., Fan Y., Haehnel I., Libutti S. K., Kayton M. L., Grikscheit T., Chabot J., Nowygrod R., and Greenberg S., Characterization of a novel tumor-derived cytokine. Endothelial-monocyte activating polypeptide II, Journal of Biological Chemistry. (1994) 269, no. 40, 25106–25119, https://doi.org/10.1016/S0021-9258(17)31505-3, 7929199.
10.1016/S0021-9258(17)31505-3
CAS PubMed Web of Science® Google Scholar
24 Schwarz R. E. and Schwarz M. A., In vivo therapy of local tumor progression by targeting vascular endothelium with EMAP-II, Journal of Surgical Research. (2004) 120, no. 1, 64–72, https://doi.org/10.1016/j.jss.2003.10.005, 2-s2.0-2542467676, 15172191.
10.1016/j.jss.2003.10.005
CAS PubMed Web of Science® Google Scholar
25 Park S. G., Kang Y. S., Ahn Y. H., Lee S. H., Kim K. R., Kim K. W., Koh G. Y., Ko Y. G., and Kim S., Dose-dependent biphasic activity of tRNA synthetase-associating factor, p43, in angiogenesis, Journal of Biological Chemistry. (2002) 277, no. 47, 45243–45248, https://doi.org/10.1074/jbc.M207934200, 2-s2.0-0037160096, 12237313.
10.1074/jbc.M207934200
CAS PubMed Web of Science® Google Scholar
26 Tas M. P. and Murray J. C., Endothelial-monocyte-activating polypeptide II, International Journal of Biochemistry & Cell Biology. (1996) 28, no. 8, 837–841, https://doi.org/10.1016/1357-2725(96)00038-6, 2-s2.0-0030220829.
10.1016/1357-2725(96)00038-6
CAS PubMed Web of Science® Google Scholar
27 Murray J. C. and Tas M. P. R., Endothelial monocyte-activating polypeptide 2: a novel injury signal? The New Angiotherapy, 2001, The Humana Press, Clifton NJ, USA, 491–498.
10.1385/1-59259-126-4:491
Google Scholar
28 Awasthi N., Zhang C., Hinz S., Schwarz M. A., and Schwarz R. E., Enhancing sorafenib-mediated sensitization to gemcitabine in experimental pancreatic cancer through EMAP II, Journal of Experimental & Clinical Cancer Research. (2013) 32, no. 1, https://doi.org/10.1186/1756-9966-32-12, 2-s2.0-84874545727.
10.1186/1756-9966-32-12
PubMed Web of Science® Google Scholar
29 Mogylnytska L. A., Endothelial monocyte-activating polypeptide-II: properties, functions, and pathogenetic significance, Fiziolohichnyĭ Zhurnal. (2015) 61, no. 1, 102–111, https://doi.org/10.15407/fz61.01.102, 2-s2.0-84930805355, 26040042.
10.15407/fz61.01.102
CAS PubMed Google Scholar
30 Lozhko D., Stanek J., Kazimierczuk K., Zawadzka-Kazimierczuk A., Kozminski W., Zhukov I., and Kornelyuk A., 1H, 13C, and 15N chemical shifts assignments for human endothelial monocyte-activating polypeptide EMAP II, Biomolecular NMR Assignments. (2013) 7, no. 1, 25–29, https://doi.org/10.1007/s12104-012-9369-y, 2-s2.0-84874992763.
10.1007/s12104-012-9369-y
CAS PubMed Web of Science® Google Scholar
31 Liu L., Xie H., Xue Y., Liu Y., Li Z., and Wang P., Endothelial-monocyte-activating polypeptide II induces rat C6 glioma cell apoptosis via the mitochondrial pathway, Biochemical and Biophysical Research Communications. (2015) 457, no. 4, 595–601.
10.1016/j.bbrc.2015.01.030
CAS PubMed Web of Science® Google Scholar
32 Berger A. C., Alexander H. R., Tang G., Wu P. S., Hewitt S. M., Turner E., Kruger E., Figg W. D., Grove A., Kohn E., Stern D., and Libutti S. K., Endothelial monocyte activating polypeptide II induces endothelial cell apoptosis and may inhibit tumor angiogenesis, Microvascular Research. (2000) 60, no. 1, 70–80, https://doi.org/10.1006/mvre.2000.2249, 2-s2.0-0033947124, 10873516.
