DNA Sensing in Mismatch Repair-Deficient Tumor Cells Is Essential for Anti-tumor Immunity

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Hypermutated cancers with DNA mismatch repair deficiency (dMMR) show high response rates to anti-PD-1 therapy, likely due to increased neoantigens.
• The mechanisms underlying resistance to anti-PD-1 therapy in dMMR cancers are not fully understood.

Purpose of the Study:

• To investigate the role of intracellular DNA sensing pathways in dMMR cancer immunity and response to checkpoint blockade.
• To identify novel biomarkers for predicting immunotherapy outcomes in dMMR cancers.

Main Methods:

• Utilized tumor models with deficiency in the DNA mismatch repair gene Mlh1 (dMLH1).
• Assessed cytosolic DNA accumulation, IFN-β production, and cGAS-STING pathway activation.
• Evaluated T cell priming, tumor infiltration, and response to checkpoint blockade in various tumor models.
• Analyzed clinical data from human dMMR cancers to correlate cGAS/STING expression with prognosis.

Main Results:

• dMLH1 tumor cells accumulate cytosolic DNA, leading to cGAS-STING-dependent IFN-β production, which promotes slow tumor progression and sensitivity to checkpoint blockade.
• In models with fixed neoantigens, dMLH1 tumors induced potent T cell priming and overcame resistance to checkpoint therapy independently of tumor mutational burden.
• Loss of STING or cGAS in tumor cells reduced T cell infiltration and conferred resistance to checkpoint blockade.
• Downregulation of cGAS/STING in human dMMR cancers correlated with poor prognosis.

Conclusions:

• Intratumoral DNA sensing via the cGAS-STING pathway is essential for dMMR-triggered anti-tumor immunity and response to checkpoint blockade.
• The cGAS-STING pathway represents a critical mechanism linking dMMR to effective anti-cancer immunity.
• cGAS/STING expression serves as a potential biomarker for predicting immunotherapy response and patient prognosis in dMMR cancers.