Tumor CD73/A2aR adenosine immunosuppressive axis and tumor-infiltrating lymphocytes in diffuse large B-cell lymphoma: correlations with clinicopathological characteristics and clinical outcome
Corresponding Author
Xianhuo Wang
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
X.W., T.Z. and Z.S. contributed equally to this workCorrespondence to: Huilai Zhang, Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, Tel.: +86-22-23340123; Fax: +86-22-23537796, E-mail: [email protected]; or Ping Wang, Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, E-mail: [email protected]; or Xianhuo Wang, Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, E-mail: [email protected]; or Lanfang Li, Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, E-mail: [email protected]Search for more papers by this authorTingting Zhang
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
Shanxi Medical University, Fenyang College, Fenyang, Shanxi, China
X.W., T.Z. and Z.S. contributed equally to this workSearch for more papers by this authorZheng Song
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
X.W., T.Z. and Z.S. contributed equally to this workSearch for more papers by this authorLinyu Li
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
Search for more papers by this authorXuhan Zhang
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
Search for more papers by this authorJing Liu
Panovue Biological Technology Co., Ltd, Beijing, China
Search for more papers by this authorXianming Liu
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
Search for more papers by this authorLihua Qiu
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
Search for more papers by this authorZhengzi Qian
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
Search for more papers by this authorShiyong Zhou
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
Search for more papers by this authorLixia Feng
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
Search for more papers by this authorGe Hu
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
Search for more papers by this authorBin Meng
Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
Search for more papers by this authorQiongli Zhai
Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
Search for more papers by this authorXiubao Ren
Department of Immunology/Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
Search for more papers by this authorKai Fu
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
Search for more papers by this authorCorresponding Author
Lanfang Li
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
Correspondence to: Huilai Zhang, Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, Tel.: +86-22-23340123; Fax: +86-22-23537796, E-mail: [email protected]; or Ping Wang, Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, E-mail: [email protected]; or Xianhuo Wang, Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, E-mail: [email protected]; or Lanfang Li, Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, E-mail: [email protected]Search for more papers by this authorCorresponding Author
Ping Wang
Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
Correspondence to: Huilai Zhang, Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, Tel.: +86-22-23340123; Fax: +86-22-23537796, E-mail: [email protected]; or Ping Wang, Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, E-mail: [email protected]; or Xianhuo Wang, Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, E-mail: [email protected]; or Lanfang Li, Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, E-mail: [email protected]Search for more papers by this authorCorresponding Author
Huilai Zhang
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
Correspondence to: Huilai Zhang, Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, Tel.: +86-22-23340123; Fax: +86-22-23537796, E-mail: [email protected]; or Ping Wang, Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, E-mail: [email protected]; or Xianhuo Wang, Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, E-mail: [email protected]; or Lanfang Li, Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, E-mail: [email protected]Search for more papers by this authorCorresponding Author
Xianhuo Wang
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
X.W., T.Z. and Z.S. contributed equally to this workCorrespondence to: Huilai Zhang, Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, Tel.: +86-22-23340123; Fax: +86-22-23537796, E-mail: [email protected]; or Ping Wang, Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, E-mail: [email protected]; or Xianhuo Wang, Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, E-mail: [email protected]; or Lanfang Li, Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, E-mail: [email protected]Search for more papers by this authorTingting Zhang
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
Shanxi Medical University, Fenyang College, Fenyang, Shanxi, China
X.W., T.Z. and Z.S. contributed equally to this workSearch for more papers by this authorZheng Song
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
X.W., T.Z. and Z.S. contributed equally to this workSearch for more papers by this authorLinyu Li
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
Search for more papers by this authorXuhan Zhang
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
Search for more papers by this authorJing Liu
Panovue Biological Technology Co., Ltd, Beijing, China
Search for more papers by this authorXianming Liu
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
Search for more papers by this authorLihua Qiu
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
Search for more papers by this authorZhengzi Qian
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
Search for more papers by this authorShiyong Zhou
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
Search for more papers by this authorLixia Feng
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
Search for more papers by this authorGe Hu
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
Search for more papers by this authorBin Meng
Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
Search for more papers by this authorQiongli Zhai
Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
Search for more papers by this authorXiubao Ren