10.1006/mvre.2000.2249
CAS PubMed Web of Science® Google Scholar
33 Barnett G., Jakobsen A. M., Tas M., Rice K., Carmichael J., and Murray J. C., Prostate adenocarcinoma cells release the novel proinflammatory polypeptide EMAP-II in response to stress, Cancer Research. (2000) 60, no. 11, 2850–2857, 10850427.
CAS PubMed Web of Science® Google Scholar
34 Youssef M. M. S., Symonds P., Ellis I. O., and Murray J. C., EMAP-II-dependent lymphocyte killing is associated with hypoxia in colorectal cancer, British Journal of Cancer. (2006) 95, no. 6, 735–743, https://doi.org/10.1038/sj.bjc.6603299, 2-s2.0-33748572590, 16929248.
10.1038/sj.bjc.6603299
CAS PubMed Web of Science® Google Scholar
35 Liu J., Liu L., Xue Y., Meng F., Li S., Wang P., and Liu Y., Anti-neoplastic activity of low-dose endothelial-monocyte activating polypeptide-II results from defective autophagy and G2/M arrest mediated by PI3K/Akt/FoxO1 axis in human glioblastoma stem cells, Biochemical Pharmacology. (2014) 89, no. 4, 477–489, https://doi.org/10.1016/j.bcp.2014.04.014, 2-s2.0-84901592475, 24792437.
10.1016/j.bcp.2014.04.014
CAS PubMed Web of Science® Google Scholar
36 Li Z., Ma J., Liu L., Liu X., Wang P., Liu Y., and Li Z., Endothelial-monocyte activating polypeptide II suppresses the in vitro glioblastoma-induced angiogenesis by inducing autophagy, Frontiers in Cellular Neuroscience. (2017) 10.
Google Scholar
37 Chen J., Liu L., Liu Y., Liu X., Qu C., and Meng F., Low-dose endothelial-monocyte-activating polypeptide-II induced autophagy by down-regulating mi R-20a in U-87 and U-251 glioma cells, Frontiers in Cellular Neuroscience. (2016) 10.
10.3389/fncel.2016.00128
Web of Science® Google Scholar
38 Wu P. C., Alexander H. R., Huang J., Hwu P., Gnant M., Berger A. C., Turner E., Wilson O., and Libutti S. K., In vivo sensitivity of human melanoma to tumor necrosis factor (TNF)-alpha is determined by tumor production of the novel cytokine endothelial-monocyte activating polypeptide II (EMAPII), Cancer Research. (1999) 59, no. 1, 205–212, 9892208.
CAS PubMed Web of Science® Google Scholar
39 van Horssen R., Rens J. A., Schipper D., Eggermont A. M., and ten Hagen T. L., EMAP-II facilitates TNF-R1 apoptotic signalling in endothelial cells and induces TRADD mobilization, Apoptosis. (2006) 11, no. 12, 2137–2145, https://doi.org/10.1007/s10495-006-0284-5, 2-s2.0-33845371903, 17051333.
10.1007/s10495-006-0284-5
CAS PubMed Web of Science® Google Scholar
40 Li Z., Liu X.-B., Liu Y.-H., Xue Y. X., Wang P., Liu L. B., Liu J., Yao Y. L., and Ma J., Roles of serine/threonine phosphatases in low-dose endothelial monocyte-activating polypeptide-II-induced opening of blood-tumor barrier, Journal of Molecular Neuroscience. (2015) 57, no. 1, 11–20, https://doi.org/10.1007/s12031-015-0604-8, 2-s2.0-84939573935, 26087743.
10.1007/s12031-015-0604-8
PubMed Web of Science® Google Scholar
41 Li Z., Liu Y. H., Liu X. B., Xue Y. X., Wang P., and Liu L. B., Low-dose endothelial monocyte-activating polypeptide-II increases permeability of blood-tumor barrier via a PKC-ζ/PP2A-dependent signaling mechanism, Experimental Cell Research. (2015) 331, no. 2, 257–266, https://doi.org/10.1016/j.yexcr.2014.12.021, 2-s2.0-84964308941.
10.1016/j.yexcr.2014.12.021
CAS PubMed Web of Science® Google Scholar
42 Liu J., Liu L., Chao S., Liu Y., Liu X., Zheng J., Chen J., Gong W., Teng H., Li Z., Wang P., and Xue Y., The role of miR-330-3p/PKC-α signaling pathway in low-dose endothelial-monocyte activating polypeptide-II increasing the permeability of blood-tumor barrier, Frontiers in Cellular Neuroscience. (2017) 11, https://doi.org/10.3389/fncel.2017.00358, 2-s2.0-85040909364, 29311822.
