Contrasting responses to neoadjuvant immunotherapy in synchronous transverse colon cancers with discordant mismatch...

Mismatch repair (MMR) status is a critical predictive biomarker for immune checkpoint inhibitor (ICI) efficacy in colorectal cancer (CRC); however, direct in vivo comparisons of ICI responsiveness between MMR-deficient (dMMR) and MMR-proficient (pMMR) tumors within the same patient are exceedingly rare. We report an exceptional case of synchronous transverse colon cancer with discordant MMR status that demonstrated strikingly divergent responses to neoadjuvant immunotherapy. A 75-year-old woman with a history of dyslipidemia presented with anemia. She was diagnosed with two synchronous transverse colon tumors: a locally advanced, centrally located dMMR adenocarcinoma with suspected invasion of adjacent structures, and a separate early-stage pMMR carcinoma near the splenic flexure. Given the advanced dMMR status of the primary lesion, neoadjuvant immunotherapy with pembrolizumab was administered, resulting in marked radiologic tumor regression. Subsequent open surgery was performed. Pathological examination revealed a complete pathological response in the dMMR tumor, but no evidence of treatment effect in the pMMR lesion (T1bN0). The patient remained recurrence-free for 3 months. Retrospective immunohistochemical analysis of pretreatment biopsy specimens demonstrated dense CD8-positive T-cell infiltration in the dMMR tumor, whereas CD8 expression was minimal in the pMMR tumor. This case represents a rare intra-patient demonstration of dMMR status, together with a CD8-rich tumor microenvironment, conferring considerable sensitivity to ICI therapy, and pMMR status exhibiting resistance, despite identical systemic immune exposure. Our findings suggest that MMR status may serve as a clinically relevant biomarker for response to neoadjuvant immunotherapy in CRC and highlight the importance of independent biomarker assessment for each synchronous tumor.