Th165 - The ATP-binding Cassette Membrane Transporter MDR1 Promotes Tumor-specific CD8 T Cell Persistence

Abstract Text: Multidrug resistance-1 (MDR1) is an ATP-binding cassette (ABC) membrane transporter known for effluxing chemotherapeutic drugs out of tumor cells. MDR1 is also expressed in normal cells, including immune cells, although its physiologic role is not well understood. MDR1 is dynamically expressed during CD8 T cell development and has been shown to promote survival of CD8 T cells responding to acute infection; however, little is known about the role of ABC transporters in tumor-specific CD8 T cells (TST).

We previously developed a clinically-relevant genetic liver cancer mouse model in which adoptively transferred TST initially differentiate to a reversible dysfunctional state and later to an epigenetically-encoded fixed dysfunctional state driven by persistent tumor antigen stimulation. Surprisingly, late dysfunctional TST displayed the highest capacity to efflux ABC transporter substrates, greater than early dysfunctional TST or memory CD8 T cells. We similarly observed elevated efflux capacity in tumor-reactive CD8 T cells isolated from human hepatocellular carcinoma samples. RNA-sequencing confirmed increased expression of Mdr1a in late dysfunctional TST. We used CRISPR/Cas9 technology to generate MDR1-deficient TST, which displayed increased mitochondrial reactive oxygen species and persisted more poorly than MDR1-sufficient TST when adoptively transferred to tumor-bearing mice or exposed to cytotoxic chemotherapy.

Our findings show that MDR1-mediated efflux is important for TST persistence and fitness, suggesting a role in mediating anti-tumor T cell responses in patients and regulating persistence following lymphodepletion. Future studies will explore the mechanisms underlying MDR1 function in CD8 T cells and test whether MDR1 modulation can improve anti-tumor adoptive T cell therapies.