MCRS1 sensitizes T cell–dependent immunotherapy by augmenting MHC-I expression in solid tumors

• DOI: 10.1084/jem.20240959
• Publication Date: 2024-11-15T14:55:26Z
• Authors: Xue Li; Han Yi; Zheyu Jin; Kaitao Jiang; Kangkang Xue; Jin Wang; Yuping Qian; Qian Xiang; Sijing Zhu; Runhe Yan; Yulong Yang; Shenfei Sun; Kai Li; Zichu Zhou; Wei Yu; Ning Jiang; Chen Ding; Xinhua Lin; Jiang Zhong; Yuchao Dong; Yanfang Liu; Xiaofei Yu
• Keywords: 0303 health sciences; 03 medical and health sciences

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.