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Viral molecular mimicry influences the antitumor immune response in murine and human melanoma

Chiaro, Jacopo, Kasanen, Henna H.E., Whalley, Thomas, Capasso, Cristian, Grönholm, Mikaela, Feola, Sara, Peltonen, Karita, Hamdan, Firas, Hernberg, Micaela, Mäkelä, Siru, Karhapää, Hanna, Brown, Paul E., Martins, Beatriz, Fusciello, Manlio, Ylösmäki, Erkko O., Greco, Dario, Kreutzman, Anna S., Mustjoki, Satu, Szomolay, Barbara and Cerullo, Vincenzo 2021. Viral molecular mimicry influences the antitumor immune response in murine and human melanoma. Cancer Immunology Research 9 (8) , pp. 981-983. 10.1158/2326-6066.CIR-20-0814

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Molecular mimicry is one of the leading mechanisms by which infectious agents can induce autoimmunity. Whether a similar mechanism triggers an antitumor immune response is unexplored, and the role of antiviral T cells infiltrating the tumor has remained anecdotal. To address these questions, we first developed a bioinformatic tool to identify tumor peptides with high similarity to viral epitopes. Using peptides identified by this tool, we demonstrated that, in mice, preexisting immunity toward specific viral epitopes enhanced the efficacy of cancer immunotherapy via molecular mimicry in different settings. To understand whether this mechanism could partly explain immunotherapy responsiveness in humans, we analyzed a cohort of patients with melanoma undergoing anti-PD1 treatment who had a high IgG titer for cytomegalovirus (CMV). In this cohort of patients, we showed that high levels of CMV-specific antibodies were associated with prolonged progression-free survival and found that, in some cases, peripheral blood mononuclear cells (PBMC) could cross-react with both melanoma and CMV homologous peptides. Finally, T-cell receptor sequencing revealed expansion of the same CD8+ T-cell clones when PBMCs were expanded with tumor or homologous viral peptides. In conclusion, we have demonstrated that preexisting immunity and molecular mimicry could influence the response to immunotherapies. In addition, we have developed a free online tool that can identify tumor antigens and neoantigens highly similar to pathogen antigens to exploit molecular mimicry and cross-reactive T cells in cancer vaccine development.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Advanced Research Computing @ Cardiff (ARCCA)
Additional Information: This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs International 4.0 License.
Publisher: American Association for Cancer Research
ISSN: 2326-6066
Date of First Compliant Deposit: 23 May 2022
Date of Acceptance: 3 June 2021
Last Modified: 24 May 2022 10:11

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