摘要
Colorectal cancer has one of the highest mortality rates among malignant tumors,and most patients with non-microsatellite instability-high (MSI-H) colorectal cancer do not benefit from targeted therapy or immune checkpoint inhibitors.Identification of immunogenic neoantigens is a promising strategy for inducing specific antitumor T cells for cancer immunotherapy.Here,we screened potential high-frequency neoepitopes from non-MSI-H colorectal cancer and tested their abilities to induce tumorspecific cytotoxic T cell responses.Three HLA-A2-restricted neoepitopes (P31,P50,and P52) were immunogenic and could induce cytotoxic T lymphocytes in peripheral blood mononuclear cells from healthy donors and colorectal cancer patients.Cytotoxic T lymphocytes induced in HLA-A2.1/K^(b) transgenic mice could recognize and lyse mutant neoepitope-transfected HLA-A2^(+) cancer cells.Adoptive transfer of cytotoxic T lymphocytes induced by the peptide pool of these three neoepitopes effectively inhibited tumor growth and increased the therapeutic effects of anti-PD-1 antibody.These results revealed the potential of high-frequency mutation-specific peptide-based immunotherapy as a personalized treatment approach for patients with non-MSI-H colorectal cancer.The combination of adoptive T cell therapy based on these neoepitopes with immune checkpoint inhibitors,such as anti-PD-1,could provide a promising treatment strategy for non-MSI-H colorectal cancer.
基金
supported by the National Natural Science Foundation of China (U20A20369, 81822043, and 81601448)
the Foundation of Henan Province (19A180007)。
