Academic Journal
Hsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation
| العنوان: | Hsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation |
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| المؤلفون: | Xu, Xiaoyan, Xie, Tingxue, Zhou, Mengxin, Sun, Yaqin, Wang, Fengqi, Tian, Yanan, Chen, Ziyan, Xie, Yanqi, Wu, Ronghai, Cen, Xufeng, Zhou, Jichun, Hou, Tingjun, Zhang, Lei, Huang, Chaoyang, Zhao, Qingwei, Wang, Dongrui, Xia, Hongguang |
| المساهمون: | National Natural Science Foundation of China, Natural Science Foundation of Zhejiang Province |
| المصدر: | Nature Communications ; volume 15, issue 1 ; ISSN 2041-1723 |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2024 |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1038/s41467-024-48597-3 |
| الاتاحة: | http://dx.doi.org/10.1038/s41467-024-48597-3 https://www.nature.com/articles/s41467-024-48597-3.pdf https://www.nature.com/articles/s41467-024-48597-3 |
| Rights: | https://creativecommons.org/licenses/by/4.0 ; https://creativecommons.org/licenses/by/4.0 |
| رقم الانضمام: | edsbas.DB5F2EA3 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41467-024-48597-3 |
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