Immune and Stromal Classification of Colorectal Cancer Is Associated with Molecular Subtypes and Relevant for Precision Immunotherapy

Purpose: The tumor microenvironment is formed by many distinct and interacting cell populations, and its composition may predict patient9s prognosis and response to therapies. Colorectal cancer (CRC) is a heterogeneous disease in which immune classifications and four consensus molecular subgroups (CMS) have been described. Our aim was to integrate the composition of the tumor microenvironment with the consensus molecular classification of CRC. Experimental design: We retrospectively analyzed the composition and the functional orientation of the immune, fibroblastic and angiogenic microenvironment of 1388 CRC tumors from three independent cohorts using transcriptomics. We validated our findings using immunohistochemistry. Results: We report that CRC molecular subgroups and microenvironmental signatures are highly correlated. Out of the four molecular subgroups, two highly express immune-specific genes. The good-prognosis microsatellite-instable-enriched subgroup (CMS1) is characterized by overexpression of genes specific to cytotoxic lymphocytes. In contrast, the poor-prognosis Mesenchymal subgroup (CMS4) expresses markers of lymphocytes and of cells of monocytic origin. The Mesenchymal subgroup also displays an angiogenic, inflammatory and immunosuppressive signature, a coordinated pattern that we also found in breast (n=254), ovarian (n=97), lung (n=80) and kidney (n=143) cancers. Pathological examination revealed that the Mesenchymal subtype is characterized by a high density of fibroblasts that likely produce the chemokines and cytokines which favor tumor-associated inflammation and support angiogenesis, resulting in a poor prognosis. In contrast, the Canonical (CMS2) and Metabolic (CMS3) subtypes with intermediate prognosis exhibit low immune and inflammatory signatures. Conclusions: The distinct immune orientations of the CRC molecular subtypes pave the way for tailored immunotherapies.