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TRIP13: A promising cancer immunotherapy target

Shengnan Jing

Institute of Pain Medicine and Special Environmental Medicine, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China

Contribution: Project administration (equal), Writing - original draft (equal)

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Liya Zhao,

Liya Zhao

Institute of Pain Medicine and Special Environmental Medicine, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China

Contribution: Investigation (equal)

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Liwen Zhao,

Liwen Zhao

Institute of Pain Medicine and Special Environmental Medicine, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China

Contribution: Software (equal)

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Yong-Jing Gao,

Corresponding Author

Yong-Jing Gao

[email protected]

orcid.org/0000-0002-7432-7458

Institute of Pain Medicine and Special Environmental Medicine, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China

Correspondence Yong-Jing Gao and Tianzhen He, Institute of Pain Medicine, Nantong University, 9 Seyuan Rd, Nantong 226019, Jiangsu, China.

Email: [email protected] and [email protected]

Contribution: Supervision (equal), Writing - review & editing (equal)

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Tianzhen He,

Corresponding Author

Tianzhen He

[email protected]

orcid.org/0000-0001-7873-853X

Institute of Pain Medicine and Special Environmental Medicine, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China

Correspondence Yong-Jing Gao and Tianzhen He, Institute of Pain Medicine, Nantong University, 9 Seyuan Rd, Nantong 226019, Jiangsu, China.

Email: [email protected] and [email protected]

Contribution: Investigation (equal), Supervision (equal), Writing - original draft (equal), Writing - review & editing (equal)

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Shengnan Jing,

Shengnan Jing

Institute of Pain Medicine and Special Environmental Medicine, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China

Contribution: Project administration (equal), Writing - original draft (equal)

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Liya Zhao,

Liya Zhao

Institute of Pain Medicine and Special Environmental Medicine, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China

Contribution: Investigation (equal)

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Liwen Zhao,

Liwen Zhao

Institute of Pain Medicine and Special Environmental Medicine, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China

Contribution: Software (equal)

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Yong-Jing Gao,

Corresponding Author

Yong-Jing Gao

[email protected]

orcid.org/0000-0002-7432-7458

Institute of Pain Medicine and Special Environmental Medicine, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China

Correspondence Yong-Jing Gao and Tianzhen He, Institute of Pain Medicine, Nantong University, 9 Seyuan Rd, Nantong 226019, Jiangsu, China.

Email: [email protected] and [email protected]

Contribution: Supervision (equal), Writing - review & editing (equal)

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Tianzhen He,

Corresponding Author

Tianzhen He

[email protected]

orcid.org/0000-0001-7873-853X

Institute of Pain Medicine and Special Environmental Medicine, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China

Correspondence Yong-Jing Gao and Tianzhen He, Institute of Pain Medicine, Nantong University, 9 Seyuan Rd, Nantong 226019, Jiangsu, China.

Email: [email protected] and [email protected]

Contribution: Investigation (equal), Supervision (equal), Writing - original draft (equal), Writing - review & editing (equal)

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First published: 11 October 2024

https://doi.org/10.1002/cai2.147

Citations: 1

Shengnan Jing and Liya Zhao contributed equally to this work and shared the co-first authorship.

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Abstract

The tumor microenvironment (TME) facilitates tumor development through intricate intercellular signaling, thereby supporting tumor growth and suppressing the immune response. Thyroid hormone receptor interactor 13 (TRIP13), an AAA+ ATPase, modulates the conformation of client macromolecules, consequently influencing cellular signaling pathways. TRIP13 has been implicated in processes such as proliferation, invasion, migration, and metastasis during tumor progression. Recent studies have revealed that TRIP13 also plays a role in immune response suppression within the TME. Thus, inhibiting these functions of TRIP13 could potentially enhance immune responses and improve the efficacy of immune checkpoint inhibition. This review summarizes the recent research progress of TRIP13 and discusses the potential of targeting TRIP13 to improve immune-based therapies for patients with cancer.

Abbreviations

BRCA: breast cancer
HNSC: head and neck squamous cell carcinoma
KIRC: kidney renal clear cell carcinoma
LUAD: lung adenocarcinoma
STAD: stomach adenocarcinoma
THCA: thyroid carcinoma
THYM: thymoma

1 INTRODUCTION

Thyroid hormone receptor interactor 13 (TRIP13) is a member of the AAA+ ATPase family that generates mechanical forces through ATP hydrolysis reactions. Existing as homohexamers, TRIP13 uses ATP as its energy source and interacts with its analog pontocerebellar hypoplasia type 2 (PCH2). PCH2 binding to hsp70-Hsp90 organizing protein 1 (Hop1) induces structural changes, displacing Hop1 from DNA [1]. TRIP13/PCH2 functions as an ATP-dependent hydrolase and uses phosphate hydrolysis to generate energy for conformational changes, exerting mechanical force on its substrate Hop1 [2]. TRIP13 was also identified as a kinetochore protein and it interacts with the silencing protein MAD2L1 binding protein (also known as p31^comet) [3]. In cancer cells, TRIP13 was reported to interact with mitotic arrest deficient 2 (MAD2), actinin alpha 4 [4], NIMA-related kinase 2 [5], epidermal growth factor receptor [6], and fibroblast growth factor receptor 4 (FGFR4) [7], thereby promoting tumor progression. Its role in ensuring the accurate alignment of chromosomes during mitosis aligns with its association with various cancers. TRIP13 is upregulated in several types of cancers, including colorectal cancer [8], head and neck cancer [9], breast cancer [10], lung cancer [11], liver cancer [12], prostate cancer [13], multiple myeloma [14], and human chronic lymphoblastic leukemia [15]. Overexpression of TRIP13 has been linked to accelerated tumor growth in squamous cell cancer of the head and neck [9] and lung adenocarcinoma [16]. Blocking TRIP13 has been demonstrated to slow tumor growth in hepatocellular carcinoma, head and neck cancer, and colon cancer [17, 18]. Moreover, in cutaneous melanoma [19], prostate cancer [13], and lung adenocarcinoma [16], TRIP13 plays a crucial role in maintaining tumor “stem” or triggering cells and facilitating their movement. These findings underscore the significance of TRIP13 in tumor progression.

TRIP13 also has a significant role in the immune system. A TRIP13-like ATPase was identified as instrumental in regulating bacterial defense against bacteriophages [20]. Previous studies also underscore TRIP13's substantial involvement in the immune system's response to tumors. This is achieved through TRIP13 regulation of the migration of normal cells to the tumor microenvironment (TME), thereby facilitating tumor survival. Among these cells are myelin stromal cells and immune cells including CD3⁺ T cells, CD4⁺ T cells, and CD8⁺ T cells, all of which tumors can exploit to modulate immune responses. While TRIP13's contribution to tumor growth has been extensively discussed [21], this review emphasizes recent findings on the emerging roles for TRIP13 in suppressing the immune response within the TME.

