MDR1 promotes CD8 T cell persistence in tumors and protects against cytotoxic chemotherapy

Multidrug transporters, including multidrug resistance-1 (MDR1), are recognized chiefly for effluxing chemotherapeutic drugs out of tumor cells. However, they are also expressed in many normal cells and tissues, including lymphocytes, but their physiological role is less well-understood. Here, we investigated the role of MDR1 in tumor-specific CD8 T cells (TST), which are critical in antitumor immunity and key targets of immunotherapies. Using a clinically-relevant genetic liver cancer mouse model, we investigated the efflux dynamics of TST as they underwent activation, proliferation, and differentiation to dysfunctional states in tumor-bearing hosts. Surprisingly, we found that late-stage/terminally dysfunctional TST had the highest efflux capacity in both murine and human liver tumors. TST upregulated transcription of Abcb1a , encoding MDR1. We used CRISPR/Cas9 to generate MDR1-deficient TST, which persisted poorly in tumor-bearing mice as compared to MDR1-sufficient TST. MDR1 expression improved TST viability and reduced reactive oxygen species accumulation. Loss of MDR1 made T cells more susceptible to cytotoxic chemotherapy-induced cell death. Our findings demonstrate a role for MDR1 in regulating TST persistence and oxidative stress, with implications for antitumor T cell therapies in patients and immune regulation following cytotoxic chemotherapy.