10.3389/fncel.2017.00358
PubMed Web of Science® Google Scholar
43 Chen L., Xue Y., Zheng J., Liu X., Liu J., Chen J., Li Z., Xi Z., Teng H., Wang P., Liu L., and Liu Y., miR-429 regulated by endothelial monocyte activating polypeptide-II (EMAP-II) influences blood-tumor barrier permeability by inhibiting the expressions of ZO-1, occludin and claudin-5, Frontiers in Molecular Neuroscience. (2018) 11, https://doi.org/10.3389/fnmol.2018.00035, 2-s2.0-85043592709, 29467620.
10.3389/fnmol.2018.00035
PubMed Web of Science® Google Scholar
44 Li Z., Liu Y. H., Xue Y. X., Liu L. B., and Wang P., Low-dose endothelial monocyte-activating polypeptide-ii increases permeability of blood-tumor barrier by caveolae-mediated transcellular pathway, Journal of Molecular Neuroscience. (2014) 52, no. 3, 313–322, https://doi.org/10.1007/s12031-013-0148-8, 2-s2.0-84894345539, 24526454.
10.1007/s12031-013-0148-8
CAS PubMed Web of Science® Google Scholar
45 Murray J. C., Symonds P., Ward W., Huggins M., Tiga A., Rice K., Heng Y. M., Todd I., and Robins R. A., Colorectal cancer cells induce lymphocyte apoptosis by an endothelial monocyte-activating polypeptide-II-dependent mechanism, Journal of Immunology. (2004) 172, no. 1, 274–281, https://doi.org/10.4049/jimmunol.172.1.274, 2-s2.0-0346734185, 14688335.
10.4049/jimmunol.172.1.274
CAS PubMed Web of Science® Google Scholar
46 Murray J. C., Heng Y. M., Symonds P., Rice K., Ward W., Huggins M., Todd I., and Robins R. A., Endothelial monocyte-activating polypeptide-II (EMAP-II): a novel inducer of lymphocyte apoptosis, Journal of Leukocyte Biology. (2004) 75, no. 5, 772–776, https://doi.org/10.1189/jlb.1003487, 2-s2.0-2342559234, 14982944.
10.1189/jlb.1003487
CAS PubMed Web of Science® Google Scholar
47 Faisel W., Symonds P., Panjwani S., Heng Y., and Murray J. C., Cell-surface associated p43/endothelial-monocyte-activating-polypeptide-II in hepatocellular carcinoma cells induces apoptosis in T-lymphocytes, Asian Journal of Surgery. (2007) 30, no. 1, 13–22, https://doi.org/10.1016/S1015-9584(09)60122-6, 2-s2.0-33947413515, 17337366.
10.1016/S1015-9584(09)60122-6
PubMed Web of Science® Google Scholar
48 Saber M. M. and Clauss M., EMAP-II-induced immune suppression in colorectal cancer, Immunotherapy. (2017) 3, no. 2, https://doi.org/10.4172/2471-9552-C1-005.
10.4172/2471-9552-C1-005
Google Scholar
49 Saber M. M., The use of the cytokines EMAP-II, IL-1, 9, and IL-10 as biomarkers to determine prognosis of non–Hodgkin’s lymphoma, Journal of Clinical and Cellular Immunology. (2016) 7, no. 4.
10.4172/2155-9899.1000437
Google Scholar
50 Sen E., Ulger F., Kaya A., Akar N., and Gonullu U., Serum endothelial monocyte-activating polypeptide-II: a novel biomarker in patients with non-small-cell lung cancer, Clinical Lung Cancer. (2008) 9, no. 3, 166–170, https://doi.org/10.3816/CLC.2008.n.025, 2-s2.0-45849092273, 18621627.
10.3816/CLC.2008.n.025
CAS PubMed Web of Science® Google Scholar
51 Stathaki M., Armakolas A., Dimakakos A., Kaklamanis L., Vlachos I., Konstantoulakis M. M., Zografos G., and Koutsilieris M., Kisspeptin effect on endothelial monocyte activating polypeptide II (EMAP-II)-associated lymphocyte cell death and metastases in colorectal cancer patients, Molecular Medicine. (2014) 20, no. 1, 80–92, https://doi.org/10.2119/molmed.2013.00151, 2-s2.0-84897880906, 24395571.
