Frameshift mutations, neoantigens and tumor-specific CD8(+) T cells in microsatellite unstable colorectal cancers

Abstract

Microsatellite unstable colorectal cancers (CRC) express frameshift mutation-derived tumor-specific neoantigens. We recently showed that: (i) frameshift mutations were correlated with tumor-infiltrating CD8(+) T cell density, (ii) neoantigen-specific cytotoxic T cells could be obtained in patients whose tumors harbored these mutations, underlining the interest of developing personalized immunotherapy strategies in these cancers.

Keywords: Adoptive cell transfer; colorectal cancer; frameshift mutation; immunotherapy; microsatellite instablility; neoantigen; neopeptide; tumor-specific CD8+ T cell.

Figures

Figure 1.

How CD8+ T lymphocytes could target tumor-specific frameshift mutation-derived neoantigens. (A) MSI tumors are prone to insertions and deletions in repeat sequences. In coding repeat sequences (as illustrated here with the 10 adenine tract within TGFBR2 gene, first coding repeat sequence shown by Linnebacher M. et al. to be involved in the production of an immunogenic frameshift peptide10), this can lead to a shift in the open reading frame and to the synthesis of a neoprotein expressed only in tumor cells harboring this mutation. Intracellular degradation of this neoantigen can release immunogenic neopeptides presented on HLA-I molecules by mutated tumor cells. Contrary to self peptides subjected to self-tolerance, neopeptides are more likely to be recognized by specific CD8+ T lymphocytes which could accumulate within MSI-tumor nests as frameshift mutations accumulate within tumor cells. Nevertheless when intratumoral T lymphocyte activity is dampened, by immune checkpoint inhibitory signals for instance, tumor cells fail to be eliminated. (B) Immunotherapy strategies, favoring active tumor-specific immune responses, could be highly beneficial in the context of MSI-CRCs. PD-1 pathway-blockade (1) has already shown very promising results. Other strategies could be of interest, like adoptive transfer of autologous tumor-specific cytotoxic T lymphocytes previously stimulated in vitro, e.g., with artificial antigen presenting cells (2) or cancer vaccination.