Hsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation

Xiaoyan Xu, Tingxue Xie, Mengxin Zhou, Yaqin Sun, Fengqi Wang, Yanan Tian, Ziyan Chen, Yanqi Xie, Ronghai Wu, Xufeng Cen, Jichun Zhou, Tingjun Hou, Lei Zhang, Chaoyang Huang, Qingwei Zhao, Dongrui Wang () and Hongguang Xia ()
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Xiaoyan Xu: Zhejiang University School of Medicine
Tingxue Xie: Zhejiang University School of Medicine
Mengxin Zhou: Zhejiang University School of Medicine
Yaqin Sun: Zhejiang University School of Medicine
Fengqi Wang: Zhejiang University School of Medicine
Yanan Tian: Zhejiang University School of Medicine
Ziyan Chen: the First Affiliated Hospital, Zhejiang University School of Medicine
Yanqi Xie: Zhejiang University School of Medicine
Ronghai Wu: Hangzhou PhecdaMed Co.Ltd
Xufeng Cen: Zhejiang University School of Medicine
Jichun Zhou: Zhejiang University School of Medicine
Tingjun Hou: Zhejiang University
Lei Zhang: Zhejiang University School of Medicine
Chaoyang Huang: Zhejiang University School of Medicine
Qingwei Zhao: Zhejiang University School of Medicine
Dongrui Wang: Zhejiang University School of Medicine
Hongguang Xia: Zhejiang University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Immune checkpoint inhibition targeting the PD-1/PD-L1 pathway has become a powerful clinical strategy for treating cancer, but its efficacy is complicated by various resistance mechanisms. One of the reasons for the resistance is the internalization and recycling of PD-L1 itself upon antibody binding. The inhibition of lysosome-mediated degradation of PD-L1 is critical for preserving the amount of PD-L1 recycling back to the cell membrane. In this study, we find that Hsc70 promotes PD-L1 degradation through the endosome-lysosome pathway and reduces PD-L1 recycling to the cell membrane. This effect is dependent on Hsc70-PD-L1 binding which inhibits the CMTM6-PD-L1 interaction. We further identify an Hsp90α/β inhibitor, AUY-922, which induces Hsc70 expression and PD-L1 lysosomal degradation. Either Hsc70 overexpression or AUY-922 treatment can reduce PD-L1 expression, inhibit tumor growth and promote anti-tumor immunity in female mice; AUY-922 can further enhance the anti-tumor efficacy of anti-PD-L1 and anti-CTLA4 treatment. Our study elucidates a molecular mechanism of Hsc70-mediated PD-L1 lysosomal degradation and provides a target and therapeutic strategies for tumor immunotherapy.

Date: 2024
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DOI: 10.1038/s41467-024-48597-3

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