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Article

Improved Immunotherapy Outcomes via Cuproptosis Upregulation of HLA-DRA Expression: Promoting the Aggregation of CD4+ and CD8+T Lymphocytes in Clear Cell Renal Cell Carcinoma

Urology Surgery Department, The First Affiliated Hospital of Harbin Medical University, Youzheng Street #37, Nangang District, Harbin 150001, China
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Author to whom correspondence should be addressed.
Pharmaceuticals 2024, 17(6), 678; https://0-doi-org.brum.beds.ac.uk/10.3390/ph17060678
Submission received: 14 April 2024 / Revised: 16 May 2024 / Accepted: 18 May 2024 / Published: 24 May 2024
(This article belongs to the Special Issue Data-Driven Biomarker and Drug Discovery for Complex Disease)

Abstract

Immunotherapy has shown promising clinical results in clear cell renal cell carcinoma (ccRCC), but low clinical target response rates due to dysfunction of the major histocompatibility complex (MHC) and an inhibitory tumor immune microenvironment (TIME) have largely limited the associated clinical benefits. In the present study, we explored the feasibility of enhancing tumor-specific-MHC-II-HLA-DRA expression, counteracting the TIME’s suppressive effects, thereby improving the sensitivity of immune checkpoint inhibitor (ICI) therapy from the standpoint of cuproptosis. Immunohistochemical staining and in vitro experiments validated the expression of HLA-DRA in ccRCC and its positive impact on ICI therapy. Subsequently, we observed that cuproptosis upregulated HLA-DRA expression in a dose-dependent manner, further confirming the link between cuproptosis and HLA-DRA. In vivo experiments showed that cuproptosis increased the sensitivity to ICI treatment, and implementing cuproptosis alongside anti-PD-1 treatment curtailed tumor growth. Mechanistically, cuproptosis upregulates HLA-DRA expression at the transcriptional level in a dose-dependent manner by inducing the production of reactive oxygen species; high levels of HLA-DRA promote the expression of chemokines CCL5, CXCL9, and CXCL10 in the TIME, inhibiting the development of a pro-tumor microenvironment by promoting the infiltration of CD4+T and CD8+T cells, thereby synergizing ICI therapy and exerting anti-tumor effects. Taken together, this work highlights the role of cuproptosis in mediating TIME remodeling and synergistic immunotherapy, providing new evidence that cuproptosis can evoke effective anti-tumor immune responses.
Keywords: cuproptosis; human leukocyte antigen; tumor-specific major histocompatibility complex-II-II; clear cell renal cell carcinoma; immunotherapy; immune checkpoint inhibitors cuproptosis; human leukocyte antigen; tumor-specific major histocompatibility complex-II-II; clear cell renal cell carcinoma; immunotherapy; immune checkpoint inhibitors

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MDPI and ACS Style

Wang, B.; Liu, Y.; Xiong, F.; Wang, C. Improved Immunotherapy Outcomes via Cuproptosis Upregulation of HLA-DRA Expression: Promoting the Aggregation of CD4+ and CD8+T Lymphocytes in Clear Cell Renal Cell Carcinoma. Pharmaceuticals 2024, 17, 678. https://0-doi-org.brum.beds.ac.uk/10.3390/ph17060678

AMA Style

Wang B, Liu Y, Xiong F, Wang C. Improved Immunotherapy Outcomes via Cuproptosis Upregulation of HLA-DRA Expression: Promoting the Aggregation of CD4+ and CD8+T Lymphocytes in Clear Cell Renal Cell Carcinoma. Pharmaceuticals. 2024; 17(6):678. https://0-doi-org.brum.beds.ac.uk/10.3390/ph17060678

Chicago/Turabian Style

Wang, Bowen, Yiwen Liu, Feng Xiong, and Chunyang Wang. 2024. "Improved Immunotherapy Outcomes via Cuproptosis Upregulation of HLA-DRA Expression: Promoting the Aggregation of CD4+ and CD8+T Lymphocytes in Clear Cell Renal Cell Carcinoma" Pharmaceuticals 17, no. 6: 678. https://0-doi-org.brum.beds.ac.uk/10.3390/ph17060678

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