Comprehensive spatial and immune profiling of metastatic mismatch repair-deficient colorectal cancer reveals response to immunotherapy

초록

Introduction Mismatch repair-deficient (dMMR) colorectal cancers (CRCs) exhibit variable clinical responses to immune checkpoint inhibitors (ICIs) despite their high immunogenicity.Methods To investigate the molecular and spatial determinants of this heterogeneity, we analyzed five metastatic sites (colon, liver, peritoneum, left ovary, and right ovary) from a dMMR CRC patient treated with pembrolizumab using bulk and single-cell RNA sequencing combined with multiplex immunohistochemistry.Results Responsive lesions were characterized by enriched cytotoxic and interferon-gamma signatures, greater CD8+ T-cell infiltration, and close spatial proximity between programmed death-ligand 1(PD-L1)+ tumor cells and M1-like macrophages. In contrast, resistant lesions demonstrated reduced effector cell presence and were enriched in immunosuppressive programs, including SPP1+ and CD163+ macrophages, noncanonical WNT5A/B signaling, and TGF-beta-mediated matrix remodeling.Conclusion Collectively, these findings highlight the importance of spatial immune architecture and macrophage polarization in shaping ICI responses in dMMR CRC and underscore the need for spatial profiling to guide immunotherapy strategies in metastatic disease.

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