PD-L1 protects tumor-associated dendritic cells from ferroptosis during immunogenic chemotherapy

Abstract

Summary: Dendritic cells (DCs) express high levels of PD-L1 in the tumor microenvironment. However, the physiological functions of PD-L1 on DCs remain incompletely understood. Here, we explored the roles of PD-L1 signaling during immunogenic chemotherapy. We found that antitumor efficacy was dramatically reduced in the absence of PD-L1 on DCs. Chemotherapy reshaped the tumor immune microenvironment, particularly the DC compartment. In the absence of PD-L1, DCs were more susceptible to the cytotoxicity induced by chemotherapy. Mechanistically, loss of PD-L1 led to the downregulation of SLC7A11, resulting in increased lipid peroxidation that caused DCs to succumb to ferroptosis and dampened antitumor immune responses. Mice with Pdl1-deficient DCs were less efficient at priming T cells during chemotherapy. In cancer patients, a higher level of PD-L1 on DCs correlated with better prognosis after immunogenic chemotherapy. Collectively, these findings reveal an underappreciated role of PD-L1 in orchestrating DC survival, which is critical during chemoimmunotherapy.

Keywords

• CP: Cancer
• CP: Immunology