A TGFβ-dependent stromal subset underlies immune checkpoint inhibitor efficacy in DNA mismatch repair-deficient/microsatellite instability-high colorectal cancer.

Patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer represent a biomarker-defined population with distinct clinicopathologic features who are susceptible to immune checkpoint inhibitors (ICI). However, their survival outcomes vary considerably and nearly half of them exhibit primary resistance to current ICIs, suggesting substantial molecular heterogeneity even among tumors with dMMR/MSI-H. We conducted an extensive analysis of the tumor microenvironment (TME) using multiple transcriptomic, proteomic, and IHC cohorts of colorectal cancer, comprising 222 dMMR/MSI-H and 1440 MMR-proficient/microsatellite stable tumors. We developed a TGF beta-responsive stromal gene signature and then identified a unique poor prognostic subgroup of patients with dMMR/MSI-H colorectal cancers, characterized by the upregulation of transcriptional programs, including the TGF beta-rich active TME, angiogenesis, M2 macrophage polarization, and the extracellular matrix signature predictive of ICI resistance. The TGF beta-dependent stromal subset within dMMR/MSI-H tumors exhibiting poor survival outcomes was further recapitulated by proteomic datasets and IHC for VCAN protein expressed by cancer-associated fibroblasts. Meanwhile, this dMMR/MSI-H stromal subgroup was enriched neither with CD8(+) T-cell infiltration nor common genomic alterations, such as mutation density and BRAF mutations, compared with dMMR/MSI-H tumors without TGF beta-dependent stromal activation. In conclusion, this study revealed a novel stromal subgroup of patients with dMMR/MSI-H colorectal cancer, demonstrating a TGF beta-rich tumor-promoting TME and unfavorable survival outcomes.