10.2119/molmed.2013.00151
PubMed Web of Science® Google Scholar
52 Chen Y., Zhang J., Cui W., and Silverstein R. L., CD36, a signaling receptor and fatty acid transporter that regulates immune cell metabolism and fate, Journal of Experimental Medicine. (2022) 219, no. 6, 1–15.
10.1084/jem.20211314
Web of Science® Google Scholar
53 Febbraio M., Hajjar D. P., and Silverstein R. L., CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism, Journal of Clinical Investigation. (2001) 108, no. 6, 785–791, https://doi.org/10.1172/JCI14006, 2-s2.0-0034833822.
10.1172/JCI14006
CAS PubMed Web of Science® Google Scholar
54 Kuemmerle N. B., Rysman E., Lombardo P. S., Flanagan A. J., Lipe B. C., Wells W. A., Pettus J. R., Froehlich H. M., Memoli V. A., Morganelli P. M., and Swinnen J. V., Lipoprotein lipase links dietary fat to solid tumor cell proliferation, Molecular Cancer Therapeutics. (2011) 10, no. 3, 427–436, https://doi.org/10.1158/1535-7163.MCT-10-0802, 2-s2.0-79955761333, 21282354.
10.1158/1535-7163.MCT-10-0802
CAS PubMed Web of Science® Google Scholar
55 Kennedy D. J. and Kashyap S. R., Pathogenic role of scavenger receptor CD36 in the metabolic syndrome and diabetes, Metabolic Syndrome and Related Disorders. (2011) 9, no. 4, 239–245, https://doi.org/10.1089/met.2011.0003, 2-s2.0-79960825294, 21428745.
10.1089/met.2011.0003
CAS PubMed Web of Science® Google Scholar
56 Feng W. W., Wilkins O., Bang S., Ung M., Li J., An J., del Genio C., Canfield K., DiRenzo J., Wells W., Gaur A., Robey R. B., Guo J. Y., Powles R. L., Sotiriou C., Pusztai L., Febbraio M., Cheng C., Kinlaw W. B., and Kurokawa M., CD36-mediated metabolic rewiring of breast cancer cells promotes resistance to HER2-targeted therapies, Cell Reports. (2019) 29, no. 11, 3405–3420.e5, https://doi.org/10.1016/j.celrep.2019.11.008, 31825825.
10.1016/j.celrep.2019.11.008
CAS PubMed Web of Science® Google Scholar
57 Hale J. S., Otvos B., Sinyuk M., Alvarado A. G., Hitomi M., Stoltz K., Wu Q., Flavahan W., Levison B., Johansen M. L., Schmitt D., Neltner J. M., Huang P., Ren B., Sloan A. E., Silverstein R. L., Gladson C. L., DiDonato J. A., Brown J. M., McIntyre T., Hazen S. L., Horbinski C., Rich J. N., and Lathia J. D., Cancer stem cell-specific scavenger receptor CD36 drives glioblastoma progression, Stem Cells. (2014) 32, no. 7, 1746–1758, https://doi.org/10.1002/stem.1716, 2-s2.0-84902578963, 24737733.
10.1002/stem.1716
CAS PubMed Web of Science® Google Scholar
58 Martini C., De Nichilo M., King D. P., Cockshell M. P., Ebert B., Dale B., Ebert L. M., Woods A., and Bonder C. S., CD36 promotes vasculogenic mimicry in melanoma by mediating adhesion to the extracellular matrix, BMC Cancer. (2021) 21.
10.1186/s12885-021-08482-4
PubMed Web of Science® Google Scholar
59 Ueno S., Yamaguchi M., Kimura M., Odagiri H., Shiraki K., Uemoto S., Nakamura N., Zhang W., Shiku H., and Kobayashi T., Expression of CD29 on lymphoma cells and/or CD36 on microvascular endothels correlates with high serum LDH level in diffuse large B-cell lymphomas (DLBCLs) and is frequent in de novo CD5-positive DLBCLs, International Journal of Oncology. (2005) 27, no. 5, 1241–1246, 16211218.
CAS PubMed Web of Science® Google Scholar
60 Rutella S., Rumi C., Puggioni P., Barberi T., Di Mario A., Larocca L. M., and Leone G., Expression of thrombospondin receptor (CD36) in B-cell chronic lymphocytic leukemia as an indicator of tumor cell dissemination, Haematologica. (1999) 84, no. 5, 419–424.
