2. Academic Validation
  3. Cediranib enhances the transcription of MHC-I by upregulating IRF-1

Cediranib enhances the transcription of MHC-I by upregulating IRF-1

  • Biochem Pharmacol. 2024 Feb 1:221:116036. doi: 10.1016/j.bcp.2024.116036.
Jie Zhang 1,  Hongjie Guo 1,  Longsheng Wang 1,  Mingming Zheng 1,  Shijia Kong 1,  Honghai Wu 1,  Lin Zhao 1,  Qiong Zhao 2,  Xiaochun Yang 3,  Qiaojun He 4,  Xi Chen 1,  Ling Ding 5,  Bo Yang 6
Affiliations

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 Department of Thoracic Oncology, Shulan（Hangzhou）Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou 310022, 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; Nanhu Brain-computer Interface Institute, Hangzhou 311100, China.
  • 4 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.
  • 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; The Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou 310018, China; Cancer Center of Zhejiang University, Hangzhou 310058, China; School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, 310015, China. Electronic address: yang924@zju.edu.cn.
PMID: 38301967 DOI: 10.1016/j.bcp.2024.116036
Abstract

Diminished or lost Major Histocompatibility Complex class I (MHC-I) expression is frequently observed in tumors, which obstructs the immune recognition of tumor cells by cytotoxic T cells. Restoring MHC-I expression by promoting its transcription and improving protein stability have been promising strategies for reestablishing anti-tumor immune responses. Here, through cell-based screening models, we found that cediranib significantly upregulated MHC-I expression in tumor cells. This finding was confirmed in various non-small cell lung Cancer (NSCLC) cell lines and primary patient-derived lung Cancer cells. Furthermore, we discovered cediranib achieved MHC-I upregulation through transcriptional regulation. interferon regulatory factor 1 (IRF-1) was required for cediranib induced MHC-I transcription and the absence of IRF-1 eliminated this effect. Continuing our research, we found cediranib triggered STAT1 phosphorylation and promoted IRF-1 transcription subsequently, thus enhancing downstream MHC-I transcription. In vivo study, we further confirmed that cediranib increased MHC-I expression, enhanced CD8+ T cell infiltration, and improved the efficacy of anti-PD-L1 therapy. Collectively, our study demonstrated that cediranib could elevate MHC-I expression and enhance responsiveness to immune therapy, thereby providing a theoretical foundation for its potential clinical trials in combination with immunotherapy.

Keywords

Cediranib; IRF-1; Immunotherapy; MHC-I; PD-L1.

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