{"entity":{"id":"paper-grasso-immune-evasion-colorectal-cancer-discov-2018","kind":"paper","name":"Genetic mechanisms of immune evasion in colorectal cancer","aka":[],"tldr":"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.","asOf":"2026-09-24","links":[{"label":"Grasso et al., Cancer Discov 2018: genetic mechanisms of immune evasion in 1,211 colorectal cancers","url":"https://doi.org/10.1158/2159-8290.CD-17-1327"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/29510987/"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":[],"targets":["b2m","apc","ctnnb1","mmr"],"drugs":[],"companies":[],"institutions":["dana-farber","ucsf"],"pathways":["antigen-presentation-immunoediting","immune-desert-exclusion","wnt"],"terms":["neoantigen","msi","immune-exclusion","cold-vs-hot"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["cancer-discovery"],"dependsOn":[],"notes":[],"journal":"Cancer Discovery","year":2018,"doi":"10.1158/2159-8290.CD-17-1327","pmid":"29510987","authors":"Grasso CS, Giannakis M, Wells DK, et al.","paperType":"translational","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."],"whatItMeans":"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."],"changedPractice":false,"participants":1211},"route":"/key-papers/paper-grasso-immune-evasion-colorectal-cancer-discov-2018/","neighbours":{"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"}],"target":[{"id":"apc","kind":"target","name":"APC","route":"/targets/apc/"},{"id":"b2m","kind":"target","name":"B2M","route":"/targets/b2m/"},{"id":"ctnnb1","kind":"target","name":"CTNNB1","route":"/targets/ctnnb1/"},{"id":"mmr","kind":"target","name":"Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)","route":"/targets/mmr/"}],"institution":[{"id":"dana-farber","kind":"institution","name":"Dana-Farber Brigham Cancer Center","route":"/institutions/dana-farber/"},{"id":"ucsf","kind":"institution","name":"UCSF Helen Diller Family Comprehensive Cancer Center","route":"/institutions/ucsf/"}],"pathway":[{"id":"antigen-presentation-immunoediting","kind":"pathway","name":"Antigen presentation & immune editing","route":"/pathways/antigen-presentation-immunoediting/"},{"id":"immune-desert-exclusion","kind":"pathway","name":"Cold tumours: immune deserts and exclusion","route":"/pathways/immune-desert-exclusion/"},{"id":"wnt","kind":"pathway","name":"Wnt / β-catenin","route":"/pathways/wnt/"}],"term":[{"id":"cold-vs-hot","kind":"term","name":"Hot vs cold tumours","route":"/terms/cold-vs-hot/"},{"id":"immune-exclusion","kind":"term","name":"Immune exclusion","route":"/terms/immune-exclusion/"},{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/"},{"id":"neoantigen","kind":"term","name":"Neoantigen","route":"/terms/neoantigen/"}],"journal":[{"id":"cancer-discovery","kind":"journal","name":"Cancer Discovery","route":"/journals/cancer-discovery/"}]}}