2 THE ROLE OF TRIP13 IN PHYSIOLOGICAL PROCESSES

TRIP13/PCH2 plays a significant role in mitosis, specifically during the transition from metaphase to anaphase and in the spindle assembly checkpoint (SAC). Its activity also influences the anaphase-promoting complex (APC) [22]. Before progressing into anaphase, the cell must ensure proper chromosome organization and biorientation to facilitate the smooth separation of sister chromatids. This intricate process requires multiple proteins for precise timing and reliable reactions.

Activating the APC is crucial for movement of sister chromatids but comes with a compromise in security during the metaphase-anaphase transition. Cell division cycle 20 (CDC20), which is usually inhibited by the mitotic checkpoint complex (MCC), triggers the APC. Mad2 is a mitotic checkpoint gene that encodes a protein that exists in two distinct isoforms: the open (O-) form and the closed (C-) form [22]. O-Mad2 undergoes a transformation to C-Mad2 upon kinetochore detachment. Subsequently, C-Mad2 binds to CDC20, inhibiting its function and impeding mitotic progression [23]. To proceed, disassembling the MCC is necessary, and this process is mediated by p31^comet [24]. Structural mimicry is believed to occur, partly from the structural similarities between p31^comet and C-Mad2 [25]. However, ATP is essential for this process, and TRIP13/PCH2 plays a role in this step (Figure 1). Thus, TRIP13/PCH2 plays a crucial function in activating the SAC and in the development of the MCC.

Details are in the caption following the image — **Figure 1**
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Schematic of ATP hydrolysis of TRIP13 in mitosis and meiosis. During mitosis, TRIP13 binds to the N terminus of MAD2, in the presence of p31^comet, causing the conversion of C-MAD2 into O-MAD2. TRIP13 inhibits the spontaneous conversion of O-Mad2 into C-Mad2, preserving a reservoir of soluble O-Mad2. O-Mad2 is then attracted to kinetochores during mitosis, contributing to the formation of the mitotic checkpoint complex. During meiosis, TRIP13 facilitates the removal of various HORMAD proteins, resulting in the synthesis of the synaptonemal complex. C-MAD2, closed MAD2; MAD2, mitotic arrest deficient 2; O-MAD2, open-MAD2; PCH2, pontocerebellar hypoplasia type 2; TRIP13, thyroid hormone receptor interactor 13.

TRIP13/PCH2 is also implicated in the G2/prophase stage of meiosis [26] (Figure 1). TRIP13 influences the frequency of double-strand breaks, which are crucial in meiosis. Homologous recombination then requires the formation of a protein complex to guide proper chromosomal pairing. The meiotic checkpoint in budding yeast prevents chromosomal segregation in cases of recombination or chromosome synapsis deficiencies, as evidenced by induced mutations in the PCH2 gene [26].

TRIP13/PCH2 is vital for the synaptonemal complex (SC) formation, which is responsible for chromosome pair formation. Meiocytes lacking TRIP13 showed an increase in pericentric synaptic forks, a decrease in crossovers, and disrupted chiasma distribution (sites where homologous chromosomes contact) [27]. Synthesis of the SC during meiosis necessitates the removal of HORMA-domain proteins (HORMADS). PCH2 is essential for the SC formation by facilitating Hop1 removal from chromosomes [28]. TRIP13 facilitates the removal of various HORMADS, such as HORMAD1 and HORMAD2, in mouse spermatocytes [29]. These findings indicate the crucial and active role of TRIP13/PCH2 in eliminating multiple proteins during SC formation and subsequent meiosis.

3 THE ROLE OF TRIP13 IN CANCER

The role of TRIP13/PCH2 in maintaining correct chromosomal biorientation during mitosis should not be surprising given that it is linked to many cancers. TRIP13 overexpression promotes invasion and proliferation of squamous cell carcinoma of the head and neck [9]. Additionally, TRIP13 overexpression mitigates the mitotic delay induced by Mad2 overexpression, while TRIP13 downregulation exacerbated the effects of Mad2 overexpression. Both Mad2 and TRIP13 overexpression promote proliferation in cells and tumor xenografts, indicating the potential of TRIP13 inhibition as a therapeutic strategy for cancer treatment [24]. Additionally, Mad2 has been implicated in ovarian cancer treatment resistance [30]. Epithelial ovarian cancer (EOC) cell lines (SKOV-3, HEY, and OVCAR-3) exhibited higher TRIP13 expression compared with normal cell lines [31]. Knockdown of TRIP13 in EOC cells induced cell death, reduced cell invasion and migration, and hindered proliferation [31]. These findings indicates that TRIP13 aids tumor cell growth and highlights TRIP13 as a potential target for cancer treatment.

4 TRIP13 AND IMMUNE CELL INFILTRATION

4.1 Roles of infiltrating immune cells in the TME

Tumor-infiltrating immune cells (TIICs) are pivotal components of the TME and hold significant implications for both prognostic assessment and therapeutic interventions in patients with cancer [32-34]. Tumor-infiltrating lymphocytes (TILs) have been extensively studied as a specific subset of TIICs, and their association with positive outcomes in breast cancer has been previously documented [35-37]. Elevated levels of TILs within tumor masses correlated with improved overall survival and may serve as indicators of heightened responsiveness to chemotherapy or radiotherapy [38-44]. Furthermore, the presence of TILs has been associated with a reduced rate of distant recurrence and enhanced metastasis-free survival in various types of cancers [39, 45-47]. However, the relationship between TIL abundance and treatment response is not always consistent, indicating that the distinct immune phenotypes exhibited by TILs play a critical role in prognostic evaluation [35].

de Visser et al. [48] reported a potential association between B lymphocytes and tumor promotion. Their findings demonstrated that genetically removing mature B and T lymphocytes in a mouse model restricted the advancement of cancerous growths, as these tumors failed to attract innate immune cells. Moreover, the transfer of B lymphocytes or serum from HPV16 mice to B- and T-cell-deficient/HPV16 mice led to the restoration of innate immune cell infiltration into premalignant tissue, thereby reinstating conditions conducive to full malignancy. Furthermore, the substantial presence of regulatory T cells (Tregs) within various tumor types contributes to the establishment of an immunosuppressive microenvironment, thereby impeding an effective immune response against the tumor and promoting its growth [49-51]. The positive impact of inhibiting Treg cell functions has been observed in animal models, leading to enhanced T-cell-mediated antitumor responses and the regression of experimental tumors [52, 53].

