Neoantigen-reactive T cells exhibit effective anti-tumor activity against colorectal cancer

Abstract

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.

Colorectal cancer vaccines: The current scenario and future prospects

“…HLA genotypes are also significant information for deterring the affinity of presentation and binding in subsequent steps ( 101 ). Computational approaches based on machine learning algorithms such as NetMHCpan, NetMHCIIpan, and MuPeXI predict and prioritize neopeptides ( 26 ).…”

Neoantigen Cancer Vaccines: Generation, Optimization, and Therapeutic Targeting Strategies

“…Out of the 26 targets, only one neoepitope tested to be reactive in studies using the patient cells. The low specificity of neoantigen identification is recognized within the field and has directed investigations into novel identification methods meant to improve the viability of therapeutic neoantigen targeting [39][40][41][42][43].…”

“…Research efforts have been established to explore the feasibility of neoantigen-based immunotherapeutic approaches in a wide spectrum of cancer types. These include the expansion of research studies to include common high-risk malignancies such as gastric [42], colorectal [40], bladder [98], and lung cancer [99].…”

Neoantigens and their clinical applications in human gastrointestinal cancers

“…They have used transcriptome sequencing and WES and specified various neoantigens (TSHZ3-L523P, NRAS-G12D, TP53-R248W, EYA2-V333I, RARAR83H, TASP1-P161L, MOSPD1-V63I, RAP1GAP-S215R, SEC11A-R11L, NAV2-D1973N, HAVCR2-F39V, SMPDL3BT452M, ULK1-S248L, and LRFN3-R118Q) eliciting a heightened neoantigen-reactive T cell (NRT) response. Moreover, based on their findings, neoantigen-containing peptides ULK1-S248L and SEC11A-R11L from HLA-A0201 + PW11 induced specific CTL responses more effectively [143]. Most recently, a personalized immunopeptidome analysis introduced by Minegishi et al significantly facilitated direct identification of neoantigens and was promised as a novel landscape of immunopeptides diagnosis for further application in cancer immunotherapy [144].…”