Non-mutational neoantigens in disease

Abstract

The ability of mammals to mount adaptive immune responses culminating with the establishment of immunological memory is predicated on the ability of the mature T cell repertoire to recognize antigenic peptides presented by syngeneic MHC class I and II molecules. Although it is widely believed that mature T cells are highly skewed towards the recognition of antigenic peptides originating from genetically diverse (for example, foreign or mutated) protein-coding regions, preclinical and clinical data rather demonstrate that novel antigenic determinants efficiently recognized by mature T cells can emerge from a variety of non-mutational mechanisms. In this Review, we describe various mechanisms that underlie the formation of bona fide non-mutational neoantigens, such as epitope mimicry, upregulation of cryptic epitopes, usage of non-canonical initiation codons, alternative RNA splicing, and defective ribosomal RNA processing, as well as both enzymatic and non-enzymatic post-translational protein modifications. Moreover, we discuss the implications of the immune recognition of non-mutational neoantigens for human disease.

Figure 1.. Mimicry and crypticity in non-mutational neo-antigenicity.

Autoreactivity against non-mutational neoantigens can emerge from a variety of mechanisms including epitope mimicry and crypticity. Such autoreactive responses are invariably driven by T cell clones escaping (leaky) thymic selection. On the one hand, pathogen-derived epitopes exhibiting considerable structural resemblance to self peptides can drive potent autoreactive responses, at least in individuals with one or more risk factors (see Box 1). On the other hand, purely self peptides (at least from a genetic standpoint), as well as defective ribosomal products (DRiPs) and short-lived proteins (SLiPs) that are normally not presented on MHC class I or II molecules, may elicit autoreactivity downstream of accrued antigen presentation as a consequence of: (1) usage of non-canonical open reading frames (ORFs), (2) alternative RNA splicing, (3) increased expression levels, (4) decreased competition for binding to MHC class I or II molecules, and/or (5) stress conditions that overall alter antigen processing and presentation. APC, antigen-presenting cell; ER, endoplasmic reticulum.

Figure 2.. Protein modifications in non-mutational neo-antigenicity.

Loss of peripheral tolerance and consequent autoreactivity against non-mutated neoepitopes can emerge from a number of protein modifications associated with altered cellular homeostasis, encompassing: (1) the direct replacement of one or more amino acids during translation, (2) peptide splicing within the proteasome, endosomes/lysosomes, other protease-containing compartments, (3) a variety of enzymatic or non-enzymatic post-translational protein modifications (PTMs) such as citrullination, oxidation and glycation, and (4) altered protease activity and consequent generation of novel cleavage products. AA, amino acid; APC, antigen-presenting cell; ER, endoplasmic reticulum.