CAS PubMed Web of Science® Google Scholar
61 Cheson B. D., Horning S. J., Coiffier B., Shipp M. A., Fisher R. I., Connors J. M., Lister T. A., Vose J., Grillo-López A., Hagenbeek A., Cabanillas F., Klippensten D., Hiddemann W., Castellino R., Harris N. L., Armitage J. O., Carter W., Hoppe R., and Canellos G. P., Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas, Journal of Clinical Oncology. (1999) 17, no. 4, https://doi.org/10.1200/JCO.1999.17.4.1244.
10.1200/JCO.1999.17.4.1244
Web of Science® Google Scholar
62 Swerdlow S. H., Campo E., Pileri S. A., Harris N. L., Stein H., Siebert R., Advani R., Ghielmini M., Salles G. A., Zelenetz A. D., and Jaffe E. S., The 2016 revision of the World Health Organization classification of lymphoid neoplasms, Blood. (2016) 127, no. 20, 2375–2390, https://doi.org/10.1182/blood-2016-01-643569, 2-s2.0-84971566127, 26980727.
10.1182/blood-2016-01-643569
CAS PubMed Web of Science® Google Scholar
63 Jang R. W., Caraiscos V. B., Swami N., Banerjee S., Mak E., Kaya E., Rodin G., Bryson J., Ridley J. Z., le L. W., and Zimmermann C., Simple prognostic model for patients with advanced cancer based on performance status, Journal of Oncology Practice. (2014) 10, no. 5, e335–e341, https://doi.org/10.1200/JOP.2014.001457, 2-s2.0-84911888352.
10.1200/JOP.2014.001457
PubMed Google Scholar
64 Johnson S. A., Kumar A., Matasar M. J., Schöder H., and Rademaker J., Imaging for staging and response assessment in lymphoma, Radiology. (2015) 276, no. 2, 323–338, https://doi.org/10.1148/radiol.2015142088, 2-s2.0-84938681343.
10.1148/radiol.2015142088
PubMed Web of Science® Google Scholar
65 Freedman A. S., Jacobson C. A., Mauch P., and Aster J. C., V. T. DeVita, T. S. Lawrence, and S. A. Rosenberg, Chapter 103: Non-Hodgkin’s lymphoma DeVita, Hellman, and Rosenberg’s Cancer: Principles and Practice of Oncology, 2015, 10th edition, Lippincott Williams & Wilkins, Philadelphia, PA,USA, 1552–1583.
Google Scholar
66 Zgodzinski W., Grywalska E., Zinkiewicz K., Surdacka A., Majewski M., Zakoscielny A., Bury P., Rolinski J., and Wallner G. T., Peripheral blood T lymphocytes are downregulated by the PD-1/PD-L1 axis in advanced gastric cancer, Archives in Medical Science. (2019) 15, no. 3, 774–783, https://doi.org/10.5114/aoms.2018.75092, 2-s2.0-85065256627, 31110545.
10.5114/aoms.2018.75092
CAS PubMed Web of Science® Google Scholar
67 Grywalska E., Smarz-Widelska I., Korona-Głowniak I., Mertowski S., Gosik K., Hymos A., Ludian J., Niedźwiedzka-Rystwej P., Roliński J., and Załuska W., PD-1 and PD-L1 expression on circulating lymphocytes as a marker of Epstein-Barr virus reactivation-associated proliferative glomerulonephritis, International Journal of Molecular Sciences. (2020) 21, no. 21, https://doi.org/10.3390/ijms21218001, 33121190.
10.3390/ijms21218001
PubMed Web of Science® Google Scholar
68 Sun P., Jin Q., Nie S., Jia S., Li Y., Li X., and Guo F., Unlike PD-L1, PD-1 is downregulated on partial immune cells in type 2 diabetes, Journal of Diabetes Research. (2019) 2019, 8, 5035261, https://doi.org/10.1155/2019/5035261, 2-s2.0-85065078469.
10.1155/2019/5035261
PubMed Web of Science® Google Scholar
69 Winkler S., Hoppe P., Haderlein M., Hecht M., Fietkau R., and Distel L. V., Ex vivo apoptosis in CD8+ lymphocytes predicts rectal cancer patient outcome, Gastroenterology Research and Practice. (2016) 2016, 7, 5076542, https://doi.org/10.1155/2016/5076542, 2-s2.0-84975223596.
