Colorectal cancers exhibiting microsatellite instability (MSI) arise from a defect in the DNA mismatch repair (MMR) system, leading to the accumulation of frameshift mutations. These tumors are characterized by a microenvironment richer in cytotoxic CD8 T lymphocytes and by a more favorable prognosis than microsatellite-stable (MSS) tumors, with a reduced risk of metastasis. The mechanisms linking MMR deficiency, immune infiltration, and patient survival nevertheless remained poorly understood. The authors therefore conducted an integrated analysis of the genetic, genomic, and immune landscapes of these tumors.
The work shows that MSI tumors display an increased number of infiltrating cytotoxic T lymphocytes, enhanced in situ proliferation of these cells, and a greater number of frameshift mutations, which are potential sources of immunogenic neoantigens. The number of these mutations was positively correlated with CD8+ cell density, but not with FOXP3+ cells. Using predictive algorithms, the team estimated which exome mutations would give rise to neopeptides presented in the context of HLA class I: the frequency of mutations generating neoepitopes proved lower than expected by chance, a genetic signature of negative selection of antigenic variants, that is, of an immunoediting process. In vitro stimulation of peripheral T lymphocytes also yielded neopeptide-specific cytotoxic lymphocytes only in MSI patients carrying the corresponding mutations, notably in the ASTE1, HNF1A, and TGFRB2 genes. These lymphocytes were capable of killing MSI tumor cell lines, and such cells could be visualized in situ, attesting to active immunosurveillance encountered in vivo.
To link this immune context to prognosis, the authors relied on the Immunoscore, a standardized test based on the densities of CD3 and CD8 lymphocytes within the tumor and at its invasive margin. Among MSI patients, only those with a high Immunoscore showed prolonged survival. Multivariate analyses establish the superiority of the Immunoscore over MSI status in predicting recurrence and survival, with the Immunoscore moreover retaining prognostic value in MSS patients. The good prognosis of MSI tumors thus appears attributable to major differences in the density and quality of infiltrating immune cells. MSI patients, who harbor naturally strong cytotoxic responses, respond effectively to immunotherapies, as illustrated by clinical trials using anti-CTLA-4, anti-PD-1, and anti-PD-L1 antibodies. The authors suggest that the Immunoscore, now incorporated into the WHO classification of digestive tumors and into ESMO recommendations, could serve not only for prognosis but also for selecting patients likely to respond to immunotherapies, including within the MSI subgroup.