T cell–derived IFNγ signaling shapes cancer chemosensitivity.
Major finding: T cell–derived IFNγ signaling shapes cancer chemosensitivity.
Mechanism: T-cell IFNγ reshapes glutathione and cysteine metabolism in fibroblasts, restoring chemosensitivity.
Impact: Immunotherapy may enhance chemotherapy in ovarian cancer by reducing chemoresistance.
Platinum-based chemotherapy often produces a positive initial response in patients with ovarian cancer, but drug resistance and relapse are common. Tumor-infiltrating T cells contribute to antitumor immunity, but whether CD8+ T cells affect chemoresistance remains unknown. Wang and colleagues investigated the interactions between CD8+ T cells, fibroblasts, and tumor cells, the main cellular components of the tumor microenvironment, and explored their role in chemoresistance. Co-culturing ovarian cancer cells with fibroblasts resulted in reduced apoptosis in response to cisplatin, and the addition of CD8+ T cells abolished the fibroblast-mediated chemoresistance. The enhancement of cisplatin sensitivity by CD8+ T cells required the production of IFNγ. Fibroblasts promoted cisplatin resistance by reducing the intracellular accumulation of cisplatin in the tumor cells, which could be reversed by IFNγ. Mechanistically, fibroblasts released glutathione (GSH) and cysteine (the rate-limiting substrate for GSH synthesis), which was taken up by tumor cells, resulting in increased intracellular GSH. GSH can chelate cisplatin, thereby reducing intracellular cisplatin accumulation and promoting chemoresistance. IFNγ promoted expression of gamma-glutamyltransferase 5 (GGT5), an enzyme that breaks down extracellular GSH. Therefore, IFNγ production by T cells can accelerate the degradation of GSH released by fibroblasts. Further, IFNγ activation of JAK/STAT signaling resulted in reduced expression of the system xc− cystine/glutamate antiporter, which exchanges extracellular cystine for intracellular glutamate. This resulted in reduced conversion of cystine to cysteine by fibroblasts, further restricting intracellular GSH in tumor cells. Examination of data from patients with high-grade serous ovarian carcinoma treated with platinum-based chemotherapy confirmed these results. High levels of tumor stromal fibroblasts correlated with chemoresistance, whereas high levels of CD8+ T cells correlated with chemosensitivity. Together, these findings indicate that the number of fibroblasts and CD8+ T cells affects the response to platinum chemotherapy, and suggest that immunotherapy may reduce resistance to platinum-based chemotherapy in patients with ovarian cancer.