Screening and identification of HLA-A2-restricted neoepitopes for immunotherapy of non-microsatellite instability-high colorectal cancer.

Ranran Shi, Yubing Li, Ling Ran, Yu Dong, Xiuman Zhou, Jingwen Tang, Lu Han, Mingshuang Wang, Liwei Pang, Yuanming Qi, Yahong Wu, Yanfeng Gao

Science China. Life sciences 2022 Mar

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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 tumor-specific 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/Kb 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. © 2021. Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature.

Citation

Ranran Shi, Yubing Li, Ling Ran, Yu Dong, Xiuman Zhou, Jingwen Tang, Lu Han, Mingshuang Wang, Liwei Pang, Yuanming Qi, Yahong Wu, Yanfeng Gao. Screening and identification of HLA-A2-restricted neoepitopes for immunotherapy of non-microsatellite instability-high colorectal cancer. Science China. Life sciences. 2022 Mar;65(3):572-587