标题：Correlation between density of CD8+ T cell infiltrates in microsatellite unstable colorectal cancers and frameshift mutations: a rationale for personalized immunotherapy

作者：Maby PTougeron DHamieh MMlecnik BKora HBindea GAngell HKFredriksen TElie NFauquembergue EDrouet ALeprince JBenichou JMauillon JLe Pessot FSesboué RFrebourg TGalon JLatouche JB

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• 文献摘要：

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

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