Tumor-infiltrating lymphocytes in colorectal cancers with microsatellite instability are correlated with the number and spectrum of frameshift mutations

Abstract

Colorectal cancers with microsatellite instability are characterized by an important density of tumor-infiltrating lymphocytes and a good prognosis. Microsatellite instability results from the inactivation of the DNA mismatch repair system and induces secondary somatic frameshift mutations within target genes harboring repeat sequences in their coding frame. By disrupting the open reading frame, frameshift mutations can result in the appearance of potentially immunogenic neopeptides. To determine the frameshift mutations inducing a T-cell response during the development of a tumor with microsatellite instability, we studied in 61 colorectal cancer patients with microsatellite instability, using a fluorescent multiplex PCR comparative analysis, the relative frequency of frameshift mutations within 19 target genes and analyzed the correlation of these frameshift mutations with the density of CD3 þ tumor-infiltrating lymphocytes. The four most frequently mutated genes were ACVR2 (92%), TAF1B (84%), ASTE1/HT001 (80%) and TGFBR2 (77%). The vast majority (95%) of the tumors exhibited at least three frameshift mutations, and the number of frameshift mutations was associated with tumor progression (TNM stage, wall invasion and tumor diameter). Tumor-infiltrating lymphocyte density was associated with the overall number of frameshift mutations and with the presence of frameshift mutations within two target genes, namely ASTE1/HT001 and PTEN. These results strongly argue for the clinical relevance of immunotherapy of colorectal cancers with microsatellite instability.

Immune Cells in Colorectal Cancer: Prognostic Relevance and Role of MSI

“…In contrast, pronounced lymphocytic infiltration is marked in high-graded microsatellite instable (MSI-H) CRC and might explain the better clinical outcome in these patients [64]. It has been postulated that MSI-H CRC are more immunogenic than microsatellite stable (MSS) tumors because of the generation of a large number of abnormal peptides by frameshift mutations [49,[65][66][67][68][69][70]. However, in the analysis of Chiba et al [52] there was no significant increase in the number of CD8 + IEL in cases with MSI.…”

Medullary carcinoma of the colon: a distinct morphology reveals a distinctive immunoregulatory microenvironment

“…1 Microsatellite unstable colorectal carcinomas characteristically contain higher numbers of tumor-infiltrating lymphocytes, 2 presumably in response to a milieu of neopeptides generated by frameshift mutations caused by defective mismatch-repair proteins. 3 As a group, microsatellite unstable colorectal carcinomas have a more indolent clinical course with a more favorable prognosis over microsatellite stable colorectal carcinomas. 4,5 This holds true even for medullary carcinoma of the colon, a unique subtype of microsatellite unstable CRC, where the histomorphology of an 'undifferentiated' or 'poorly differentiated' pattern would seem to suggest otherwise.…”

The significance of tumor-associated immune response in molecular taxonomy, prognosis and therapy of colorectal cancer patients

“…dMMR tumors often contain intra-epithelial T cells in response to the expression of neo-antigens on the cell surface (34). This could be the explanation for the better prognosis observed in patients with dMMR tumors.…”