Dual-specificity phosphatases (DUSPs) are a subset of protein tyrosine phosphatases (PTPs), many of which dephosphorylate the residues of phosphor-serine/threonine and phosphor-tyrosine on mitogen-activated protein kinases (MAPKs), and hence are also referred to as MAPK phosphatases (MKPs). Homologue of Vaccinia virus H1 phosphatase gene clone 5 (HVH-5), also known as DUSP8, is a unique member of the DUSPs family of phosphatases. Accumulating evidence has shown that DUSP8 plays an important role in phosphorylation-mediated signal transduction of MAPK signaling ranging from cell oxidative stress response, cell apoptosis and various human diseases. It is generally believed that DUSP8 exhibits significant dephosphorylation activity against JNK, however, with the deepening of research, plenty of new literature reports that DUSP8 also has effective dephosphorylation activity on p38 MAPK and ERKs, successfully affects the transduction of MAPKs pathway, indicating that DUSP8 presents a unknown diversity of DUSPs family on distinct corresponding dephosphorylated substrates in different biological events. Therefore, the in-depth study of DUSP8 not only throws a new light on the multi-biological function of DUSPs, but also is much valuable for the reveal of complex pathobiology of clinical diseases. In this review, we provide a detail overview of DUSP8 phosphatase structure, biological function and expression regulation, as well as its role in related clinical human diseases, which might be help for the understanding of biological function of DUSP8 and the development of prevention, diagnosis and therapeutics in related human diseases.
Tumor-associated macrophages (TAMs) are crucially associated with tumor development and progression; however, it remains unclear how the tumor microenvironment (TME) rewires the metabolic circuits and preferentially induces TAMs to polarize toward a protumoral phenotype. Here, we report that polyunsaturated fatty acids (PUFAs) in malignant ascites promote protumoral M2-like TAMs deposition and facilitate peritoneal metastases of epithelial ovarian cancer (EOC). We demonstrated that PUFAs in the lipid-enriched malignant ascites inactivate RhoA, reducing nuclear YAP1 in macrophages and promoting protumoral M2-like TAMs polarization with OXPHOS metabolism. Conditional Yap1 depletion in murine MΦs leads to skew macrophage polarization toward protumoral M2-like TAMs that, in turn, suppress CD8+ T cell infiltration and aggravate tumor colonization in vivo. Noticeably, the significance of nuclear YAP1 depletion was evinced in the infiltrating TAMs in tumor spheroids of malignant ascites from EOC patients. In contrast, restored nuclear YAP1 expression in TAMs by pharmacological suppression of MST1/2 enhances tumoricidal M1-like TAMs population and CD8+ T cells infiltration, restricting EOC peritoneal metastasis. These results indicate that PUFAs are a key player in promoting tumor-infiltrated TAMs polarization that, in turn, facilitates EOC tumor growth and metastasis.
Ovarian cancer is one of the most severe gynecologic malignancies with high mortality. Although programmed cell death 1 (PD-1) or PD-ligand 1 (PD-L1) immune checkpoint blockade (ICBs) has been used therapeutically in gynecologic cancers and has a clinically significant response in endometrial cancer, the response rate remains poor and has no different from the conventional therapies in ovarian cancer. The highly immunosuppressive microenvironment in ovarian cancer, consisting of inhibitory ligands, suppressive mediators, and cell subsets, leads to CD8+ T cell dysfunction and exhaustion and contributes to the limited efficacy of immunotherapeutic approaches. Correlative human studies have highlighted the potential importance of chemokines on the status of CD8+ T cell infiltration into tumors and on patient survival. Here, we show that CXCL10, an IFN-γ induced chemokine, derived from ovarian cancer cells, contributes to impairing CD8+ T cell antitumor immunity by regulating CD8+ T cell exhaustion in the tumor microenvironment. Clinically, we found that CXCL10 and its receptor CXCR3 had a strong positive correlation with exhausted T cell signature genes in ovarian cancer patients in TCGA and in-house cohort. Functionally, we showed that CD8+ T cell exhaustion was induced by CXCL10 activation by CRISPRa from ovarian cancer cells, whereas inhibition by CRISPRi restored CD8+ T cell antitumor immunity ex vivo and in vivo. Mechanically, ovarian cancer cells-derived CXCL10 induced the expression of CD8+ T cells exhaustion transcription factors in a CXCR3-dependent manner, driving PD-1 and TIM-3 expression on CD8+ T cells. Therapeutically, suppressing CXCL10 secretion from ovarian cancer cells enhanced the response to anti-PD-1 immunotherapy in the orthotopic mouse model. The results suggest that selectively inhibiting the oncogenic CXCL10 production may work effectively with ICBs in ovarian cancer immunotherapy. Our findings advance the understanding of the low response rate of immunotherapy in ovarian cancer and explore the potential mechanism underlying the induction of CD8+ T cell exhaustion in the tumor microenvironment. Citation Format: Runying Long, Tao Ding, Michelle K.L Siu, David W Chan, Jiangnan He, Annie NY Cheung, Kwan Man, Hextan YS NGAN, Karen KL Chan. Oncogenic CXCL10 triggers CD8+ T cell exhaustion in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 617.
Introduction: Sterol-O acyltransferase 1 (SOAT1) functions by converting cholesterol and acyl-CoA into cholesterol ester and coA-SH. High SOAT1 expression with its mediated tumorigenesis has been shown in multiple cancers. Studies showed that SOAT1 inhibition by its inhibitors augmented the outcome of immunotherapies, in terms of the immune checkpoint blockades, cancer vaccines, and CAR-T cells, by boosting the function of T cells. However, in order to have a better understanding of the role played by SOAT1 in the tumor microenvironment of ovarian cancer (OC) and optimize strategies of combination immunotherapy, it’s necessary to detect the role of SOAT1 in OC cells on T cell-mediated immune response. Methods: SOAT1 knockdown was manipulated by siRNAs transfection. SOAT1 was inhibited by avasimibe and OC cells were treated in different doses of avasimibe. qPCR was performed to detect gene expressions in ovarian cancer cells. T cells, isolated and activated from healthy donors, were cocultured with SOAT1-silenced and avasimibe pre-treated OC cells and their tumor-conditioned medium (TCM). Flow cytometry analysis was used to measure cytotoxic secretory molecules of human T cells, like IFN-r, TNF-a, and Granzyme B. Results: The downregulation of intracellular cytotoxic cytokines was shown in the T cells cocultured with SOAT1-silenced and avasimibe-pretreated OC cells or treated by their TCM, thereby impairing the cytotoxic capacity of T cells, compared to the corresponding control group. qPCR results showed that several immunosuppressive cytokines, like IL-6, IL-8, TGF- were upregulated in the SOAT1-silenced or avasimibe-treated OC cells. Conclusion: SOAT1 inhibition in ovarian tumor cells impairs CD8+ T cell cytotoxic function, to some extent, via the upregulation of immunosuppressive-related cytokines. Citation Format: Jiangnan He, Michelle K.Y. Siu, Runying Long, Ruiqian Zhang, Mingo M.H. Yung, Hextan Y. S. Ngan, Karen K.L. Chan. The role of SOAT1 on CD8+T cells-mediated immune response in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5880.
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