# Genetic mechanisms of immune evasion in colorectal cancer

Source: https://onco.cc/key-papers/paper-grasso-immune-evasion-colorectal-cancer-discov-2018/  
OnCo record `paper-grasso-immune-evasion-colorectal-cancer-discov-2018` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Even the bowel cancers that immunotherapy can cure have often already learned to hide: across 1,211 tumours, the highly mutated ones had frequently destroyed the machinery that displays their abnormal proteins to the immune system.

## Summary

1,211 colorectal cancer primary tumour samples were analysed, including 179 classified as microsatellite instability-high and the completed TCGA cohort of 592. MSI-high tumours had a high rate of significantly mutated genes in immune-modulating pathways and in the antigen presentation machinery, including biallelic losses of B2M and HLA genes through copy-number alteration and copy-neutral loss of heterozygosity. WNT and beta-catenin signalling genes were significantly mutated in all subtypes, and activated WNT signalling correlated with the absence of T-cell infiltration. The authors concluded that MSI-high cancers frequently undergo immunoediting that lets them escape despite high mutational load and frequent lymphocytic infiltration, and that WNT-driven T-cell exclusion may be reversible.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Cancer Discovery
- Year: 2018
- DOI: 10.1158/2159-8290.CD-17-1327
- Authors: Grasso CS, Giannakis M, Wells DK, et al.
- Findings: Biallelic B2M and HLA loss in MSI-high tumours through copy-number change and copy-neutral loss of heterozygosity.; WNT and beta-catenin pathway mutation in every subtype, correlated with the absence of T-cell infiltration.
- What it means: It gives a genetic account of both immunotherapy failures: why some mismatch repair deficient tumours resist, and why the microsatellite-stable majority has no T cells in it to begin with.
- Caveats: Primary tumours, not samples taken at the point of checkpoint inhibitor failure.; The WNT-to-exclusion link is correlative in patients and mechanistic only in models.

## Sources

- Grasso et al., Cancer Discov 2018: genetic mechanisms of immune evasion in 1,211 colorectal cancers: https://doi.org/10.1158/2159-8290.CD-17-1327
- PubMed: https://pubmed.ncbi.nlm.nih.gov/29510987/

## Connected records

- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- targets: [APC](https://onco.cc/targets/apc/), [B2M](https://onco.cc/targets/b2m/), [CTNNB1](https://onco.cc/targets/ctnnb1/), [Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)](https://onco.cc/targets/mmr/)
- institutions: [Dana-Farber Brigham Cancer Center](https://onco.cc/institutions/dana-farber/), [UCSF Helen Diller Family Comprehensive Cancer Center](https://onco.cc/institutions/ucsf/)
- pathways: [Antigen presentation & immune editing](https://onco.cc/pathways/antigen-presentation-immunoediting/), [Cold tumours: immune deserts and exclusion](https://onco.cc/pathways/immune-desert-exclusion/), [Wnt / β-catenin](https://onco.cc/pathways/wnt/)
- terms: [Hot vs cold tumours](https://onco.cc/terms/cold-vs-hot/), [Immune exclusion](https://onco.cc/terms/immune-exclusion/), [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/), [Neoantigen](https://onco.cc/terms/neoantigen/)
- journals: [Cancer Discovery](https://onco.cc/journals/cancer-discovery/)

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