PD-L1 protects tumor-associated dendritic cells from ferroptosis during immunogenic chemotherapy
Kaimin Xiao,
Silin Zhang,
Qi Peng,
Yuxia Du,
Xiyue Yao,
Ian-Ian Ng,
Haidong Tang
Affiliations
Kaimin Xiao
State Key Laboratory of Molecular Oncology, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China; Joint Graduate Program of Peking-Tsinghua-NIBS, School of Life Sciences, Tsinghua University, Beijing 100084, China
Silin Zhang
State Key Laboratory of Molecular Oncology, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China
Qi Peng
State Key Laboratory of Molecular Oncology, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China; Joint Graduate Program of Peking-Tsinghua-NIBS, School of Life Sciences, Tsinghua University, Beijing 100084, China
Yuxia Du
Department of General Practice, The Second Affiliated Hospital of Fujian Medical University, Quanzhou City, Fujian Province 362000, China
Xiyue Yao
State Key Laboratory of Molecular Oncology, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China
Ian-Ian Ng
State Key Laboratory of Molecular Oncology, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China
Haidong Tang
State Key Laboratory of Molecular Oncology, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China; Corresponding author
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.
