Correlation between Density of CD8+ T-cell Infiltrate in Microsatellite Unstable Colorectal Cancers and Frameshift Mutations: A Rationale for Personalized Immunotherapy

摘要: Colorectal cancers with microsatellite instability (MSI) represent 15% of all colorectal cancers, including Lynch syndrome as the most frequent hereditary form this disease. Notably, MSI have a higher density tumor-infiltrating lymphocytes (TIL) than other cancers. This feature is thought to reflect accumulation frameshift mutations in sequences that are repeated within gene coding regions, thereby leading synthesis neoantigens recognized by CD8(+) T cells. However, there has yet be clear link established between TIL and cancer. In study, we examined 103 from two independent cohorts where 19 genes were analyzed CD3(+), CD8(+), FOXP3(+) densities quantitated. We found correlated positively total number mutations. increased when present ASTE1, HNF1A, or TCF7L2 genes, increasing even further at least one these was tumor Through vitro assays using engineered antigen-presenting cells, able stimulate peripheral cytotoxic cells obtained cancer patients peptides derived their tumors. Taken together, our results highlight importance cell immune response against cancer-specific neoantigens, establishing preclinical rationale target them personalized cellular immunotherapy strategy, an especially appealing goal for syndrome.