Human leukocyte antigen (HLA)–self peptide complexes with homology to vaccine neoantigens (HLA–self peptide complexes)

Human leukocyte antigen (HLA)–self peptide complexes with homology to vaccine neoantigens are molecular assemblies where a self-derived peptide is presented by HLA molecules, sharing structural or sequence similarity with a neoantigen targeted by a vaccine (Luksza et al., 2017, Nature). These complexes are central to the immune system's ability to distinguish between "self" and "non-self," a process critical for maintaining immune tolerance and preventing autoimmunity (Abbas et al., 2021, Cellular and Molecular Immunology). In the context of cancer immunotherapy, these complexes represent a significant safety hurdle; if a vaccine-induced T-cell response targets a neoantigen that is too similar to a self-peptide, the resulting cross-reactivity can lead to the destruction of healthy tissues, manifesting as immune-related adverse events (irAEs) (Babb et al., 2023, Frontiers in Immunology). Furthermore, high homology between tumor neoantigens and the self-immunopeptidome often results in poor immunogenicity because the relevant T cells may have been deleted or inactivated during central or peripheral tolerance (Ghorani et al., 2020, Journal for ImmunoTherapy of Cancer). Consequently, these complexes are not "targets" in the traditional sense of drug binding, but are instead critical "off-targets" or "decoy targets" that must be computationally screened and avoided during the design of personalized mRNA or peptide vaccines (Sahin et al., 2017, Nature). Therapeutic strategies such as checkpoint inhibition (e.g., using Pembrolizumab) may inadvertently lower the threshold for T-cell activation against these homologous self-complexes, exacerbating autoimmune risks (Postow et al., 2018, New England Journal of Medicine).

Other names

MHC-self peptide complexesCross-reactive self-antigensHomologous self-immunopeptidomeMolecular mimicry targets

Induction of T-cell cross-reactivity and potential breaking of immune tolerance through molecular mimicry between vaccine-derived antigens and endogenous HLA-presented self-peptides.