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

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Pancreatic cancer resists T cell immunity, limiting immunotherapy effectiveness.
• Dampened antigen presentation is a key mechanism of this resistance.

Purpose of the Study:

• To identify regulators of T cell-mediated anti-tumor immunity in pancreatic cancer.
• To investigate the role of MCRS1 in overcoming immunotherapy resistance.

Main Methods:

• High-throughput CRISPR activation screening in mouse pancreatic cancer cells.
• In vitro and in vivo assays to assess T cell-mediated immunity.
• Analysis of MCRS1 interaction with YY1 and its effect on MHC-I gene expression.
• Correlation analysis of MCRS1 expression with patient survival and immunotherapy response.

Main Results:

• MCRS1 significantly increased sensitivity of pancreatic cancer cells to T cell immunity.
• MCRS1, via interaction with YY1, enhances chromatin accessibility and expression of MHC-I genes.
• Elevated MCRS1 reversed MHC-I suppression, activated anti-tumor T cells, and sensitized tumors to α-PD-1 therapy.
• High MCRS1 expression correlated with increased T cell infiltration, improved survival in pancreatic cancer patients, and predicted response to α-PD-1 therapy in lung cancer patients.

Conclusions:

• MCRS1 sensitizes cancer cells to T cell immunity by transcriptionally overcoming MHC-I suppression.
• MCRS1 enhances the efficacy of α-PD-1 immunotherapy in preclinical models and is a potential biomarker for treatment response in human cancers.
• Targeting MCRS1 may improve immunotherapy outcomes for solid tumors.