Like TILs, tumor-associated macrophages (TAMs) represent a distinct immune population crucial in regulating the interaction between cancer and the immune system. Clinicopathological studies have indicated the adverse clinical implications associated with TAM accumulation [54-64]. Additionally, natural killer (NK) cells exert a beneficial influence on immunosurveillance [65-67]. Early investigations in animal models revealed the pivotal role of NK cells in impeding the dissemination of cancer cells to distant sites [68-72]. Studies demonstrated that the clearance of tumor cells in the lungs primarily relied on NK cells. Additionally, the rate of NK cell-mediated elimination of tumor cells in the lungs was inversely related to the formation of experimental metastases in the lungs and other organs after intravenous injection of tumor cell suspensions [68-71]. Elevated levels of tumor-infiltrating NK cells have been linked to improved prognosis in certain types of solid tumors. However, the immunosuppressive TME hampers the efficacy of these cells, thereby facilitating cancer progression [72]. In the TME, dendritic cells (DCs) are highly effective antigen-presenting cells that initiate primary immune responses against carcinoma [73]. Mast cells, myeloid-derived suppressor cells, and monocytes have been associated with an inflammatory microenvironment that promotes tumor growth [57, 74, 75]. Moreover, elevated neutrophil counts correlated with poor prognoses across various carcinoma types [59]. Eosinophils play a multifaceted function within the TME. Leveraging a diverse array of mediators and receptors, eosinophils actively engage in both innate and adaptive immune processes, including type 1 and type 2 immunity, thereby exerting influence over the TME and subsequent tumor outcomes [76]. Activated eosinophils in the TME modulate tumor growth by orchestrating the behavior of other immune cells through the release of cytokines [76].

Taken together, these results demonstrate that the presence of infiltrating immune cells within the TME holds significant prognostic implications for the survival outcomes of patients with cancer.

4.2 TRIP13 inhibits antitumor immune responses

Previous studies have indicated that TRIP13 may have a notable effect on tumor progression by activating immune cells that infiltrate the tumor. Among these cells, tumor-infiltrating CD8⁺ T cells are recognized as the key players in exerting antitumor effects. Granzyme B and perforin are essential cytotoxic components in NK cells and cytotoxic T lymphocytes, facilitating tumor cell apoptosis [77]. Inhibition of TRIP13 leads to upregulation of cytotoxic mediators, thereby activating an antitumor immune response. Tumor cells with TRIP13 knockdown exhibit increased granzyme B activation [7]. These findings suggest that the cytotoxic effects of TRIP13 on tumor cells may be attributed to the increased secretion of these mediators. Furthermore, a previous study of a myeloma model demonstrated that the suppression of TRIP13 leads to a notable increase in the infiltration of CD3⁺, CD4⁺, and CD8⁺ T cells [78]. In hepatocellular carcinoma, elevated TRIP13 expression was associated with the enhanced infiltration of Th2 cells and reduced infiltration of neutrophils, Th17 cells, and dendritic cells [79].

DCZ0415, a small molecule inhibitor of TRIP13, has been shown to significantly enhance the secretion of cytotoxic mediators, including granzyme B, perforin, and interferon-γ. This increased secretion may be responsible for the observed cytotoxic effects of DCZ0415 against murine MC38 cells. Furthermore, the combination of DCZ0415 with immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4) in tumors increased cytotoxicity and promoted tumor regression [7]. In an immunocompetent syngeneic pancreatic ductal adenocarcinoma model, treatment with DCZ0415 resulted in an enhanced immune response. This was achieved through the downregulation of PD-1 or programmed death-ligand 1 (PD-L1) expression, upregulation of granzyme B/perforin expression, and augmentation of CD3/CD4 T cell infiltration [80]. Moreover, DCZ0415 augmented the antitumorigenic and antimetastatic properties of gemcitabine by inhibiting proliferation and angiogenesis, stimulating apoptosis, and boosting the immune response [80]. These findings indicate that TRIP13 depletion significantly impedes tumor progression by fostering increased immune cell infiltration.

4.3 The molecular mechanism of TRIP13 in antitumor immune responses

TRIP13 inhibition presents a promising avenue for immunotherapy against tumors, although further elucidation of its mechanism in cancer immunotherapy is warranted. Administration of DCZ0415 to immunocompetent myeloma models resulted in an upregulation of immune cell populations (CD3, CD4, and CD8) and an inactivation of nuclear factor-κB and Wnt/β-catenin signaling, suggesting the immunotherapeutic potential of TRIP13 inhibition [78]. TRIP13 blockade led to the signal transducer and activator of transcription 3 (STAT3) inactivation, promoting antitumor immunity, and impeding tumor growth [7]. Previous studies have shown the pivotal role of STAT3 in the regulation of the antitumor immune response through various mechanisms, including suppression of the production of immunosuppressive factors (Tregs), upregulation of immune checkpoint molecules PD-1 and CTLA-4, and inhibition of the antitumorigenic functions of CD8⁺ T cells [81]. Additionally, tumor progression has been linked to heightened activation of the FGFR4-STAT3 axis, which is induced by elevated TRIP13 levels and can be inhibited by DCZ0415 [7]. Subsequent studies showed that DCZ04145 inhibits the TRIP13-FGFR4-STAT3 axis in colorectal cancer, thereby inhibiting cancer progression and metastasis and stimulating the antitumor immune response [7]. These findings support the potential of targeting the TRIP13-FGFR4-STAT3 axis as a promising strategy for tumor immunotherapy (Figure 2).

5 TRIP13 IS A POTENTIAL REGULATOR OF TUMOR IMMUNE INFILTRATION

In addition to the prior studies highlighting TRIP13's role in regulating infiltrating T cells, we conducted further investigations into its putative immune regulatory functions using database analyses. Using the TIMER 2.0 database, we explored the association between TRIP13 expression and immune infiltration levels across various types of cancer. A significant negative correlation was observed between TRIP13 expression and CD8⁺ T cells in six out of 40 distinct cancer types (adjusted p < 0.05) (Supporting Information S1: Table S1). Notably, a positive correlation was detected between TRIP13 expression and CD8⁺ T cells in lung adenocarcinoma (LUAD) (adjusted p < 0.01). Furthermore, TRIP13 expression exhibited a significant positive correlation with CD4⁺ T cells in 10 out of 40 cancer types (adjusted p < 0.05).

TRIP13 expression exhibited a significant positive correlation with Tregs in kidney renal clear cell carcinoma (KIRC), kidney chromophobe, thyroid carcinoma (THCA), and liver hepatocellular carcinoma. Conversely, a significant negative correlation was observed between TRIP13 expression and the presence of Tregs and B cells across 12 different cancer types (adjusted p < 0.05). TRIP13 expression showed a significant positive correlation with B cells in THCA (adjusted p < 0.001) and with neutrophils in stomach adenocarcinoma (STAD), KIRC, and kidney renal papillary cell carcinoma (adjusted p < 0.05).

