Interrogating the immune landscape of microsatellite stable <scp>RAS</scp> ‐mutated colon cancer

To explore the immune microenvironment of RAS-mutated (RASmt) microsatellite stable (MSS) colon cancer (CC), we retrospectively performed whole exome sequencing, RNA sequencing, and robust digital pathology analyses and studied immune markers in a cohort of 161 patients treated with standard-of-care therapies with early stage disease (both fresh frozen and formalin-fixed paraffin-embedded [FFPE] samples) or 121 patients with metastatic setting (primary tumor FFPE samples). Only a small proportion of cases exhibited a highly infiltrated immune microenvironment, with a strong association between Immunoscore^® (IS)-high (13% of the samples) and Tumor Lymphocytes Infiltrating Score (TuLIS)-high scores (25% of the samples). Immunoscore Immune-Checkpoint (ISIC)-high tumors (52% of the samples) shared a similar microenvironment composition to IS-high and TuLIS-like high tumors and displayed higher mutational burdens than ISIC-low tumors. In conclusion, a substantial proportion of MSS RASmt CCs exhibit high ISIC scores, meriting evaluation in prospective trials of immunotherapy-based combination regimens.