Cisplatin and gemcitabine exert opposite effects on immunotherapy with PD-1 antibody in K-ras-driven cancer

Immunochemotherapy using PD-1/PD-L1 antibodies in combination with chemotherapeutic agents has become a mainstream treatment for cancer patients, but it remains unclear which drug combinations would produce best therapeutic outcome. The purpose of this study was to investigate two common chemotherapeutic drugs, gemcitabine and cisplatin, for their impacts on the therapeutic efficacy of PD-1 antibody in K-ras-driven cancers known to overexpress PD-L1. Both in vitro assays and syngeneic mouse tumor models were used in this study. Biochemical and molecular assays were used to determine the effects of drugs on T cell functions in cell culture models and in mouse/human tumor tissues. Allograft tumor models with K-ras mutation were used to investigate the combination effect of gemcitabine or cisplatin with immunotherapy. Data of lung cancer patients with K-ras mutation treated with cisplatin and toripalimab were analyzed to evaluate the clinical relevance of the lab findings. Cisplatin and gemcitabine unexpectedly exert opposite effect on the therapeutic activity of PD-1 antibody in vivo. Gemcitabine antagonizes the therapeutic effect of PD-1 antibody due to its significant inhibition on CD8+ T cell infiltration, which was observed both in mouse tumor allografts and in human pancreatic cancer tissues. In contrast, cisplatin shows synergistic activity with PD-1 antibody by activation of CD8+ T cells through the DNA damage-mediated cGAS-STING sensing mechanism, leading to increase of T cell infiltration and secretion of antitumor cytokines. Clinical data show that a combination of cisplatin with PD-1 antibody toripalimab could be effective in advanced lung cancer patients with K-ras mutation who failed prior therapies. Our study shows that a key factor in selecting chemotherapeutic agents for immunochemotherapy is the drug’s impact on T cell functions, and that cisplatin-based chemotherapy is an excellent choice for combination with immune checkpoint antibody to achieve favorable clinical outcome.