Notably, TRIP13 expression exhibited a significant negative correlation with monocytes in 8 different cancer types (adjusted p < 0.05), while showing a significant positive correlation with macrophage M1 cells in 13 types of cancers (adjusted p < 0.05) and macrophage M2 cells in prostate adenocarcinoma (adjusted p < 0.001). However, it exhibited a negative correlation with macrophage M1 cells in thymoma (THYM) (adjusted p < 0.05) and macrophage M2 cells in six types of cancers (adjusted p < 0.05). Furthermore, TRIP13 expression exhibited a significant positive correlation with DCs in THCA and rectum adenocarcinoma (adjusted p < 0.05), while showing a significant negative correlation with DCs in luminal A breast cancer (BRCA-LumA), LUAD, KIRC, and mesothelioma (adjusted p < 0.05). TRIP13 expression showed a significant positive correlation with NK cells in colon adenocarcinoma and testicular germ cell tumors (adjusted p < 0.05) and a significant negative correlation with NK cells in human papillomavirus-negative head and neck squamous cell carcinoma (HNSC-HPV⁻), BRCA-LumA, HNSC, STAD, and THYM (adjusted p < 0.05). TRIP13 expression displayed a significant negative correlation with mast cells in 11 different cancer types (adjusted p < 0.05). No significant correlation was observed between TRIP13 expression and eosinophil cells. Collectively, these findings strongly suggest that TRIP13 may serve as a significant regulator of tumor immune infiltration in the context of cancer therapy.

6 DISCUSSION AND CONCLUSIONS

As a protein involved in regulating chromosomal alignment during mitosis, the association of TRIP13/PCH2 with a variety of malignancies is not surprising. Studies have indicated that TRIP13 may represent an attractive target for cancer therapy. Additionally, TRIP13 plays a crucial function within the immune system. The TME consists of a diverse array of innate and adaptive immune cells, cancer cells, endothelial cells, and fibroblasts, including B and T cells, dendritic cells, myeloid-derived suppressor cells, mast cells, NK cells, neutrophils, eosinophils, and macrophages (M1/M2) [82, 83]. Cancer development and progression are significantly influenced by the TME. Some evidence suggests that cellular interactions between immune cells and cancer cells may promote cancer cell proliferation. Previous studies have also identified the crucial functions of TRIP13 in tumor immunity, specifically in facilitating tumor survival by modulating the recruitment of immune cells, including CD3⁺ T cells, CD4⁺ T cells, and CD8⁺ T cells, to the TME. As demonstrated in earlier studies, the depletion of TRIP13 made it easier for immune responses to be activated within the TME, ultimately impeding tumor progression [78]. TRIP13 in tumor cells possesses the ability to suppress immune responses, thereby promoting tumor progression.

More research is required to determine whether TRIP13-mediated tumor growth leads to the upregulation of immune checkpoint inhibitors beyond PD-1/PD-L1/CTLA-4. Identifying the specific genes within immune cells that are regulated by TRIP13 is also critical. The exploration of these genes holds promise for the development of immunotherapeutic targets aimed at cancer prevention. Furthermore, to advance TRIP13-based cancer immunotherapy, it is imperative to gain a deeper understanding of TRIP13's role in other infiltrating immune cells, such as regulatory T cells and macrophages. Fully elucidating the involvement of TRIP13 in the function and regulation of these immune cells will be essential for developing effective immunotherapeutic strategies targeting TRIP13 for cancer treatment.

TRIP13 facilitated the upregulation of STAT3 expression, hence inducing anticancer immunity and impeding tumor advancement [7]. Tumor progression was observed as a result of elevated TRIP13 levels, which led to hyperactivation of the FGFR4-STAT3 axis [7]. DCZ0415 inhibits this axis, thereby inhibiting the progression and metastasis of colorectal cancer while stimulating the antitumor immune response [7]. These findings indicate that targeting the TRIP13-FGFR4-STAT3 axis holds promise as a strategy for tumor immunotherapy. By directing the development of targeted pharmacologic strategies to reduce or eliminate the effects of infiltrating immune suppression in patients with cancer, a targeted TRIP13-FGFR4-STAT3 therapy enhances the efficacy of therapeutic cancer vaccines and other immune cell-based cancer immunotherapies. A targeted TRIP13-FGFR4-STAT3 therapy may enhance the efficacy of therapeutic cancer vaccines and other immune cell-based cancer immunotherapies and reduce or eliminate the effects of infiltrating immune suppression in cancer patients.

A recent study showed that blocking TRIP13 with DCZ0415 inhibits PD-1/PD-L1 expression and increases T cell infiltration into the TME via modulation of the FGFR4/STAT3 axis, hence fostering antitumor immunity and preventing tumor growth [80]. Therefore, the combination of DCZ0415 with first-line cancer therapy medicines holds significant promise as a therapeutic approach for treating cancer. The combined therapy not only decreased tumor growth but also increased the infiltration of cytotoxic T cells while it decreased PD-1 expression, therefore enhancing antitumor immunity. One limitation of DCZ0415 is its effectiveness at high concentrations/doses [7, 80]. Hence, developing novel, safe, and potent derivatives of DCZ0415 or exploring alternatives such as anti-TRIP13 antibodies or TRIP13 short hairpin RNA viruses is critical. These innovations could be instrumental in future clinical studies, offering improved efficacy and broader applicability in cancer therapy.

AUTHOR CONTRIBUTIONS

Shengnan Jing: Project administration (equal); writing—original draft (equal). Liya Zhao: Investigation (equal). Liwen Zhao: Software (equal). Yong-Jing Gao: Supervision (equal); writing—review and editing (equal). Tianzhen He: Investigation (equal); supervision (equal); writing—original draft (equal); writing—review and editing (equal).

ACKNOWLEDGMENTS

None.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

ETHICS STATEMENT

Not applicable.

INFORMED CONSENT

Not applicable.

Open Research

DATA AVAILABILITY STATEMENT

Data from this study are available upon request from the authors.

