Pre‐existing heterologous T‐cell immunity and neoantigen immunogenicity

Abstract

Neoantigens are tumor‐specific mutated proteins that are exempt from central tolerance and are therefore capable of efficiently eliciting effective T‐cell responses. The identification of immunogenic neoantigens in tumor‐specific mutated proteins has promising clinical implications for cancer immunotherapy. However, the factors that may contribute to neoantigen immunogenicity are not yet fully understood. Through molecular mimicry of antigens arising during cancer progression, the gut microbiota and previously encountered pathogens potentially have profound impacts on T‐cell responses to previously unencountered tumor neoantigens. Here, we review the characteristics of immunogenic neoantigens and how host exposure to microbes may affect T‐cell responses to neoantigens. We address the hypothesis that pre‐existing heterologous memory T‐cell immunity is a major factor that influences neoantigen immunogenicity in individual cancer patients. Accumulating data suggest that differences in individual histories of microbial exposure should be taken into account during the optimisation of algorithms that predict neoantigen immunogenicity.

Characterization of CD8 + T-cell responses to non-anchor-type HLA class I neoantigens with single amino-acid substitutions

“…Generated microbial-specific memory T cells can cross-react with neoantigens, and consequently lead to heterogeneous responses among different individuals. 50 , 51 Indeed, T-cell cross-reactivity against microbial antigens and neoantigens has been observed in long-term survivors of pancreatic cancer. 52 Such TCR recognition probability derived from homology to microbial antigens can be estimated and used to improve immunogenic neoantigen prediction.…”

Modulation of Anti-Tumour Immune Responses by Probiotic Bacteria

“…Once there, they provide assistance to cytotoxic T cells, either through cytokine production or the induction of co-stimulatory signals [31]. Alternatively, it is possible that cross-reactivity may allow them to recognize antigens on tumour cells, as has been previously reported [32][33][34].…”

Broadly reactive human CD4+ T cells against Enterobacteriaceae are found in the naïve repertoire and are clonally expanded in the memory repertoire

“…Cross‐reactive T cells can be a double‐edged sword, as shown recently in the case of Candida ‐induced Th17 cells that, while ensuring intestinal homeostasis, can contribute to lung inflammation and immunopathology upon cross‐recognition of airborne Aspergillus fumigatus [47]. Finally, T cells against gut microbiota and other environmental microbes cross‐reactive against neoantigens may affect immunogenicity of cancer and can account for the efficacy of immune checkpoint inhibitors [reviewed in 48].…”