MCRS1 sensitizes T cell–dependent immunotherapy by augmenting MHC-I expression in solid tumors
Dampened antigen presentation underscores the resistance of pancreatic cancer to T cell-mediated anti-tumor immunity, rendering immunotherapy largely ineffective. By high-throughput CRISPR activation perturbation, we discovered that the transcriptional regulator MCRS1 significantly augmented the sensitivity of mouse pancreatic cancer cells to T cell immunity in vitro and in vivo. Mechanistically, MCRS1 interacted with the transcription factor and genome organizer YY1 to coordinately increase the chromatin accessibility and expression of MHC-I genes. Elevated MCRS1 subverted MHC-I suppression and activated anti-tumor T cells, which sensitized mouse pancreatic cancer to α-PD-1 therapy. Remarkably, high MCRS1 expression was associated with increased T cell infiltration and extended survival of patients with pancreatic cancer and was predictive of favorable responses to α-PD-1 therapy in patients with lung cancer. Together, our study uncovers that MCRS1 sensitizes cancer cells to T cell immunity by transcriptionally subverting MHC-I suppression, which enhances the effectiveness of α-PD-1 therapy in mice and humans, paving the way to further improve immunotherapy against solid tumors.
Authors
- Yanfang Liu (ORCID: https://orcid.org/0000-0002-2923-0729)
- Zheyu Jin (ORCID: https://orcid.org/0000-0002-8006-8974)
- Shenfei Sun (ORCID: https://orcid.org/0000-0002-5034-4333)
- Wei Yu (ORCID: https://orcid.org/0000-0001-9898-4607)
- Yulong Yang
- Kai Li (ORCID: https://orcid.org/0000-0001-6544-6052)
- Jiang Zhong (ORCID: https://orcid.org/0000-0003-1801-9642)
- Qian Xiang (ORCID: https://orcid.org/0009-0002-3830-2867)
- Sijing Zhu
- Yuping Qian (ORCID: https://orcid.org/0000-0002-9352-0157)
- Xiaofei Yu (ORCID: https://orcid.org/0000-0002-1712-331X)
- Yuchao Dong (ORCID: https://orcid.org/0000-0002-1910-792X)
- Jin Wang
- Chen Ding (ORCID: https://orcid.org/0000-0001-8673-3464)
- Kaming Xue
- Yi Han (ORCID: https://orcid.org/0000-0002-3941-9998)
- Xinhua Lin (ORCID: https://orcid.org/0000-0002-1063-749X)
- Xue Li (ORCID: https://orcid.org/0000-0001-6214-4243)
- Kaitao Jiang
- Ning Jiang (ORCID: https://orcid.org/0000-0003-0664-6286)
- Zichu Zhou
- Rui‐Ling Yan (ORCID: https://orcid.org/0009-0001-5555-0304)
Institutions
- Second Military Medical University (CN)
- Fudan University (CN)
- Institute of Human Sciences (AT)
- Changhai Hospital (CN)
- Zhongshan Hospital (CN)
- Institute of Immunology (HR)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2024-11-15
- DOI
- https://doi.org/10.1084/jem.20240959
- Citations
- 4
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 1.13
Funders
- Natural Science Foundation of Shanghai
- Westlake University
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Fudan University
- Soochow University
- State Key Laboratory of Genetic Engineering
- University of Texas MD Anderson Cancer Center
- National Outstanding Youth Science Fund Project of National Natural Science Foundation of China
- National Key Research and Development Program of China