Supporting Information

REFERENCES

1Chen C, Jomaa A, Ortega J, Alani EE. Pch2 is a hexameric ring ATPase that remodels the chromosome axis protein Hop1. Proc Nat Acad Sci. 2014; 111(1): E44–E53. https://doi.org/10.1073/pnas.1310755111
10.1073/pnas.1310755111
CAS PubMed Google Scholar
2Yedidi RS, Wendler P, Enenkel C. AAA-ATPases in protein degradation. Front Mol Biosci. 2017; 4:42. https://doi.org/10.3389/fmolb.2017.00042
10.3389/fmolb.2017.00042
PubMed Web of Science® Google Scholar
3Tipton AR, Wang K, Oladimeji P, Sufi S, Gu Z, Liu ST. Identification of novel mitosis regulators through data mining with human centromere/kinetochore proteins as group queries. BMC Cell Biol. 2012; 13:15. https://doi.org/10.1186/1471-2121-13-15
10.1186/1471-2121-13-15
CAS PubMed Web of Science® Google Scholar
4Zhu MX, Wei CY, Zhang PF, Gao DM, Chen J, Zhao Y, et al. Elevated TRIP13 drives the AKT/mTOR pathway to induce the progression of hepatocellular carcinoma via interacting with ACTN4. J Exp Clin Cancer Res. 2019; 38(1): 409. https://doi.org/10.1186/s13046-019-1401-y
10.1186/s13046-019-1401-y
PubMed Web of Science® Google Scholar
5Li C, Xia J, Franqui-Machin R, Chen F, He Y, Ashby TC, et al. TRIP13 modulates protein deubiquitination and accelerates tumor development and progression of B cell malignancies. J Clin Invest. 2021; 131(14):e146893. https://doi.org/10.1172/JCI146893
10.1172/JCI146893
CAS PubMed Google Scholar
6Gao Y, Liu S, Guo Q, Zhang S, Zhao Y, Wang H, et al. Increased expression of TRIP13 drives the tumorigenesis of bladder cancer in association with the EGFR signaling pathway. Int J Biol Sci. 2019; 15(7): 1488–1499. https://doi.org/10.7150/ijbs.32718
10.7150/ijbs.32718
CAS PubMed Web of Science® Google Scholar
7Agarwal S, Afaq F, Bajpai P, Kim HG, Elkholy A, Behring M, et al. DCZ0415, a small-molecule inhibitor targeting TRIP13, inhibits EMT and metastasis via inactivation of the FGFR4/STAT3 axis and the Wnt/β-catenin pathway in colorectal cancer. Mol Oncol. 2022; 16(8): 1728–1745. https://doi.org/10.1002/1878-0261.13201
10.1002/1878-0261.13201
CAS PubMed Web of Science® Google Scholar
8Sheng N, Yan L, Wu K, You W, Gong J, Hu L, et al. TRIP13 promotes tumor growth and is associated with poor prognosis in colorectal cancer. Cell Death Dis. 2018; 9(3): 402. https://doi.org/10.1038/s41419-018-0434-z
10.1038/s41419-018-0434-z
PubMed Web of Science® Google Scholar
9Banerjee R, Russo N, Liu M, Basrur V, Bellile E, Palanisamy N, et al. TRIP13 promotes error-prone nonhomologous end joining and induces chemoresistance in head and neck cancer. Nat Commun. 2014; 5: 4527. https://doi.org/10.1038/ncomms5527
10.1038/ncomms5527
CAS PubMed Web of Science® Google Scholar
10Lan J, Huang J, Tao X, Gao Y, Zhang L, Huang W, et al. Evaluation of the TRIP13 level in breast cancer and insights into potential molecular pathways. J Cell Mol Med. 2022; 26(9): 2673–2685. https://doi.org/10.1111/jcmm.17278
10.1111/jcmm.17278
CAS PubMed Web of Science® Google Scholar
11Li ZH, Lei L, Fei LR, Huang WJ, Zheng YW, Yang MQ, et al. TRIP13 promotes the proliferation and invasion of lung cancer cells via the Wnt signaling pathway and epithelial-mesenchymal transition. J Mol Histol. 2021; 52(1): 11–20. https://doi.org/10.1007/s10735-020-09919-z
10.1007/s10735-020-09919-z
CAS PubMed Web of Science® Google Scholar
12Yao J, Zhang X, Li J, Zhao D, Gao B, Zhou H, et al. Silencing TRIP13 inhibits cell growth and metastasis of hepatocellular carcinoma by activating of TGF-β1/smad3. Cancer Cell Int. 2018; 18: 208. https://doi.org/10.1186/s12935-018-0704-y
10.1186/s12935-018-0704-y
CAS PubMed Web of Science® Google Scholar
13Dong L, Ding H, Li Y, Xue D, Li Z, Liu Y, et al. TRIP13 is a predictor for poor prognosis and regulates cell proliferation, migration and invasion in prostate cancer. Int J Biiol Macromol. 2019; 121: 200–206. https://doi.org/10.1016/j.ijbiomac.2018.09.168
10.1016/j.ijbiomac.2018.09.168
CAS PubMed Web of Science® Google Scholar
14Tao Y, Yang G, Yang H, Song D, Hu L, Xie B, et al. TRIP13 impairs mitotic checkpoint surveillance and is associated with poor prognosis in multiple myeloma. Oncotarget. 2017; 8(16): 26718–26731. https://doi.org/10.18632/oncotarget.14957
10.18632/oncotarget.14957
PubMed Google Scholar
15Zhou KS, Zhang Q, Zhang WT, Liu YY, Wu SS, Zhou J, et al. Study on the expression of TRIP13 mRNA in chronic lymphocytic leukemia B lymphocyte and the molecular mechanism of TRIP13 mediated JVM-2 cell proliferation and apoptosis. Zhonghua Xue Ye Xue Za Zhi. 2017; 38(7): 618–622. https://doi.org/10.3760/cma.j.issn.0253-2727.2017.07.013
10.3760/cma.j.issn.0253-2727.2017.07.013
CAS PubMed Google Scholar
16Li W, Zhang G, Li X, Wang X, Li Q, Hong L, et al. Thyroid hormone receptor interactor 13 (TRIP13) overexpression associated with tumor progression and poor prognosis in lung adenocarcinoma. Biochem Biophys Res Commun. 2018; 499(3): 416–424. https://doi.org/10.1016/j.bbrc.2018.03.129
10.1016/j.bbrc.2018.03.129
CAS PubMed Web of Science® Google Scholar
17Rios Garcia M, Meissburger B, Chan J, de Guia RM, Mattijssen F, Roessler S, et al. Trip13 depletion in liver cancer induces a lipogenic response contributing to Plin2-dependent mitotic cell death. Adv Sci. 2022; 9(29):e2104291. https://doi.org/10.1002/advs.202104291
10.1002/advs.202104291
CAS Google Scholar
18Ju L, Li X, Shao J, Lu R, Wang Y, Bian Z. Upregulation of thyroid hormone receptor interactor 13 is associated with human hepatocellular carcinoma. Oncol Rep. 2018; 40(6): 3794–3802. https://doi.org/10.3892/or.2018.6767
10.3892/or.2018.6767
CAS PubMed Web of Science® Google Scholar
19Lu W, Mengxuan Z, Ming R, Zixu G, Yong Z, Simin Z, et al. TRIP13/FLNA complex promotes tumor progression and is associated with unfavorable outcomes in melanoma. J Oncol. 2022; 2022:1419179. https://doi.org/10.1155/2022/1419179
10.1155/2022/1419179
PubMed Google Scholar
20Ye Q, Lau RK, Mathews IT, Birkholz EA, Watrous JD, Azimi CS, et al. HORMA domain proteins and a Trip13-like ATPase regulate bacterial cGAS-like enzymes to mediate bacteriophage immunity. Mol Cell. 2020; 77(4): 709–722. https://doi.org/10.1016/j.molcel.2019.12.009
10.1016/j.molcel.2019.12.009
CAS PubMed Web of Science® Google Scholar
21Lu S, Qian J, Guo M, Gu C, Yang Y. Insights into a crucial role of TRIP13 in human cancer. Comput Struct Biotechnol J. 2019; 17: 854–861. https://doi.org/10.1016/j.csbj.2019.06.005
10.1016/j.csbj.2019.06.005
CAS PubMed Web of Science® Google Scholar
22Vader G. Pch2TRIP13: controlling cell division through regulation of HORMA domains. Chromosoma. 2015; 124(3): 333–339. https://doi.org/10.1007/s00412-015-0516-y
10.1007/s00412-015-0516-y
CAS PubMed Web of Science® Google Scholar
23Mapelli M, Massimiliano L, Santaguida S, Musacchio A. The Mad2 conformational dimer: structure and implications for the spindle assembly checkpoint. Cell. 2007; 131(4): 730–743. https://doi.org/10.1016/j.cell.2007.08.049
10.1016/j.cell.2007.08.049
CAS PubMed Web of Science® Google Scholar
24Marks DH, Thomas R, Chin Y, Shah R, Khoo C, Benezra R. Mad2 overexpression uncovers a critical role for TRIP13 in mitotic exit. Cell Rep. 2017; 19(9): 1832–1845. https://doi.org/10.1016/j.celrep.2017.05.021
10.1016/j.celrep.2017.05.021
CAS PubMed Web of Science® Google Scholar
25Yang M, Li B, Tomchick DR, Machius M, Rizo J, Yu H, et al. p31comet blocks Mad2 activation through structural mimicry. Cell. 2007; 131(4): 744–755. https://doi.org/10.1016/j.cell.2007.08.048
10.1016/j.cell.2007.08.048
CAS PubMed Web of Science® Google Scholar
