Viral Molecular Mimicry Influences the Antitumor Immune Response in Murine and Human Melanoma

Abstract

Molecular mimicry is known to be one of the leading mechanisms by which infectious agents may induce autoimmunity. However, whether a similar mechanism triggers anti-tumor immune response is unexplored, and the role of anti-viral T-cells infiltrating the tumor has remained anecdotal. To address this question, we first developed a bioinformatic tool to identify tumor peptides with high similarity to viral epitopes. Using peptides identified by this tool, we showed that, in mice, viral pre-existing immunity enhanced the efficacy of cancer immunotherapy via molecular mimicry. Specifically, when treated with a cancer vaccine consisting of peptides with a high degree of homology with specific viral peptides, the mice with induced pre-existing immunity to these viral peptides showed significantly better anti-tumor response. To understand whether this mechanism could partly explain immunotherapy-response in humans, we analyzed a cohort of melanoma patients undergoing PD1 treatment with high IgG titer for Cytomegalovirus (CMV). In this cohort of patients, we showed that high level of CMV-antibodies was associated with a prolonged progression free survival, and found that in some cases PBMCs could cross-react with both melanoma and CMV homologous peptides. Finally, T cell TCR sequencing revealed expansion of the same CD8+ T-cell clones, when PBMCs were pulsed with tumor- or homologous viral peptides. In conclusion, we have demonstrated that pre-existing immunity and molecular mimicry could explain part of the response observed in immunotherapy. Most importantly, we have developed a tool able to identify tumor antigens and neoantigens based on their similarity to pathogen antigens, in order to exploit molecular mimicry and cross-reactive T-cells in cancer vaccine development.

Therapeutic Cancer Vaccination with Immunopeptidomics-Discovered Antigens Confers Protective Antitumor Efficacy

“…Additionally, peptides originating from source proteins having a function in cancer biology (such as Ski) were included despite showing lower putative MHC-I binding ( Table 1 ). Additionally, one group (peptide pool #4) was selected based on an in-house developed tool to estimate peptide immunogenicity using peptide similarity to viral epitopes [ 25 ]. In short, peptide similarity to viral peptides was computed via pairwise weighted alignment.…”

A novel immunopeptidomic-based pipeline for the generation of personalized oncolytic cancer vaccines

“…To ensure a more accurate selection of the candidates, we focused the choice on peptides that meet both criteria of I) source protein overexpressed compared to normal colon and mTEC and II) of being true MHC-I strong ligands. The second parallel approach represents the main novelty introduced in our pipeline and it consisted in selecting peptides based on their similarity to antigen pathogen by exploiting HEX, a tool previously developed in our laboratory and successfully validated both in pre-clinical and clinical settings (1).The main idea relies on the intrinsic degeneracy of the T cell receptor (TCR), defined as the ability of a single TCR to recognize more than one antigen, generating a phenomenon known as cross-reactivity. This property is an essential feature to broaden the breadth of the T cell repertoire and for instance it allows anti-viral memory CD8+T cells generated by prior infections to recognize unrelated viruses, as demonstrated in several studies in human and murine models (26,27).…”

“…For each peptide, the Uniprot ID, the aminoacid sequence, the similar pathogen species with the respective viral peptides with sequence similarity are shown. The last column indicates whether (1) or not (0) the peptide has been already described in a published ligandome data set.…”

“…The immunopeptidome profile was carefully analyzed and found to be qualitatively in line with already published dataset; the result list of peptides was then investigated through two approaches: RNA seq and the HEX software. The latter is a tool that identifies tumor antigens similar to pathogen antigens, exploiting the cross-mimicry and crossreactive T cells for clinical applications (1). The peptides derived from those analyses were then investigated in vivo, by pre-immunizing mice with the adjuvant poly:(IC) and the peptides; the splenocytes were then harvested and functional characterization was performed by interferon-g ELISpot (Enzyme-Linked Immunospot), deconvoluting the single peptide immunogenicity.…”

Pathogens: Our Allies against Cancer?

“…6 Furthermore, in a controlled murine model experiment, we have shown that mice pre-vaccinated with viral epitopes with a high degree of similarity to tumor epitopes respond more robustly to treatment compared to naive mice. 7 Very recently, antigens derived from the extracellular commensal intestinal microbiota, which are known to be presented to the immune system via the major histocompatibility complex (MHC) class II pathway, have also been shown to be crosspresented through the intracellular MHC class I pathway. Specific CD8 + T cells crossreact with neoantigens and are able to control tumor growth in an animal model.…”