Peptide vaccine from cancer-testis antigen ODF2 can potentiate the cytotoxic T lymphocyte infiltration through IL-15 in non-MSI-H colorectal cancer

About 85% of patients with colorectal cancer (CRC) have the non-microsatellite instability-high (non-MSI-H) subtype, and many cannot benefit from immune checkpoint blockade. A potential reason for this is that most non-MSI-H colorectal cancers are immunologically cold due to poor CD8(+) T cell infiltration. In the present study, we screened for potential cancer-testis antigens (CTAs) by comparing the bioinformatics of CD8(+) T effector memory (Tem) cell infiltration between MSI-H and non-MSI-H CRC. Two ODF2-derived epitope peptides, P433 and P609, displayed immunogenicity and increased the proportion of CD8(+) T effector memory (Tem) cells in vitro and in vivo. The adoptive transfer of peptide pool-induced CTLs inhibited tumor growth and enhanced CD8(+) T cell infiltration in tumor-bearing NOD/SCID mice. The mechanistic study showed that knockdown of ODF2 in CRC cells promoted interleukin-15 expression, which facilitated CD8(+) T cell proliferation. In conclusion, ODF2, a CTA, was negatively correlated with CD8(+) T cell infiltration in cold non-MSI-H CRC and was selected based on the results of bioinformatics analyses. The corresponding HLA-A2 restricted epitope peptide induced antigen-specific CTLs. Immunotherapy targeting ODF2 could improve CTA infiltration via upregulating IL-15 in non-MSI-H CRC. This tumor antigen screening strategy could be exploited to develop therapeutic vaccines targeting non-MSI-H CRC.

Automated summary

The majority of non-microsatellite instability-high colorectal cancers are immunologically cold due to poor CD8(+) T cell infiltration. The discovered cancer-testis antigen (CTA) ODF2 is negatively correlated with CD8(+) T cell infiltration and can improve CTA infiltration through upregulating interleukin-15.