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

Abstract

Purpose: The tumor microenvironment is formed by many distinct and interacting cell populations, and its composition may predict patients' prognosis and response to therapies. Colorectal cancer 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 colorectal cancer.Experimental Design: We retrospectively analyzed the composition and the functional orientation of the immune, fibroblastic, and angiogenic microenvironment of 1,388 colorectal cancer tumors from three independent cohorts using transcriptomics. We validated our findings using immunohistochemistry.Results: We report that colorectal cancer 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 ¼ 254), ovarian (n ¼ 97), lung (n ¼ 80), and kidney (n ¼ 143) cancers. Pathologic examination revealed that the mesenchymal subtype is characterized by a high density of fibroblasts that likely produce the chemokines and cytokines that 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 colorectal cancer molecular subtypes pave the way for tailored immunotherapies.

Caracterización de pacientes con cáncer colorrectal esporádico basado en la nueva subclasificación molecular de consenso

“…Se ha descrito como lesión precursora a los pólipos sésiles aserrados 36 . Estos tumores presentan una alta respuesta de infiltrado intratumoral, lo cual confiere a estos pacientes un buen pronós-tico y, según lo reportado, se sugiere que ello se debería a la presencia de linfocitos T citotóxicos CD8+ [37][38][39][40] . Por otra parte, se ha establecido que la mutación activante en el oncogen BRAF (V600E) provoca la activación constitutiva de la vía EGFR y en consecuencia una ineficiente respuesta al tratamiento con cetuximab o panitumumab.…”

Colorectal Cancer Consensus Molecular Subtypes Translated to Preclinical Models Uncover Potentially Targetable Cancer Cell Dependencies

“…Recognizing that the tumor microenvironment is an important contributor to gene expression signals in bulk tumor tissue (24)(25)(26), the translation of CMS classification to preclinical models, including cell lines and patient-derived xenografts (PDX) has major challenges. Although CMS labels have previously been assigned to colorectal cancer cell lines (27), development of "adapted" CMS classifiers carefully optimized for preclinical exploration is critical to investigate specific drug sensitivities of subtypes in high-throughput screens.…”

A Blueprint to Advance Colorectal Cancer Immunotherapies

“…High expression of lymphoid genes is associated with poor prognosis. Further analysis showed that this particular signature was associated with myeloid cells and fibroblasts with immunosuppressive mesenchymal markers (18) as well as a high proportion of endothelial cells and cancerassociated fibroblasts. This mesenchymal signature was identified as a marker of resistance in melanoma patients who did not respond to anti-PD-1 (19).…”

“…RNA expression profiling elucidated a T cell-rich signature present in both MSI-H and some MSS colorectal cancer patients who had a better prognosis (18). High expression of lymphoid genes is associated with poor prognosis.…”