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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.
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.
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.
Shares B2M, Antigen presentation & immune editing, Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Neoantigen.
Shares Antigen presentation & immune editing, Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Neoantigen, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR).
Shares Immune exclusion, APC, Cold tumours: immune deserts and exclusion, Hot vs cold tumours.
Shares Immune exclusion, Cold tumours: immune deserts and exclusion, Hot vs cold tumours.
Shares Immune exclusion, Antigen presentation & immune editing, Neoantigen.
Shares CTNNB1, APC, Wnt / β-catenin.
Shares APC, Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Wnt / β-catenin, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR).
Shares APC, Wnt / β-catenin, Colorectal cancer.