Genetic Mechanisms of Immune Evasion in Colorectal Cancer

TLDR

The study aimed to identify genetic drivers of immune recognition and evasion in colorectal cancer by analyzing 1,211 primary tumor samples, including 179 microsatellite instability–high cases. The authors performed a large‑scale genomic analysis of these tumors, incorporating 592 TCGA samples, to map mutations and copy‑number alterations linked to immune escape. They found that MSI‑high tumors frequently harbor mutations in immune‑modulating pathways and antigen‑presentation genes, including biallelic loss of B2M and HLA, and that activated WNT/β‑catenin signaling correlates with T‑cell exclusion across all subtypes, suggesting that immunoediting and WNT‑driven immune escape coexist and that WNT inhibitors could restore immunity in most colorectal cancers. Published in Cancer Discovery 8(6):730–749, ©2018 AACR; highlighted in the In This Issue feature, p.

Abstract

Abstract To understand the genetic drivers of immune recognition and evasion in colorectal cancer, we analyzed 1,211 colorectal cancer primary tumor samples, including 179 classified as microsatellite instability–high (MSI-high). This set includes The Cancer Genome Atlas colorectal cancer cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of colorectal cancer, had a high rate of significantly mutated genes in important immune-modulating pathways and in the antigen presentation machinery, including biallelic losses of B2M and HLA genes due to copy-number alterations and copy-neutral loss of heterozygosity. WNT/β-catenin signaling genes were significantly mutated in all colorectal cancer subtypes, and activated WNT/β-catenin signaling was correlated with the absence of T-cell infiltration. This large-scale genomic analysis of colorectal cancer demonstrates that MSI-high cases frequently undergo an immunoediting process that provides them with genetic events allowing immune escape despite high mutational load and frequent lymphocytic infiltration and, furthermore, that colorectal cancer tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion. Significance: This multi-omic analysis of 1,211 colorectal cancer primary tumors reveals that it should be possible to better monitor resistance in the 15% of cases that respond to immune blockade therapy and also to use WNT signaling inhibitors to reverse immune exclusion in the 85% of cases that currently do not. Cancer Discov; 8(6); 730–49. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 663