10.1155/2016/5076542
PubMed Web of Science® Google Scholar
70 Walankiewicz M., Grywalska E., Polak G., Korona-Glowniak I., Witt E., Surdacka A., Kotarski J., and Rolinski J., The increase of circulating PD-1- and PD-L1-expressing lymphocytes in endometriosis: correlation with clinical and laboratory parameters, Mediators of Inflammation. (2018) 2018, 12, 7041342, https://doi.org/10.1155/2018/7041342, 2-s2.0-85059261684.
10.1155/2018/7041342
PubMed Web of Science® Google Scholar
71 Zhang W., Bai J.-F., Zuo M.-X., Cao X. X., Chen M., Zhang Y., Han X., Zhong D. R., and Zhou D. B., PD-1 expression on the surface of peripheral blood CD4+ T cell and its association with the prognosis of patients with diffuse large B-cell lymphoma, Cancer Medicine. (2016) 5, no. 11, 3077–3084, https://doi.org/10.1002/cam4.874, 2-s2.0-84990834316, 27709793.
10.1002/cam4.874
CAS PubMed Web of Science® Google Scholar
72 Zuo M., Shen H., Yin J., Wang W., Zhang Y., Zhou D. B., and Zhang W., Expression of PD-1 on peripheral blood Treg cells is related to the diagnosis, prognosis and treatment of T cell non-Hodgkin lymphoma, Leukemia Research. (2018) 70, 56–61, https://doi.org/10.1016/j.leukres.2018.05.008, 2-s2.0-85047648594.
10.1016/j.leukres.2018.05.008
CAS PubMed Web of Science® Google Scholar
73 Zhang Y., Zhu W., Zhang X., Qu Q., and Zhang L., Expression and clinical significance of programmed death-1 on lymphocytes and programmed death ligand-1 on monocytes in the peripheral blood of patients with cervical cancer, Oncology Letters. (2017) 14, no. 6, 7225–7231, https://doi.org/10.3892/ol.2017.7105, 2-s2.0-85032708076, 29344157.
10.3892/ol.2017.7105
PubMed Web of Science® Google Scholar
74 Chang K., Svabek C., Vazquez-Guillamet C., Sato B., Rasche D., Wilson S., Robbins P., Ulbrandt N., Suzich J. A., Green J., Patera A. C., Blair W., Krishnan S., and Hotchkiss R., Targeting the programmed cell death 1: programmed cell death ligand 1 pathway reverses T cell exhaustion in patients with sepsis, Critical Care. (2014) 18, no. 1, https://doi.org/10.1186/cc13176, 2-s2.0-84891510610, 24387680.
10.1186/cc13176
PubMed Web of Science® Google Scholar
75 Ghobrial I. M., McCormick D. J., Kaufmann S. H., Leontovich A. A., Loegering D. A., Dai N. T., Krajnik K. L., Stenson M. J., Melhem M. F., Novak A. J., Ansell S. M., and Witzig T. E., Proteomic analysis of mantle-cell lymphoma by protein microarray, Blood. (2005) 105, no. 9, 3722–3730, https://doi.org/10.1182/blood-2004-10-3999, 2-s2.0-20944433868, 15650054.
10.1182/blood-2004-10-3999
CAS PubMed Web of Science® Google Scholar
76 Haridas S., Bowers M., Tusano J., Mehojah J., Kirkpatrick M., and Burnham D. K., The impact of Meth A fibrosarcoma derived EMAP II on dendritic cell migration, Cytokine. (2008) 44, no. 2, 304–309, https://doi.org/10.1016/j.cyto.2008.09.002, 2-s2.0-55749083195, 18951814.
10.1016/j.cyto.2008.09.002
CAS PubMed Web of Science® Google Scholar
77 Awasthi N., Schwarz M. A., and Schwarz R. E., Combination effects of bortezomib with gemcitabine and EMAP II in experimental pancreatic cancer, Cancer Biology and Therapy. (2010) 10, no. 1, 99–107, https://doi.org/10.4161/cbt.10.1.12169, 2-s2.0-77954422169, 20495354.
10.4161/cbt.10.1.12169
CAS PubMed Web of Science® Google Scholar
78 Awasthi N., Schwarz M. A., and Schwarz R. E., Enhancing cytotoxic agent activity in experimental pancreatic cancer through EMAP II combination therapy, Cancer Chemotherapy and Pharmacology. (2011) 68, no. 3, 571–582, https://doi.org/10.1007/s00280-010-1514-7, 2-s2.0-80054697777, 21110024.