Department of Immunology/Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
Search for more papers by this authorKai Fu
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
Search for more papers by this authorCorresponding Author
Lanfang Li
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
Correspondence to: Huilai Zhang, Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, Tel.: +86-22-23340123; Fax: +86-22-23537796, E-mail: [email protected]; or Ping Wang, Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, E-mail: [email protected]; or Xianhuo Wang, Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, E-mail: [email protected]; or Lanfang Li, Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, E-mail: [email protected]Search for more papers by this authorCorresponding Author
Ping Wang
Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
Correspondence to: Huilai Zhang, Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, Tel.: +86-22-23340123; Fax: +86-22-23537796, E-mail: [email protected]; or Ping Wang, Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, E-mail: [email protected]; or Xianhuo Wang, Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, E-mail: [email protected]; or Lanfang Li, Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, E-mail: [email protected]Search for more papers by this authorCorresponding Author
Huilai Zhang
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, the Sino-US Center for Lymphoma and Leukemia Research, Tianjin, China
Correspondence to: Huilai Zhang, Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, Tel.: +86-22-23340123; Fax: +86-22-23537796, E-mail: [email protected]; or Ping Wang, Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, E-mail: [email protected]; or Xianhuo Wang, Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, E-mail: [email protected]; or Lanfang Li, Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Tiyuanbei, Hexi District, Tianjin 300060, China, E-mail: [email protected]Search for more papers by this authorAbstract
Novel immune checkpoint blockades, including those targeting CD73 and A2aR, are being evaluated in malignancies in clinical trials. Here, we investigated the expression of CD73 and A2aR as well as tumor-infiltrating lymphocytes (TILs), and analyzed their correlations with clinicopathological characteristics and survival in diffuse large B-cell lymphoma (DLBCL). We found that CD73 expression on tumor cells, rather than the total protein and gene levels of CD73, was associated with survival. Patients with CD73+/Pax-5+ (median survival, 57.8 months; 95% CI, 46.4–69.3) experienced significantly poorer outcomes than those with CD73−/Pax-5+ (median survival, 73.5 months; 95% CI, 65.9–81.2). Additionally, A2aR expression on both total TILs and CD8+ TILs was correlated with survival. Patients with A2aR+ TILs (median survival, 53.3 months; 95% CI, 40.6–66.0) had a significantly shorter survival time than patients with A2aR− TILs (median survival, 74.5 months; 95% CI, 67.5–81.5). Spearman's rank test showed that CD73 expression on tumor cells was positively correlated with A2aR expression on TILs (R = 0.395, p = 0.001). We further found that patients could be more precisely stratified through the combination of CD73 tumor cell expression and A2aR TILs expression, and patients with CD73+/Pax-5+ and A2aR+ TILs experienced the worst outcome. We also revealed that patients with CD73+/Pax-5+ and low CD8+ TILs or low absolute lymphocyte counts had unfavorable outcomes. Overall, our findings uncovered that patients with CD73+ on tumor cells as well as A2aR+ on TILs or low CD8+ TILs exhibited inferior survival, supporting potential combination strategies using CD73/A2aR immunosuppressive blockades as treatment options for DLBCL patients.
Abstract
What's new?
The CD73/A2a adenosine receptor (A2aR) immunosuppressive axis is suspected of facilitating tumor immune escape in diffuse large B-cell lymphoma (DLBCL), a disease in which tumor immunosuppression potentially impacts therapeutic efficacy. Here, analyses show that CD73 expression on tumor cells and A2aR expression on tumor-infiltrating lymphocytes (TILs) are linked to reductions in DLBCL survival. Clinical outcome was especially poor among DLBCL patients who exhibited combined expression of CD73 on tumor cells and A2aR on TILs. The findings suggest that strategies to block CD73/A2aR, possibly in combination with other immune checkpoint antibodies, may be an effective therapeutic option in DLBCL.
Supporting Information
| Filename | Description |
|---|---|
| ijc32144-sup-0001-FigureS1.tifTIFF image, 5.4 MB | Figure S1 Representatively multispectral images of CD73 widely expressing on tumor cells (white arrows indicate CD73+/Pax-5+ tumor cells) and immune cells (yellow arrows indicate CD73+/Pax-5− immune cells) in DLBCL section. DAPI (blue), Pax-5 (green) and CD73 (red). Scans were imaged at 200 × magnification. |
| ijc32144-sup-0002-FigureS2.tifTIFF image, 986 KB | Figure S2 Association of CD73 gene expression with survival. Kaplan–Meier curves of OS in 233 DLBCL cases treated with R-CHOP-like regimen between high and low CD73 mRNA levels, which was divided into two groups according to the median value of gene expression. Log-rank test was used to derive p-value for comparisons between two groups. |
| ijc32144-sup-0003-FigureS3.tifTIFF image, 907.1 KB | Figure S3 Association of A2aR expression on CD8+ TILs with survival. Kaplan–Meier curves of OS in DLBCL patients with A2aR+/CD8+ (N = 36) and A2aR−/CD8+ (N = 29). Log-rank test was used to derive p-value for comparisons between two groups. |
| ijc32144-sup-0004-FigureS4.tifTIFF image, 2.3 MB | Figure S4 Association of absolute lymphocyte count (ALC) or combined CD73 expression on tumor cells and ALC with survival. (a) Kaplan–Meier curves of OS in DLBCL patients with normal ALC levels (N = 32) and elevated ALC levels (N = 33). (b) Kaplan–Meier curves of OS in DLBCL patients stratified according to the combination of both CD73 expression on tumor cells (CD73+/Pax-5+) and ALC levels. Log-rank tests were used to derive p-values for comparisons between two groups (a) or without adjustment for multiple comparisons among four groups (b). |
| ijc32144-sup-0005-TableS1.docxWord 2007 document , 16.2 KB | Table S1 List of primary antibodies used in this study |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood 2010; 116: 2040–5.
