Abstract
Simple SummaryCancerous cells acquire genetic mutations that can lead to changes in the amino acid sequence of proteins. These altered amino acid sequences, or “neoantigens” allow the immune system to recognize the mutated cells as “non-self” and eliminate them. This review outlines discoveries that identified neoantigens as a key immune target. Further, we discuss the development of bioinformatic and DNA sequencing technologies used to detect patient-specific mutations giving rise to neoantigens, and the methods by which neoantigens can be targeted in cancer therapy.In recent decades, adoptive cell transfer and checkpoint blockade therapies have revolutionized immunotherapeutic approaches to cancer treatment. Advances in whole exome/genome sequencing and bioinformatic detection of tumour-specific genetic variations and the amino acid sequence alterations they induce have revealed that T cell mediated anti-tumour immunity is substantially directed at mutated peptide sequences, and the identification and therapeutic targeting of patient-specific mutated peptide antigens now represents an exciting and rapidly progressing frontier of personalized medicine in the treatment of cancer. This review outlines the historical identification and validation of mutated peptide neoantigens as a target of the immune system, and the technical development of bioinformatic and experimental strategies for detecting, confirming and prioritizing both patient-specific or “private” and frequently occurring, shared “public” neoantigenic targets. Further, we examine the range of therapeutic modalities that have demonstrated preclinical and clinical anti-tumour efficacy through specifically targeting neoantigens, including adoptive T cell transfer, checkpoint blockade and neoantigen vaccination.
Highlights
The T cell arm of the adaptive immune system is exquisitely sensitive at discriminating “self” from “non-self”
mismatch repair (MMR) deficiency is correlated with tumour mutational burden (TMB) and TMB, predicted neoantigen load, tumour-infiltrating lymphocytes (TIL) presence and MMR status all independently correlate positively with response rates to checkpoint blockade with a-PD1 and a-PD-L1 antibodies [30,51,64,66,67,68,69,70,71,72,73]
Pipelines that incorporate as many of these filters as possible tend to give the most accurate predictions as to which putative neoantigens will prove to be immunogenic—for instance Tang et al demonstrated that a TruNeo pipeline that fully incorporates and differentially weights: MHC-I binding affinity; proteasomal C-terminal cleavage; TAP transport efficiency; expression abundance by RNASEQ; clonal heterogeneity and HLA-allele-specific loss of heterozygosity outperformed analyses based on MHC-binding affinity-based algorithms alone (NetMHCPan and MHCFlurry) in predictive power and accuracy in an analysis of sequence from a lung cancer patient and in retrospective analyses of published datasets [97]
Summary
The T cell arm of the adaptive immune system is exquisitely sensitive at discriminating “self” from “non-self”. Despite being “self”, these proteins exhibit incomplete central tolerance and reactive TCR can escape negative selection by virtue of truncated protein expression (MART-1/Melan-A) or transcriptional silencing (TRP-2) in medullary thymic epithelial cells (MTEC) [5,6,7,8]. These antigens have been targeted clinically, typically by infusion of clonal or Transgenic (Tg)TCR products specific for MART-1/MelanA derived peptides presented in a HLA-A*02:01 context, this is associated with severe on-target off-tumour toxicity against healthy melanocytes in the skin, eye and gut, limiting their utility as therapeutic targets [9,10,11]. This review outlines: the identification and validation of mutated peptide neoantigens as a target of the adaptive immune system in preclinical tumour models and in both retrospective and prospective analyses of patient tumours and tumour-specific T cells; the advances in DNA sequencing and bioinformatic processing technologies that have facilitated rapid and reliable analysis of patient tumour mutational profiles and peptide neoantigen prediction; and the therapeutic modalities by which peptide neoantigens have been, and can be targeted in cancer immunotherapy
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