PMID- 33689574 OWN - NLM STAT- MEDLINE DCOM- 20220418 LR - 20220531 IS - 2164-554X (Electronic) IS - 2164-5515 (Print) IS - 2164-5515 (Linking) VI - 18 IP - 1 DP - 2022 Dec 31 TI - Neoantigen-reactive T cells exhibit effective anti-tumor activity against colorectal cancer. PG - 1-11 LID - 10.1080/21645515.2021.1891814 [doi] AB - Neoantigens play a crucial role in cancer immunotherapy. However, the effectiveness and safety of neoantigen-based immunotherapies in patients with colorectal cancer (CRC), particularly in the Chinese population, have not been well studied. This study explored the feasibility and effectiveness of neoantigens in the treatment of CRC. Whole-exome sequencing (WES) and transcriptome sequencing were used to identify somatic mutations, RNA expression, and human leukocyte antigen (HLA) alleles. Neoantigen candidates were predicted, and immunogenicity was assessed. The neoantigens TSHZ3-L523P, RARA-R83H, TP53-R248W, EYA2-V333I, and NRAS-G12D from Patient 4 (PW4); TASP1-P161L, RAP1GAP-S215R, MOSPD1-V63I, and NAV2-D1973N from Patient 10 (PW10); and HAVCR2-F39V, SEC11A-R11L, SMPDL3B-T452M, LRFN3-R118Q, and ULK1-S248L from Patient 11 (HLA-A0201(+)PW11) induced a heightened neoantigen-reactive T cell (NRT) response as compared with the controls in peripheral blood lymphocytes (PBLs) isolated from patients with CRC. In addition, we identified neoantigen-containing peptides SEC11A-R11L and ULK1-S248L from HLA-A0201(+)PW11, which more effectively elicited specific CTL responses than the corresponding native peptides in PBLs isolated from HLA-A0201(+)PW11 as well as in HLA-A2.1/K(b) transgenic mice. Importantly, adoptive transfer of NRTs induced by vaccination with two mutant peptides could effectively inhibit tumor growth in tumor-bearing mouse models. These data indicate that neoantigen-containing peptides with high immunogenicity represent promising candidates for peptide-mediated personalized therapy.Abbreviations: CRC: colorectal cancer; DCs: dendritic cells; ELISPOT: enzyme-linked immunosorbent spot; E:T: effector:target; HLA: human leukocyte antigen; MHC: major histocompatibility complex; Mut: mutant type; NGS: next-generation sequencing; NRTs: neoantigen-reactive T cells; PBMCs: peripheral blood mononuclear cells; STR: short tandem repeat; PBLs: peripheral blood lymphocytes; PBS: phosphate-buffered saline; PD-1: programmed cell death protein 1; TILs: tumor-infiltrating lymphocytes; RNA-seq: RNA sequencing; Tg: transgenic; TMGs: tandem minigenes; WES: whole-exome sequencing; WT: wild-type. FAU - Yu, Yaojun AU - Yu Y AD - Department of Gastrointestinal Surgery, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Zhang, Jing AU - Zhang J AD - Department of Gastroenterology, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Ni, Leyi AU - Ni L AD - Department of Gastroenterology, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Zhu, Yuesheng AU - Zhu Y AD - Department of Gastroenterology, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Yu, Hejie AU - Yu H AD - Department of Gastroenterology, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Teng, Yangyang AU - Teng Y AD - Department of Gastroenterology, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Lin, Limiao AU - Lin L AD - Department of Gastroenterology, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Xue, Zhanxiong AU - Xue Z AD - Department of Gastroenterology, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Xue, Xiangyang AU - Xue X AD - Department of Oncology, Wenzhou Medical University School of Basic Medicine, Wenzhou, Zhejiang, China. FAU - Shen, Xian AU - Shen X AD - Department of Gastrointestinal Surgery, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. FAU - Song, Haiping AU - Song H AD - Department of Oncology, Qingdao Central Hospital, The Second Affiliated Hospital, Qingdao University, Qingdao, China. FAU - Su, Xiaoping AU - Su X AD - Department of Oncology, Wenzhou Medical University School of Basic Medicine, Wenzhou, Zhejiang, China. FAU - Sun, Weihong AU - Sun W AD - Department of Oncology, Biotherapy Center, Qingdao Central Hospital, The Second Affiliated Hospital, Qingdao University, Qingdao, China. FAU - Cai, Zhenzhai AU - Cai Z AD - Department of Gastroenterology, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210309 PL - United States TA - Hum Vaccin Immunother JT - Human vaccines & immunotherapeutics JID - 101572652 RN - 0 (Antigens, Neoplasm) RN - 0 (HLA Antigens) RN - 0 (Histocompatibility Antigens Class II) RN - 0 (Homeodomain Proteins) RN - 0 (Peptides) RN - 0 (TSHZ3 protein, human) RN - EC 3.1.4.12 (SMPDL3B protein, human) RN - EC 3.1.4.12 (Sphingomyelin Phosphodiesterase) RN - EC 3.4.- (Peptide Hydrolases) RN - EC 3.4.21.89 (SEC11A protein, human) SB - IM MH - Animals MH - Antigens, Neoplasm/therapeutic use MH - *Colorectal Neoplasms/therapy MH - HLA Antigens MH - Histocompatibility Antigens Class II/metabolism MH - Homeodomain Proteins/metabolism MH - Humans MH - Immunotherapy MH - Lymphocytes, Tumor-Infiltrating MH - Mice MH - Peptide Hydrolases/metabolism MH - Peptides MH - Sphingomyelin Phosphodiesterase/metabolism MH - *T-Lymphocytes/immunology PMC - PMC8920255 OTO - NOTNLM OT - Colorectal cancer OT - cancer vaccine OT - immunotherapy OT - neoantigens OT - tumor COIS- The authors declare that they have no conflicts of interest. EDAT- 2021/03/11 06:00 MHDA- 2022/04/19 06:00 PMCR- 2021/03/09 CRDT- 2021/03/10 17:37 PHST- 2021/03/11 06:00 [pubmed] PHST- 2022/04/19 06:00 [medline] PHST- 2021/03/10 17:37 [entrez] PHST- 2021/03/09 00:00 [pmc-release] AID - 1891814 [pii] AID - 10.1080/21645515.2021.1891814 [doi] PST - ppublish SO - Hum Vaccin Immunother. 2022 Dec 31;18(1):1-11. doi: 10.1080/21645515.2021.1891814. Epub 2021 Mar 9.