A Roadmap Toward the Definition of Actionable Tumor-Specific Antigens

Abstract

The search for tumor-specific antigens (TSAs) has considerably accelerated during the past decade due to the improvement of proteogenomic detection methods. This provides new opportunities for the development of novel antitumoral immunotherapies to mount an efficient T cell response against one or multiple types of tumors. While the identification of mutated antigens originating from coding exons has provided relatively few TSA candidates, the possibility of enlarging the repertoire of targetable TSAs by looking at antigens arising from non-canonical open reading frames opens up interesting avenues for cancer immunotherapy. In this review, we outline the potential sources of TSAs and the mechanisms responsible for their expression strictly in cancer cells. In line with the heterogeneity of cancer, we propose that discrete families of TSAs may be enriched in specific cancer types.

Keywords: alternative antigens; cancer immunotherapy; immunopeptidome; neoantigens; pan-cancer antigen research; proteogenomics; tumor-specific antigens.

Figure 1

Overview of the tumor-specific antigen production in tumor cells. At the genomic level, cancer cells accumulate tumor-specific genetic and epigenetic changes. Within genomic alteration, single-nucleotide variants (SNVs) represent an historic source of immunogenic neoantigens. Insertions/deletions (indels) or gene fusion events increase the tumor immunogenicity by generating peptide deriving from the out-of-frame translation of coding exons. Epigenetic alterations induce the aberrant expression of endogenous retroelements (EREs) which generated non-mutated cancer-specific peptides with a high immunogenic potential. In addition to genomic alterations, Post-translational modifications (PTMs) cancer-specific events such aberrant splicing events, ribosomal translation and PTMs also contribute to the generation of cancer-specific major histocompatibility complex class I (MHC I)-associated peptides (MAPs). ER: endoplasmic reticulum.