26San-Segundo PA, Roeder GS. Pch2 links chromatin silencing to meiotic checkpoint control. Cell. 1999; 97(3): 313–324. https://doi.org/10.1016/s0092-8674(00)80741-2
10.1016/S0092-8674(00)80741-2
CAS PubMed Web of Science® Google Scholar
27Roig I, Dowdle JA, Toth A, de Rooij DG, Jasin M, Keeney S. Mouse TRIP13/PCH2 is required for recombination and normal higher-order chromosome structure during meiosis. PLoS Genet. 2010; 6(8):e1001062. https://doi.org/10.1371/journal.pgen.1001062
10.1371/journal.pgen.1001062
PubMed Web of Science® Google Scholar
28Rosenberg SC, Corbett KD. The multifaceted roles of the HORMA domain in cellular signaling. J Cell Biol. 2015; 211(4): 745–755. https://doi.org/10.1083/jcb.201509076
10.1083/jcb.201509076
CAS PubMed Web of Science® Google Scholar
29Wojtasz L, Daniel K, Roig I, Bolcun-Filas E, Xu H, Boonsanay V, et al. Mouse HORMAD1 and HORMAD2, two conserved meiotic chromosomal proteins, are depleted from synapsed chromosome axes with the help of TRIP13 AAA-ATPase. PLoS Genet. 2009; 5(10):e1000702. https://doi.org/10.1371/journal.pgen.1000702
10.1371/journal.pgen.1000702
PubMed Web of Science® Google Scholar
30Furlong F, Fitzpatrick P, O'Toole S, Phelan S, McGrogan B, Maguire A, et al. Low MAD2 expression levels associate with reduced progression-free survival in patients with high-grade serous epithelial ovarian cancer. J Pathol. 2012; 226(5): 746–755. https://doi.org/10.1002/path.3035
10.1002/path.3035
CAS PubMed Web of Science® Google Scholar
31Zhou XY, Shu XM. TRIP13 promotes proliferation and invasion of epithelial ovarian cancer cells through Notch signaling pathway. Eur Rev Med Pharmacol Sci. 2019; 23(2): 522–529. https://doi.org/10.26355/eurrev_201901_16864
10.26355/eurrev_201901_16864
PubMed Web of Science® Google Scholar
32Bense RD, Sotiriou C, Piccart-Gebhart MJ, Haanen JBAG, van Vugt MATM, de Vries EGE, et al. Relevance of tumor-infiltrating immune cell composition and functionality for disease outcome in breast cancer. J Natl Cancer Inst. 2017; 109(1):djw192. https://doi.org/10.1093/jnci/djw192
10.1093/jnci/djw192
PubMed Google Scholar
33Xu Y, Lan S, Zheng Q. Prognostic significance of infiltrating immune cell subtypes in invasive ductal carcinoma of the breast. Tumori J. 2018; 104(3): 196–201. https://doi.org/10.5301/tj.5000624
10.5301/tj.5000624
CAS PubMed Google Scholar
34Zhou R, Zhang J, Zeng D, Sun H, Rong X, Shi M, et al. Immune cell infiltration as a biomarker for the diagnosis and prognosis of stage I-III colon cancer. Cancer Immunol Immunother. 2019; 68(3): 433–442. https://doi.org/10.1007/s00262-018-2289-7
10.1007/s00262-018-2289-7
CAS PubMed Web of Science® Google Scholar
35Denkert C, von Minckwitz G, Darb-Esfahani S, Lederer B, Heppner BI, Weber KE, et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol. 2018; 19(1): 40–50. https://doi.org/10.1016/S1470-2045(17)30904-X
10.1016/S1470-2045(17)30904-X
PubMed Web of Science® Google Scholar
36Desmedt C, Haibe-Kains B, Wirapati P, Buyse M, Larsimont D, Bontempi G, et al. Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes. Clin Cancer Res. 2008; 14(16): 5158–5165. https://doi.org/10.1158/1078-0432.CCR-07-4756
10.1158/1078-0432.CCR-07-4756
CAS PubMed Web of Science® Google Scholar
37Denkert C, Loibl S, Noske A, Roller M, Müller BM, Komor M, et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2010; 28(1): 105–113. https://doi.org/10.1200/JCO.2009.23.7370
10.1200/JCO.2009.23.7370
CAS PubMed Web of Science® Google Scholar
38Denkert C, von Minckwitz G, Brase JC, Sinn BV, Gade S, Kronenwett R, et al. Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J Clin Oncol. 2015; 33(9): 983–991. https://doi.org/10.1200/jco.2014.58.1967
10.1200/JCO.2014.58.1967
CAS PubMed Web of Science® Google Scholar
39Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol. 2014; 25(8): 1544–1550. https://doi.org/10.1093/annonc/mdu112
10.1093/annonc/mdu112
CAS PubMed Web of Science® Google Scholar
40Okcu O, Öztürk SD, Öztürk Ç, Şen B, Yasin Aİ, Bedir R. Tumor-infiltrating lymphocytes (TILs)/volume and prognosis: the value of TILs for survival in HER2 and TN breast cancer patients treated with chemotherapy. Ann Diagn Pathol. 2022; 58:151930. https://doi.org/10.1016/j.anndiagpath.2022.151930
10.1016/j.anndiagpath.2022.151930
PubMed Google Scholar
41Angelico G, Broggi G, Tinnirello G, Puzzo L, Vecchio GM, Salvatorelli L, et al. Tumor infiltrating lymphocytes (TILS) and PD-L1 expression in breast cancer: a review of current evidence and prognostic implications from pathologist's perspective. Cancers. 2023; 15(18):4479. https://doi.org/10.3390/cancers15184479
10.3390/cancers15184479
CAS PubMed Web of Science® Google Scholar
42Tramm T, Vinter H, Vahl P, Özcan D, Alsner J, Overgaard J. Tumor-infiltrating lymphocytes predict improved overall survival after post-mastectomy radiotherapy: a study of the randomized DBCG82bc cohort. Acta Oncol. 2022; 61(2): 153–162. https://doi.org/10.1080/0284186X.2021.1989629
10.1080/0284186X.2021.1989629
CAS PubMed Google Scholar
43Jiang D, Liu Y, Wang H, Wang H, Song Q, Sujie A, et al. Tumour infiltrating lymphocytes correlate with improved survival in patients with esophageal squamous cell carcinoma. Sci Rep. 2017; 7:44823. https://doi.org/10.1038/srep44823
10.1038/srep44823
CAS PubMed Web of Science® Google Scholar
44Cao B, Zhang Z, Wang C, Lv X. Prognostic relevance of tumor-infiltrating lymphocytes in residual tumor tissue from patients with triple-negative breast cancer following neoadjuvant chemotherapy: a systematic review and meta-analysis. Oncol Lett. 2023; 26(4): 441. https://doi.org/10.3892/ol.2023.14028
10.3892/ol.2023.14028
CAS PubMed Google Scholar
45Loi S, Sirtaine N, Piette F, Salgado R, Viale G, van Eenoo F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013; 31(7): 860–867. https://doi.org/10.1200/JCO.2011.41.0902
10.1200/JCO.2011.41.0902
CAS PubMed Web of Science® Google Scholar
46Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, et al. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol. 2014; 32(27): 2959–2966. https://doi.org/10.1200/jco.2013.55.0491
10.1200/JCO.2013.55.0491
PubMed Web of Science® Google Scholar
47Kreike B, van Kouwenhove M, Horlings H, Weigelt B, Peterse H, Bartelink H, et al. Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas. Breast Cancer Res. 2007; 9(5): R65. https://doi.org/10.1186/bcr1771
10.1186/bcr1771
CAS PubMed Web of Science® Google Scholar
48de Visser KE, Korets LV, Coussens LM. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell. 2005; 7(5): 411–423. https://doi.org/10.1016/j.ccr.2005.04.014
10.1016/j.ccr.2005.04.014
CAS PubMed Web of Science® Google Scholar
49Woo EY, Yeh H, Chu CS, Schlienger K, Carroll RG, Riley JL, et al. Cutting edge: regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J Immunol. 2002; 168(9): 4272–4276. https://doi.org/10.4049/jimmunol.168.9.4272
10.4049/jimmunol.168.9.4272
CAS PubMed Google Scholar
50Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris AL, et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol. 2006; 24(34): 5373–5380. https://doi.org/10.1200/jco.2006.05.9584
10.1200/JCO.2006.05.9584
PubMed Web of Science® Google Scholar
51Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007; 25(18): 2586–2593. https://doi.org/10.1200/jco.2006.09.4565
10.1200/JCO.2006.09.4565
PubMed Web of Science® Google Scholar
52Shimizu J, Yamazaki S, Sakaguchi S. Induction of tumor immunity by removing CD25+ CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol. 1999; 163(10): 5211–5218. https://doi.org/10.4049/jimmunol.163.10.5211