10.1007/s00280-010-1514-7
CAS PubMed Web of Science® Google Scholar
79 Koong A. C., Denko N. C., Hudson K. M., Schindler C., Swiersz L., Koch C., Evans S., Ibrahim H., le Q. T., Terris D. J., and Giaccia A. J., Candidate genes for the hypoxic tumor phenotype, Cancer Research. (2000) 60, no. 4, 883–887, 10706099.
CAS PubMed Web of Science® Google Scholar
80 Canning M. T., Postovit L. M., Clarke S. H., and Graham C. H., Oxygen-mediated regulation of gelatinase and tissue inhibitor of metalloproteinases-1 expression by invasive cells, Experimental Cell Research. (2001) 267, no. 1, 88–94, https://doi.org/10.1006/excr.2001.5243, 2-s2.0-0035399174, 11412041.
10.1006/excr.2001.5243
CAS PubMed Web of Science® Google Scholar
81 Jones D. and Dorfman D. M., Phenotypic characterization of subsets of T-cell lymphoma: towards a functional classification of T-cell lymphoma, Leukemia Lymphoma. (2001) 40, no. 5-6, 449–459, https://doi.org/10.3109/10428190109097644, 2-s2.0-0035050754, 11426518.
10.3109/10428190109097644
CAS PubMed Web of Science® Google Scholar
82 Weisberger J. A., Wu C. D., Liu Z., Wong J. Y., Melamed M. R., Darzynkiewicz Z., and Gorczyca W., Differential diagnosis of malignant lymphomas and related disorders by specific pattern of expression of immunophenotypic markers revealed by multiparameter flow cytometry (review), International Journal of Oncology. (2000) 17, no. 6, 1165–1175.
CAS PubMed Web of Science® Google Scholar
83 Orfao A., Schmitz G., Brando B., Ruiz-Arguelles A., Basso G., Braylan R., Rothe G., Lacombe F., Lanza F., Papa S., Lucio P., and San Miguel J. F., Clinically useful information provided by the flow cytometric immunophenotyping of hematological malignancies: current status and future directions, Clinical Chemistry. (1999) 45, no. 10, 1708–1717, 10508115.
CAS PubMed Web of Science® Google Scholar
84 Jennings C. D. and Foon K. A., Recent advances in flow cytometry: application to the diagnosis of hematologic malignancy, Blood. (1997) 90, no. 8, 2863–2892, https://doi.org/10.1182/blood.V90.8.2863, 9376567.
10.1182/blood.V90.8.2863
CAS PubMed Web of Science® Google Scholar
85 Jamal S., Picker L. J., Aquino D. B., McKenna R. W., Dawson D. B., and Kroft S. H., Immunophenotypic analysis of peripheral T-cell neoplasms, American Journal of Clinical Pathology. (2001) 116, no. 4, 512–526, https://doi.org/10.1309/QF6N-VAQW-N74H-4JE2, 2-s2.0-0035735802.
10.1309/QF6N-VAQW-N74H-4JE2
CAS PubMed Web of Science® Google Scholar
86 Borowitz M. J., Bray R., Gascoyne R., Melnick S., Parker J. W., Picker L., and Stetler-Stevenson M., U.S.-Canadian consensus recommendations on the immunophenotypic analysis of hematologic neoplasia by flow cytometry: data analysis and interpretation, Cytometry. (1997) 30, no. 5, 236–244, https://doi.org/10.1002/(SICI)1097-0320(19971015)30:5<236::AID-CYTO4>3.0.CO;2-F, 9383097.
10.1002/(SICI)1097-0320(19971015)30:5<236::AID-CYTO4>3.0.CO;2-F
CAS PubMed Web of Science® Google Scholar
87 Chu P. G., Chang K. L., Arber D. A., and Weiss L. M., Immunophenotyping of hematopoietic neoplasms, Seminars in Diagnostic Pathology. (2000) 17, no. 3, 236–256, 10968709.
CAS PubMed Web of Science® Google Scholar
88 Foukas P. G., Tsilivakos V., Zacharatos P., Mariatos G., Moschos S., Syrianou A., Asimacopoulos P. J., Bramis J., Fotiadis C., Kittas C., and Gorgoulis V. G., Expression of HLA-DR is reduced in tumor infiltrating immune cells (TIICs) and regional lymph nodes of non-small-cell lung carcinomas. A putative mechanism of tumor-induced immunosuppression?, Anticancer Research. (2001) 21, no. 4A, 2609–2615, 11724329.
