Regulated secretion of mutant p53 negatively affects T lymphocytes in the tumor microenvironment.

Autor: Dong X; The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China.; Key Laboratory of Medical Cell Biology, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China., Li C; The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China.; Key Laboratory of Medical Cell Biology, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China., Deng C; The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China.; Key Laboratory of Medical Cell Biology, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China., Liu J; The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China.; Key Laboratory of Medical Cell Biology, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China., Li D; Department of Medical Oncology, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China., Zhou T; The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China.; Key Laboratory of Medical Cell Biology, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China., Yang X; The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China.; Key Laboratory of Medical Cell Biology, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China., Liu Y; The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China., Guo Q; The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China.; Key Laboratory of Medical Cell Biology, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China., Feng Y; The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China.; Key Laboratory of Medical Cell Biology, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China., Yu Y; The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China., Wang Z; The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China.; Key Laboratory of Medical Cell Biology, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China., Guo W; The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China.; Key Laboratory of Medical Cell Biology, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China., Zhang S; The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China.; Key Laboratory of Medical Cell Biology, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China., Cui H; The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China.; Key Laboratory of Medical Cell Biology, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China., Jiang C; Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and & Institute, Shenyang, Liaoning Province, China., Wang X; Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China., Song X; The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China. xysong@cmu.edu.cn.; Key Laboratory of Medical Cell Biology, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China. xysong@cmu.edu.cn., Sun X; The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China. wsunxun1220@cmu.edu.cn., Cao L; The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province, China. lcao@cmu.edu.cn.; Key Laboratory of Medical Cell Biology, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, Shenyang, China. lcao@cmu.edu.cn.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2024 Jan; Vol. 43 (2), pp. 92-105. Date of Electronic Publication: 2023 Nov 11.
DOI: 10.1038/s41388-023-02886-1
Abstrakt: Several studies have demonstrated the role of the oncogenic mutant p53 in promoting tumor progression; however, there is limited information on the effects of secreted oncogenic mutant p53 on the tumor microenvironment and tumor immune escape. In this study, we found that secretion of mutant p53, determined by exosome content, is dependent on its N-terminal dileucine motif via its binding to β-adaptin, and inhibited by the CHK2-mediated-Ser 20 phosphorylation. Moreover, we observed that the mutant p53 caused downregulation and dysfunction of CD4 + T lymphocytes in vivo and downregulated the levels and activities of rate-limiting glycolytic enzymes in vitro. Furthermore, inhibition of mutant p53 secretion by knocking down AP1B1 or mutation of dileucine motif could reverse the quantity and function of CD4 + T lymphocytes and restrain the tumor growth. Our study demonstrates that the tumor-derived exosome-mediated secretion of oncogenic mutant p53 inhibits glycolysis to alter the immune microenvironment via functional suppression of CD4 + T cells, which may be the underlying mechanism for tumor immune escape. Therefore, targeting TDE-mediated p53 secretion may serve as a potential therapeutic target for cancer treatment.
(© 2023. The Author(s).)
Databáze: MEDLINE
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