Mechanisms of Low MHC I Expression and Strategies for Targeting MHC I with Small Molecules in Cancer Immunotherapy

Shijia Kong; Jie Zhang; Longsheng Wang; Wen Li; Hongjie Guo; Qiaojun He; Honggang Lou; Ling Ding; Bo Yang

doi:10.1016/j.canlet.2024.217432

Mechanisms of Low MHC I Expression and Strategies for Targeting MHC I with Small Molecules in Cancer Immunotherapy

Cancer Lett. 2024 Dec 25:217432. doi: 10.1016/j.canlet.2024.217432. Online ahead of print.

Authors

Shijia Kong¹, Jie Zhang¹, Longsheng Wang¹, Wen Li¹, Hongjie Guo², Qiaojun He³, Honggang Lou⁴, Ling Ding⁵, Bo Yang⁶

Affiliations

¹ Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
² Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, 310015, China.
³ Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; The Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310018, China; Cancer Center of Zhejiang University, Hangzhou 310058, China.
⁴ Center of Clinical Pharmacology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China. Electronic address: louhg@zju.edu.cn.
⁵ Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Nanhu Brain-computer Interface Institute, Hangzhou 311100, China. Electronic address: ld362@zju.edu.cn.
⁶ Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, 310015, China; The Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310018, China. Electronic address: yang924@zju.edu.cn.

PMID: 39730087
DOI: 10.1016/j.canlet.2024.217432

Abstract

Major histocompatibility complex (MHC) class I load antigens and present them on the cell surface, which transduces the tumor-associated antigens to CD8⁺ T cells, activating the acquired immune system. However, many tumors downregulate MHC I expression to evade immune surveillance. The low expression of MHC I not only reduce recognition by- and cytotoxicity of CD8⁺ T cells, but also seriously weakens the anti-tumor effect of immunotherapy by restoring CD8⁺ T cells, such as immune checkpoint inhibitors (ICIs). Accumulated evidence suggested that restoring MHC I expression is an effective strategy for enhancing tumor immunotherapy. This review focuses on mechanisms underlying MHC I downregulation include gene deletion and mutation, transcriptional inhibition, reduced mRNA stability, increased protein degradation, and disruption of endocytic trafficking. We also provide a comprehensive review of small molecules that restore or upregulate MHC I expression, as well as clinical trials involving the combination of ICIs and these small molecule drugs.

Keywords: Expression regulation; Immune checkpoint inhibitors; MHC I; Small molecule compounds.

Publication types

Review