10.4049/jimmunol.163.10.5211
CAS PubMed Web of Science® Google Scholar
53Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res. 1999; 59(13): 3128–3133.
CAS PubMed Web of Science® Google Scholar
54Choi J, Gyamfi J, Jang H, Koo JS. The role of tumor-associated macrophage in breast cancer biology. Histol Histopathol. 2018; 33(2): 133–145. https://doi.org/10.14670/HH-11-916
10.14670/HH-11-916
CAS PubMed Web of Science® Google Scholar
55Allavena P, Sica A, Solinas G, Porta C, Mantovani A. The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol. 2008; 66(1): 1–9. https://doi.org/10.1016/j.critrevonc.2007.07.004
10.1016/j.critrevonc.2007.07.004
PubMed Web of Science® Google Scholar
56Sica A, Bronte V. Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest. 2007; 117(5): 1155–1166. https://doi.org/10.1172/jci31422
10.1172/JCI31422
CAS PubMed Web of Science® Google Scholar
57de Palma M, Venneri MA, Galli R, Sergi LS, Politi LS, Sampaolesi M, et al. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell. 2005; 8(3): 211–226. https://doi.org/10.1016/j.ccr.2005.08.002
10.1016/j.ccr.2005.08.002
PubMed Google Scholar
58Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or Hyde. Cancer Metastasis Rev. 2007; 26(3–4): 373–400. https://doi.org/10.1007/s10555-007-9072-0
10.1007/s10555-007-9072-0
PubMed Web of Science® Google Scholar
59Murdoch C, Muthana M, Coffelt SB, Lewis CE. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer. 2008; 8(8): 618–631. https://doi.org/10.1038/nrc2444
10.1038/nrc2444
CAS PubMed Web of Science® Google Scholar
60Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity. 2010; 32(5): 593–604. https://doi.org/10.1016/j.immuni.2010.05.007
10.1016/j.immuni.2010.05.007
CAS PubMed Web of Science® Google Scholar
61Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M, et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004; 25(12): 677–686. https://doi.org/10.1016/j.it.2004.09.015
10.1016/j.it.2004.09.015
CAS PubMed Web of Science® Google Scholar
62Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008; 8: 958–969. https://doi.org/10.1038/nri2448
10.1038/nri2448
CAS PubMed Web of Science® Google Scholar
63Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004; 4(1): 71–78. https://doi.org/10.1038/nrc1256
10.1038/nrc1256
CAS PubMed Web of Science® Google Scholar
64Condeelis J, Pollard JW. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 2006; 124(2): 263–266. https://doi.org/10.1016/j.cell.2006.01.007
10.1016/j.cell.2006.01.007
CAS PubMed Web of Science® Google Scholar
65Walzer T, Jaeger S, Chaix J, Vivier E. Natural killer cells: from CD3− NKp46+ to post-genomics meta-analyses. Curr Opin Immunol. 2007; 19(3): 365–372. https://doi.org/10.1016/j.coi.2007.04.004
10.1016/j.coi.2007.04.004
CAS PubMed Web of Science® Google Scholar
66Waldhauer I, Steinle A. NK cells and cancer immunosurveillance. Oncogene. 2008; 27(45): 5932–5943. https://doi.org/10.1038/onc.2008.267
10.1038/onc.2008.267
CAS PubMed Web of Science® Google Scholar
67Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol. 2008; 9(5): 503–510. https://doi.org/10.1038/ni1582
10.1038/ni1582
CAS PubMed Web of Science® Google Scholar
68Brunda MJ, Rosenbaum D, Stern L. Inhibition of experimentally-induced murine metastases by recombinant alpha interferon: correlation between the modulatory effect of interferon treatment on natural killer cell activity and inhibition of metastases. Int J Cancer. 1984; 34(3): 421–426. https://doi.org/10.1002/ijc.2910340321
10.1002/ijc.2910340321
CAS PubMed Web of Science® Google Scholar
69Gorelik E, Herberman RB. Susceptibility of various strains of mice to urethan-induced lung tumors and depressed natural killer cell activity. J Natl Cancer Inst. 1981; 67(6): 1317–1322. https://doi.org/10.1093/jnci/67.6.1317
10.1093/jnci/67.6.1317
CAS PubMed Google Scholar
70Gorelik E, Kedar E, Sredni B, Herberman R. In vivo anti-tumor effects of local adoptive transfer of mouse and human cultured lymphoid cells. Int J Cancer. 1981; 28(2): 157–164. https://doi.org/10.1002/ijc.2910280208
10.1002/ijc.2910280208
CAS PubMed Web of Science® Google Scholar
71Hinuma S, Naruo K, Ootsu K, Houkan T, Shiho O, Tsukamoto K. Suppression of pulmonary tumour metastasis in mice by recombinant human interleukin-2: role of asialo GM1-positive cells. Immunology. 1987; 60(2): 173–179.
CAS PubMed Google Scholar
72Melaiu O, Lucarini V, Cifaldi L, Fruci D. Influence of the tumor microenvironment on NK cell function in solid tumors. Front Immunol. 2020; 10:3038. https://doi.org/10.3389/fimmu.2019.03038
10.3389/fimmu.2019.03038
PubMed Web of Science® Google Scholar
73Steinman RM. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 1991; 9: 271–296. https://doi.org/10.1146/annurev.iy.09.040191.001415
10.1146/annurev.iy.09.040191.001415
CAS PubMed Web of Science® Google Scholar
74Youn JI, Nagaraj S, Collazo M, Gabrilovich DI. Subsets of myeloid-derived suppressor cells in tumor-bearing mice. J Immunol. 2008; 181(8): 5791–5802. https://doi.org/10.4049/jimmunol.181.8.5791
10.4049/jimmunol.181.8.5791
CAS PubMed Web of Science® Google Scholar
75Coussens LM, Raymond WW, Bergers G, Laig-Webster M, Behrendtsen O, Werb Z, et al. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev. 1999; 13(11): 1382–1397. https://doi.org/10.1101/gad.13.11.1382
10.1101/gad.13.11.1382
CAS PubMed Web of Science® Google Scholar
76Ghaffari S, Rezaei N. Eosinophils in the tumor microenvironment: implications for cancer immunotherapy. J Transl Med. 2023; 21(1): 551. https://doi.org/10.1186/s12967-023-04418-7
10.1186/s12967-023-04418-7
CAS PubMed Web of Science® Google Scholar
77Fang Y, Herrick EJ, Nicholl MB. A possible role for perforin and granzyme B in resveratrol-enhanced radiosensitivity of prostate cancer. J Androl. 2012; 33(4): 752–760. https://doi.org/10.2164/jandrol.111.015164
10.2164/jandrol.111.015164
CAS PubMed Web of Science® Google Scholar
78Wang Y, Huang J, Li B, Xue H, Tricot G, Hu L, et al. A small-molecule inhibitor targeting TRIP13 suppresses multiple myeloma progression. Cancer Res. 2020; 80(3): 536–548. https://doi.org/10.1158/0008-5472.can-18-3987
10.1158/0008-5472.CAN-18-3987
CAS PubMed Web of Science® Google Scholar
79Xue J, Wu H, Shi Y, Li Z. TRIP13 overexpression in hepatocellular carcinoma: implications for poor prognosis and immune cell infiltration. Discov Oncol. 2023; 14(1): 176. https://doi.org/10.1007/s12672-023-00792-2
10.1007/s12672-023-00792-2
CAS PubMed Google Scholar
80Afaq F, Agarwal S, Bajpai P, Diffalha SA, Kim HG, Peter S, et al. Targeting of oncogenic AAA-ATPase TRIP13 reduces progression of pancreatic ductal adenocarcinoma. Neoplasia. 2024; 47:100951. https://doi.org/10.1016/j.neo.2023.100951
10.1016/j.neo.2023.100951
CAS PubMed Google Scholar
81Zou S, Tong Q, Liu B, Huang W, Tian Y, Fu X. Targeting STAT3 in cancer immunotherapy. Mol Cancer. 2020; 19(1): 145. https://doi.org/10.1186/s12943-020-01258-7
10.1186/s12943-020-01258-7
CAS PubMed Web of Science® Google Scholar
82Lu C, Liu Y, Ali NM, Zhang B, Cui X. The role of innate immune cells in the tumor microenvironment and research progress in anti-tumor therapy. Front Immunol. 2023; 13:1039260. https://doi.org/10.3389/fimmu.2022.1039260
10.3389/fimmu.2022.1039260
PubMed Google Scholar
83Chen W, Zhao X, Lu Y, Wang H, Wang X, Wang Y, et al. Clinical significance, molecular characterization, and immune microenvironment analysis of coagulation-related genes in clear cell renal cell carcinoma. Cancer Innov. 2024; 3(1):e105. https://doi.org/10.1002/cai2.105
10.1002/cai2.105
CAS PubMed Google Scholar

