Colorectal cancer patients with defective mismatch repair and high microsatellite instability (dMMR/MSI-H) tend to be more likely to benefit from immune checkpoint inhibitors (ICI), a finding that led to the recent FDA approval of the anti-PD-1 monoclonal antibody, pembrolizumab, in this context. However, many dMMR/MSI-H patients are de novo resistant to current ICI interventions. In order to better understand this discrepancy, Endo and colleagues profiled the tumor microenvironment of 220 dMMR/MSI-H colorectal cancers and 1440 MMR-proficient/microsatellite-stable tumors. Comparative transcriptomics, proteomics, and immunohistochemistry identified a subset of ICI non-responders within the dMMR/MSI-H cohort that harbored a unique subset of stromal cells driven by TGFβ. Presence of these cells was linked to poor outcome and an active tumor microenvironment with high levels of angiogenesis and immunosuppressive M2 macrophages. Additionally, the TGFβ signature correlated with the presence of an extracellular matrix signature predictive of ICI resistance. The data indicate that a TGFβ-rich stromal...

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