The impact of CXCL10 derived from ovarian cancer cells on CD8+ T cell antitumor immunity

Abstract

Ovarian cancer is among the most aggressive gynecologic malignancies threatening women’s health worldwide. Immunotherapies with immune checkpoint blockades (ICBs), such as programmed cell death 1 (PD-1) or PD-ligand 1 (PD-L1), have demonstrated considerable promise in treating various cancer types, including certain gynecological cancers like endometrial and cervical cancers. However, their effectiveness in ovarian cancer has been relatively limited. The highly immunosuppressive microenvironment in ovarian cancer, comprised of inhibitory ligands, suppressive cytokines, chemokines, and metabolic mediators, as well as specific cell subsets, leads to CD8+ T cell exhaustion, partially explains the limited efficacy of ICB therapies. Numerous studies have highlighted the crucial impact of chemokines on the differentiation and function status of CD8+ T cell infiltration into tumors and the prognosis of patients. Here, we elucidate that the interferon-gamma (IFN-γ) induced chemokine, CXCL10, originating from ovarian cancer cells, critically impaired CD8+ T cell antitumor immunity by regulating CD8+ T cell exhaustion within the tumor microenvironment. Clinically, we identified a strong positive association between CXCL10 and its receptor CXCR3 with exhausted T cell signature genes in the TCGA database, and this correlation was further verified in ovarian cancer patient tissue arrays by multiplex immunohistochemistry. Functionally, we demonstrated that IFN-γ induced the expression of CXCL10 in ovarian cancer cells, leading to CD8+ T cell exhaustion, whereas CXCL10 inhibition via CRISPRi restored CD8+ T cell antitumor immunity. Mechanically, our RNA-Seq analysis of the orthotopic ovarian cancer mouse model revealed that the knockout of Cxcl10 led to a downregulation of dual-specificity phosphatase 10 (DUSP10), which is involved in regulating JNK activity and influencing CD8+ T cell exhaustion. Therapeutically, we discovered that CXCL10-mediated CD8+ T cell exhaustion contributes to cancer progression. Suppressing CXCL10 secretion in ovarian cancer cells was found to inhibit tumor growth and prolong survival in the orthotopic ovarian cancer mouse model. Our findings discover the importance of CXCL10 in mediating CD8+ T cell exhaustion and suggest its potential as a therapeutic target in ovarian cancer treatment. Specifically, interventions aimed at inhibiting CXCL10 in cancer cells could potentially enhance the efficacy of immune checkpoint blockade immunotherapies by overcoming CD8+ T cell exhaustion.