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Volume3, Issue6

December 2024

e147

TRIP13: A promising cancer immunotherapy target

Abstract

Abbreviations

1 INTRODUCTION

2 THE ROLE OF TRIP13 IN PHYSIOLOGICAL PROCESSES

3 THE ROLE OF TRIP13 IN CANCER

4 TRIP13 AND IMMUNE CELL INFILTRATION

4.1 Roles of infiltrating immune cells in the TME

4.2 TRIP13 inhibits antitumor immune responses

4.3 The molecular mechanism of TRIP13 in antitumor immune responses

5 TRIP13 IS A POTENTIAL REGULATOR OF TUMOR IMMUNE INFILTRATION

6 DISCUSSION AND CONCLUSIONS

AUTHOR CONTRIBUTIONS

ACKNOWLEDGMENTS

CONFLICT OF INTEREST STATEMENT

ETHICS STATEMENT

INFORMED CONSENT

Open Research

DATA AVAILABILITY STATEMENT

Supporting Information

REFERENCES

Citing Literature

Figures

References

Information

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TRIP13: A promising cancer immunotherapy target

Abstract

Abbreviations

1 INTRODUCTION

2 THE ROLE OF TRIP13 IN PHYSIOLOGICAL PROCESSES

3 THE ROLE OF TRIP13 IN CANCER

4 TRIP13 AND IMMUNE CELL INFILTRATION

4.1 Roles of infiltrating immune cells in the TME

4.2 TRIP13 inhibits antitumor immune responses

4.3 The molecular mechanism of TRIP13 in antitumor immune responses

5 TRIP13 IS A POTENTIAL REGULATOR OF TUMOR IMMUNE INFILTRATION

6 DISCUSSION AND CONCLUSIONS

AUTHOR CONTRIBUTIONS

ACKNOWLEDGMENTS

CONFLICT OF INTEREST STATEMENT

ETHICS STATEMENT

INFORMED CONSENT

Open Research

DATA AVAILABILITY STATEMENT

Supporting Information

REFERENCES

Citing Literature

Figures

References

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