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In cancer, non-synonymous DNA base changes alter protein sequence and produce neoantigens that are detected by the immune system. For immune detection, neoantigens must first be presented on class I or II human leukocyte antigens (HLA) followed by recognition by peptide-specific receptors, exemplified by the T-cell receptor (TCR). Detection of neoantigens represents a unique challenge to the immune system due to their high similarity with endogenous 'self' proteins. Here, we review insights into how TCRs detect neoantigens from structural studies and delineate two broad mechanistic categories: 1) recognition of mutated 'self' peptides and 2) recognition of novel 'non-self' peptides generated through anchor residue modifications. While mutated 'self' peptides differ only by a single amino acid from an existing 'self' epitope, mutations that form anchor residues generate an entirely new epitope, hitherto unknown to the immune system. We review recent structural studies that highlight these structurally distinct mechanisms and discuss how they may lead to differential anti-tumor immune responses. We discuss how T cells specific for neoantigens derived from anchor mutations can be of high affinity and provide insights to their use in adoptive T cell transfer-based immunotherapy.

Original publication

DOI

10.3389/fimmu.2022.833017

Type

Journal article

Journal

Frontiers in immunology

Publication Date

01/2022

Volume

13

Addresses

Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Rockville, MD, United States.

Keywords

T-Lymphocytes, Humans, Neoplasms, Peptides, Receptors, Antigen, T-Cell, Immunologic Factors, Antigens, Neoplasm, Epitopes, Immunotherapy