- 2Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science 2018; 359: 1350–5.
- 3Lesokhin AM, Ansell SM, Armand P, et al. Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study. J Clin Oncol 2016; 34: 2698–704.
- 4Jin D, Fan J, Wang L, et al. CD73 on tumor cells impairs antitumor T-cell responses: a novel mechanism of tumor-induced immune suppression. Cancer Res 2010; 70: 2245–55.
- 5Zarek PE, Huang CT, Lutz ER, et al. A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood 2008; 111: 251–9.
- 6Wang L, Fan J, Thompson LF, et al. CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice. J Clin Invest 2011; 121: 2371–82.
- 7Ohta A, Gorelik E, Prasad SJ, et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci USA 2006; 103: 13132–7.
- 8Allard B, Pommey S, Smyth MJ, et al. Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clin Cancer Res 2013; 19: 5626–35.
- 9Beavis PA, Milenkovski N, Henderson MA, et al. Adenosine receptor 2A blockade increases the efficacy of anti-PD-1 through enhanced antitumor T-cell responses. Cancer Immunol Res 2015; 3: 506–17.
- 10Howitt BE, Shukla SA, Sholl LM, et al. Association of polymerase e-mutated and microsatellite-instable endometrial cancers with neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1. JAMA Oncol 2015; 1: 1319–23.
- 11Kollmann D, Schweiger T, Schwarz S, et al. PD1-positive tumor-infiltrating lymphocytes are associated with poor clinical outcome after pulmonary metastasectomy for colorectal cancer. Oncoimmunology 2017; 6: e1331194.
- 12Carey CD, Gusenleitner D, Lipschitz M, et al. Topological analysis reveals a PD-L1-associated microenvironmental niche for reed-Sternberg cells in Hodgkin lymphoma. Blood 2017; 130: 2420–30.
- 13Young A, Ngiow SF, Barkauskas DS, et al. Co-inhibition of CD73 and A2AR adenosine signaling improves anti-tumor immune responses. Cancer Cell 2016; 30: 391–403.
- 14Marinaccio C, Ingravallo G, Gaudio F, et al. T cells, mast cells and microvascular density in diffuse large B cell lymphoma. Clin Exp Med 2016; 16: 301–6.
- 15Mannino RG, Santiago-Miranda AN, Pradhan P, et al. 3D microvascular model recapitulates the diffuse large B-cell lymphoma tumor microenvironment in vitro. Lab Chip 2017; 17: 407–14.
- 16Airas L, Hellman J, Salmi M, et al. CD73 is involved in lymphocyte binding to the endothelium: characterization of lymphocyte-vascular adhesion protein 2 identifies it as CD73. J Exp Med 1995; 182: 1603–8.
- 17Buchheiser A, Ebner A, Burghoff S, et al. Inactivation of CD73 promotes atherogenesis in apolipoprotein E-deficient mice. Cardiovasc Res 2011; 92: 338–47.
- 18Thompson LF, Eltzschig HK, Ibla JC, et al. Crucial role for ecto-5′-nucleotidase (CD73) in vascular leakage during hypoxia. J Exp Med 2004; 200: 1395–405.
- 19Hasegawa T, Bouïs D, Liao H, et al. Ecto-5′ nucleotidase (CD73)-mediated adenosine generation and signaling in murine cardiac allograft vasculopathy. Circ Res 2008; 103: 1410–21.
- 20Georgiou K, Chen L, Berglund M, et al. Genetic basis of PD-L1 overexpression in diffuse large B-cell lymphomas. Blood 2016; 127: 3026–34.
- 21Young A, Mittal D, Stagg J, et al. Targeting cancer-derived adenosine: new therapeutic approaches. Cancer Discov 2014; 4: 879–88.
- 22Shook BC, Jackson PF. Adenosine a(2A) receptor antagonists and Parkinson's disease. ACS Chem Nerosci 2011; 2: 555–67.
- 23Teng MW, Ngiow SF, Ribas A, et al. Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res 2015; 75: 2139–45.
- 24Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014; 515: 568–71.
- 25Buisseret L, Pommey S, Allard B, et al. Clinical significance of CD73 in triple-negative breast cancer: multiplex analysis of a phase III clinical trial. Ann Oncol 2018; 29: 1056–62.
- 26Synnestvedt K, Furuta GT, Comerford KM, et al. Ecto-5′-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia. J Clin Invest 2002; 110: 993–1002.
- 27Hatfield SM, Kjaergaard J, Lukashev D, et al. Systemic oxygenation weakens the hypoxia and hypoxia inducible factor 1α-dependent and extracellular adenosine-mediated tumor protection. J Mol Med 2014; 92: 1283–92.
Citing Literature
