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

• Published in: Science China. Life sciences 2022-03, Vol.65 (3), p.572-587
• Main Authors: Shi, Ranran, Li, Yubing, Ran, Ling, Dong, Yu, Zhou, Xiuman, Tang, Jingwen, Han, Lu, Wang, Mingshuang, Pang, Liwei, Qi, Yuanming, Wu, Yahong, Gao, Yanfeng
• Format: Article
• Language: English
• Subjects: Adoptive transfer; Animals; Biomedical and Life Sciences; Cancer; Cancer immunotherapy; Cell Line, Tumor; Cell therapy; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - immunology; Colorectal Neoplasms - therapy; Cytotoxicity; Epitopes - immunology; Female; Histocompatibility antigen HLA; HLA-A2 Antigen - immunology; Humans; Immune checkpoint inhibitors; Immunogenicity; Immunotherapy; Immunotherapy, Adoptive; Leukocytes (mononuclear); Life Sciences; Lymphocytes; Lymphocytes T; Mice; Microsatellite Instability; Mutation; Neoantigens; Patients; PD-1 protein; Peptides; Peripheral blood mononuclear cells; Research Paper; T-Lymphocytes, Cytotoxic - immunology; Transgenic mice; Tumors
• ISSN: 1674-7305; 1869-1889
• DOI: 10.1007/s11427-021-1944-5

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/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.