T cell recruitment triggered by optimal dose platinum compounds contributes to the therapeutic efficacy of sequential PD-1 blockade in a mouse model of colon cancer

摘要

Recently, the combination of platinum chemotherapy with PD-1/PD-L1 pathway blockades has shown synergistic efficacy in a few clinical trials. However, the exact mechanisms and the optimized sequence of such combinations are not fully clear. In this study, we combined different doses of platinum agents (cisplatin or oxaliplatin) with sequential therapy of PD-1 blockade therapy (anti-PD-1 antibody or anti-PD-L1 antibody) to treat established MC38 murine colon tumors. Although 10 mg/kg platinum (cisplatin or oxaliplatin) showed no significant effect on tumor growth, its combination with sequential anti-PD-1 antibody administration caused complete tumor remission in 80-100% mice. The synergic therapeutic efficacy was found to be associated with more effector and less exhausted CD8 T cell infiltration in the tumor sites. Platinum chemotherapy is generally considered immunosuppressive, with lymphopenia and neutropenia being common side effects. However, our data showed that high-dose (20 mg/kg) platinum treatment induced lymphopenia in MC38 tumor-bearing mice, and low-dose (10 mg/kg) treatment augmented the T cell response with an increased number of peripheral T cells. Notably, increased numbers of PD-1 positive CD8 T cells were found in draining lymph nodes, peripheral blood and tumor tissues three days after 10 mg/kg oxaliplatin treatment, and increased numbers of CD8 T cells and apoptotic tumor cells were detected at the edge of tumor tissues. Further investigation showed that the death of tumor cells induced by platinum compounds promoted T cell activation. Moreover, increased expression of T cell-attracting chemokines (CXCL9, CXCL10 and CCL5) was detected in MC38 cells after platinum treatment. These data indicated that the optimal dose of platinum chemotherapy could trigger T cell activation and recruitment into tumors, and sequential PD-1 blockade could prevent newly arriving T cell from becoming exhausted in tumor sites. These findings highlight the importance of optimizing the dose and timing of platinum chemotherapy combined with PD-1 blockade and provide an indication for the improvement of combined therapies in clinical trials.