Abstract 617: Oncogenic CXCL10 triggers CD8+ T cell exhaustion in ovarian cancer

Abstract 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.