Identification of Neoantigens in Cancer Cells as Targets for Immunotherapy

Abstract

The clinical benefits of immune checkpoint blockage (ICB) therapy have been widely reported. In patients with cancer, researchers have demonstrated the clinical potential of antitumor cytotoxic T cells that can be reinvigorated or enhanced by ICB. Compared to self-antigens, neoantigens derived from tumor somatic mutations are believed to be ideal immune targets in tumors. Candidate tumor neoantigens can be identified through immunogenomic or immunopeptidomic approaches. Identification of neoantigens has revealed several points of the clinical relevance. For instance, tumor mutation burden (TMB) may be an indicator of immunotherapy. In various cancers, mutation rates accompanying neoantigen loads may be indicative of immunotherapy. Furthermore, mismatch repair-deficient tumors can be eradicated by T cells in ICB treatment. Hence, immunotherapies using vaccines or adoptive T-cell transfer targeting neoantigens are potential innovative strategies. However, significant efforts are required to identify the optimal epitopes. In this review, we summarize the recent progress in the identification of neoantigens and discussed preclinical and clinical studies based on neoantigens. We also discuss the issues remaining to be addressed before clinical applications of these new therapeutic strategies can be materialized.

Neoantigens: promising targets for cancer therapy

“…Humans have more than 24,000 distinct HLA-I (HLA-A, -B, and -C) and HLA-II (HLA-DR, HLA-DQ, and HLA-DP) alleles, and their admixture results in polymorphism diversity. [248][249][250][251] The HLA alleles of the patient determine their tumor-specific neoantigen repertoire that will be presented for T cell recognition. In addition, HLA-LOH, which occurs in 40% of NSCLC, impairs the presentation of neoantigens, facilitating immune evasion.…”

“…177 For a review and extensive discussion of these methods, we refer to prior literatures. 246,249 Prediction of HLA binding and neoantigen presentation Numerous computer prediction tools have been created for the in silico discovery of neoantigens based on MHC molecule processing and presentation, including NetChop, NetCTL and NetCTLpan 264,265 (Fig. 3).…”

“…38,238 T cell recognition: NetCTL/NetCTLpan, POPISK, PAComplex, CTLPred, EpiMatrix, TCRMatch learning algorithms, such as linear regression and artificial neural networks. 230,249 In vitro peptide-HLA binding dataset is used to train machine learning models by NetMHCpan 265 and MHCflurry 266 that are the main component of current HLA ligand identification pipelines. 38 It is noteworthy that NetMHCpan, in contrast to state-of-the-art methods, improves the prediction performance of tumor neoantigens by combining information from binding affinity data with MS peptidome data to give a "panspecific" machine-learning strategy for MHC-I alleles.…”

Anti-Tumor Effect of Parasitic Protozoans

“…Activation of naïve T lymphocytes requires T cell receptor (TCR) signaling, costimulatory signaling, and cytokine support [ 51 , 52 ]. A neoantigen peptide, uniquely encoded by mutated DNA of tumor cells, has distinct epitopes from those of normal cells and will be processed and displayed on the surface of tumor cells and antigen-presenting cells (APC) as the form of neoantigen peptide-major histocompatibility complexes (pMHC) [ 53 , 54 ]. During T cell activation, the expressed membrane proteins CD4 on T helper cells and CD8 on cytotoxic T lymphocytes, bind to MHC class II (MHC-II) or MHC-I molecules, respectively [ 55 ].…”

Mining the Immunopeptidome for Antigenic Peptides in Cancer

“…Mass spectrometry provides an important means for deciphering the immunopeptidome repertoire of tumor cells [ 2 ]. Whereas much emphasis has been placed on mutations as a source of neoantigens, the occurrence of specific mutations in peptides bound to the major histocompatibility complex (MHC) is quite variable from patient to patient [ 3 , 4 , 5 ]. Thus, there is a need to identify antigenic peptides that are commonly expressed in a cancer type that are presented through MHC class I for activation of cytotoxic CD8+ T cells [ 6 , 7 ].…”