CAS PubMed Web of Science® Google Scholar
89 Couturier J., Nuotio-Antar A. M., Agarwal N., Wilkerson G. K., Saha P., Kulkarni V., Lakhashe S. K., Esquivel J., Nehete P. N., Ruprecht R. M., and Sastry K. J., Lymphocytes upregulate CD36 in adipose tissue and liver, Adipocytes. (2019) 8, no. 1, 154–163, https://doi.org/10.1080/21623945.2019.1609202, 31035848.
10.1080/21623945.2019.1609202
CAS PubMed Web of Science® Google Scholar
90 Xu S., Chaudhary O., Rodríguez-Morales P., Sun X., Chen D., Zappasodi R., Xu Z., Pinto A. F., Williams A., Schulze I., and Farsakoglu Y., Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8⁺ T cells in tumors, Immunity. (2021) 54, no. 7, 1561–1577.e7, https://doi.org/10.1016/j.immuni.2021.05.003, 34102100.
10.1016/j.immuni.2021.05.003
CAS PubMed Web of Science® Google Scholar
91 Wang J. and Li Y., CD36 tango in cancer: signaling pathways and functions, Theranostics. (2019) 9, no. 17, 4893–4908, https://doi.org/10.7150/thno.36037, 2-s2.0-85070484064, 31410189.
10.7150/thno.36037
CAS PubMed Web of Science® Google Scholar
92 Lengyel E., Makowski L., DiGiovanni J., and Kolonin M. G., Cancer as a matter of fat: the crosstalk between adipose tissue and tumors, Trends Cancer. (2018) 4, no. 5, 374–384, https://doi.org/10.1016/j.trecan.2018.03.004, 2-s2.0-85044995689, 29709261.
10.1016/j.trecan.2018.03.004
CAS PubMed Web of Science® Google Scholar
93 Howie D., Ten Bokum A., Necula A. S., Cobbold S. P., and Waldmann H., The role of lipid metabolism in T lymphocyte differentiation and survival, Frontiers in Immunology. (2018) 8.
10.3389/fimmu.2017.01949
PubMed Web of Science® Google Scholar
94 Ma X., Xiao L., Liu L., Ye L., Su P., Bi E., Wang Q., Yang M., Qian J., and Yi Q., CD36-mediated ferroptosis dampens intratumoral CD8⁺ T cell effector function and impairs their antitumor ability, Cell Metabolism. (2021) 33, no. 5, 1001–1012.e5, https://doi.org/10.1016/j.cmet.2021.02.015, 33691090.
10.1016/j.cmet.2021.02.015
CAS PubMed Web of Science® Google Scholar
95 Wang H., Franco F., Tsui Y.-C., Xie X., Trefny M. P., Zappasodi R., Mohmood S. R., Fernández-García J., Tsai C. H., Schulze I., Picard F., Meylan E., Silverstein R., Goldberg I., Fendt S. M., Wolchok J. D., Merghoub T., Jandus C., Zippelius A., and Ho P. C., CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors, Nature Immunology. (2020) 21, no. 3, 298–308, https://doi.org/10.1038/s41590-019-0589-5, 32066953.
10.1038/s41590-019-0589-5
CAS PubMed Web of Science® Google Scholar
96 Qi J., Gu C., Wang W., Xiang M., Chen X., and Fu J., Elevated lactate dehydrogenase levels display a poor prognostic factor for non-Hodgkin’s lymphoma in intensive care unit: an analysis of the MIMIC-III database combined with external validation, Frontiers in Oncology. (2021) 11, article 753712, https://doi.org/10.3389/fonc.2021.753712, 34778068.
10.3389/fonc.2021.753712
PubMed Google Scholar
97 Fang X., Xiu B., Yang Z., Qiu W., Zhang L., Zhang S., Wu Y., Zhu X., Chen X., Xie S., Yi X., Liang A., and Zeng Y., The expression and clinical relevance of PD-1, PD-L1, and TP63 in patients with diffuse large B-cell lymphoma, Medicine. (2017) 96, no. 15, article e6398.
10.1097/MD.0000000000006398
Google Scholar

Citing Literature

All articles

EMAP II Expression Is Increased on Peripheral Blood Cells from Non-Hodgkin Lymphoma

Abstract

1. Introduction