Department of Gastrointestinal Surgery, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of Gastroenterology, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Hum Vaccin Immunother. 2022 Dec 31;18(1):1-11. doi: 10.1080/21645515.2021.1891814. Epub 2021 Mar 9.
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-A0201PW11) 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-A0201PW11, which more effectively elicited specific CTL responses than the corresponding native peptides in PBLs isolated from HLA-A0201PW11 as well as in HLA-A2.1/K 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. 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.
新抗原在癌症免疫治疗中发挥着关键作用。然而，基于新抗原的免疫疗法在结直肠癌（CRC）患者中的有效性和安全性，特别是在中国人群中的疗效，尚未得到充分研究。本研究探索了新抗原在 CRC 治疗中的可行性和有效性。我们使用全外显子组测序（WES）和转录组测序来鉴定体细胞突变、RNA 表达和人类白细胞抗原（HLA）等位基因。预测了新抗原候选物，并评估了其免疫原性。来自患者 4（PW4）的 TSHZ3-L523P、RARA-R83H、TP53-R248W、EYA2-V333I 和 NRAS-G12D；来自患者 10（PW10）的 TASP1-P161L、RAP1GAP-S215R、MOSPD1-V63I 和 NAV2-D1973N；以及来自 HLA-A0201PW11 的 HAVCR2-F39V、SEC11A-R11L、SMPDL3B-T452M、LRFN3-R118Q 和 ULK1-S248L，与从 CRC 患者中分离的外周血淋巴细胞（PBLs）中的对照相比，诱导了更高的新抗原反应性 T 细胞（NRT）反应。此外，我们鉴定了来自 HLA-A0201PW11 的新抗原肽 SEC11A-R11L 和 ULK1-S248L，与来自 HLA-A0201PW11 以及 HLA-A2.1/K 转基因小鼠的 PBLs 中相应的天然肽相比，这些肽能更有效地引发特异性 CTL 反应。重要的是，接种两种突变肽疫苗诱导的 NRT 转移可有效抑制荷瘤小鼠模型中的肿瘤生长。这些数据表明，具有高免疫原性的含新抗原肽是肽介导的个体化治疗的有前途的候选物。CRC：结直肠癌；DCs：树突状细胞；ELISPOT：酶联免疫斑点；E:T：效应物：靶标；HLA：人类白细胞抗原；MHC：主要组织相容性复合体；Mut：突变型；NGS：下一代测序；NRTs：新抗原反应性 T 细胞；PBMCs：外周血单核细胞；STR：短串联重复；PBLs：外周血淋巴细胞；PBS：磷酸盐缓冲盐水；PD-1：程序性细胞死亡蛋白 1；TILs：肿瘤浸润淋巴细胞；RNA-seq：RNA 测序；Tg：转基因；TMGs：串联 minigenes；WES：全外显子组测序；WT：野生型。
