PD-L2 of tumor-derived exosomes mediates the immune escape of cancer cells via the impaired T cell function
The function of PD-1/PD-L1 axis have been intensively studied for immune escape of various cancers. However, the underlying function of PD-L2 remains poorly understood. Here, we demonstrate that PD-L2 is majorly expressed in exosomes with surface localization by clear cell renal cell carcinoma (ccRCC) cells. Tumor cell-derived exosome PD-L2 (TDE-PD-L2) exhibits high expression compared with TDE-PD-L1 in various cancers. In the absence of adaptive immune, TDE-PD-L2 suppresses tumor growth and metastasis. Under immune competence condition, TDE-PD-L2 is hijacked by immune cells in a PD-1-dependent manner to systematically dampen function of T cells via the increased proportion of the regulatory T cells and the decreased proportion of cytotoxic CD8<sup>+</sup> T cells in both tumor-infiltrating T cells and spleen. The effects of TDE-PD-L2 on tumor is restored by antibodies targeting PD-L2. Collectively, we demonstrate that PD-1/TDE-PD-L2 axis systematically suppresses T cell functions, representing a potentially therapeutic strategy for ccRCC treatment.
Authors
- Haojing Zang (ORCID: https://orcid.org/0009-0000-5545-3603)
- Shuwen Cheng (ORCID: https://orcid.org/0000-0002-0365-7935)
- Yongbo Pan (ORCID: https://orcid.org/0000-0002-3850-7304)
- Bo Peng (ORCID: https://orcid.org/0000-0001-5286-7413)
- Hongbo Hu (ORCID: https://orcid.org/0000-0002-8177-7641)
- Shan Gao (ORCID: https://orcid.org/0000-0003-0262-4549)
- Xuetong Wang
- Yinmin Gu (ORCID: https://orcid.org/0000-0001-9825-5447)
- Tongfeng Liu
- Xiaofeng Zhu (ORCID: https://orcid.org/0009-0000-1745-2271)
- Xujie Zhao
Institutions
- University of Science and Technology of China (CN)
- Guiyang Medical University (CN)
- Shanxi Medical University (CN)
- Guizhou University (CN)
- Sichuan University (CN)
- Zhongda Hospital Southeast University (CN)
- Guangdong Academy of Medical Sciences (CN)
- State Key Laboratory of Biotherapy
- Nanjing Medical University (CN)
- Nanjing University (CN)
Publication Details
- Journal
- Cell Death and Disease
- Published
- 2024-11-07
- DOI
- https://doi.org/10.1038/s41419-024-07191-7
- Citations
- 19
- Primary Topic
- Extracellular vesicles in disease
- Type
- article
- Field-Weighted Citation Impact
- 4.44
Funders
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- China Postdoctoral Science Foundation
- Southeast University
- Fundamental Research Funds for the Central Universities