Immune checkpoint inhibitor resistance in dMMR high-grade intraepithelial neoplasia with lynch syndrome-associated colon cancer: a case report.

BACKGROUND: Immune checkpoint inhibitors demonstrate high efficacy in MSI-H/dMMR colorectal cancer, yet a subset of patients develops resistance. This case reports in situ recurrence in Lynch syndrome-associated colon cancer, with the novel observation that while the recurrent lesion responded completely to immunotherapy, a concurrent dMMR ascending colon adenoma showed resistance. CASE PRESENTATION: A patient with Lynch syndrome-associated colon cancer experienced in situ recurrence. Immunotherapy led to complete response in the recurrent lesion, but the coexisting dMMR ascending colon adenoma failed to respond. Multiplex immunofluorescence and whole-exome sequencing revealed high CD68+ macrophage infiltration, low CD8+ T cells, CD20+ B cells, and CD56+ NK cells in the adenoma, along with mutations in NRAS, CTNNB1, HLA-DQB1/DRB1/DRB5, VEGFA, TGFBI, PTGS2, and others. CONCLUSION: This case highlights marked heterogeneity in immunotherapy responses among dMMR colorectal cancer patients. Even sustained responders require ongoing colonoscopic surveillance and polypectomy when indicated, particularly those with a history of polyps. Tumor microenvironment features and specific mutations may contribute to immune escape.