Viral Molecular Mimicry Influences The Antitumor Immune Response In Murine And Human Melanoma.

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. One Sentence Summary Molecular mimicry can play a role in anti-tumor immune responses and should thus be further exploited in the development of novel cancer treatments. ### Competing Interest Statement S.M.M. has received honoraria and research funding from Novartis, Pfizer and Bristol-Myers Squibb (not related to this study). V.C. is co-founder and shareholder of the Valo Therapeutics LTD. All other authors declare to not have any conflict of interests. ### Funding Statement This work has been supported by European Research Council under the European Union’s Horizon 2020 Framework programme (H2020)/ ERC-CoG-2015 Grant Agreement n.681219. Moreover, this research was supported by Helsinki Institute of Life Science (HiLIFE), Jane and Aatos Erkko foundation and Cancer society of Finland. Additionally, this work has been supported by Finnish Cancer Organizations, Sigrid Juselius Foundation, Relander Foundation, State funding for university-level health research in Finland, Fican South funding and HiLife fellow funds from the University of Helsinki. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the HUCH ethical committee (Dnro 115/13/03/02/15). Written informed consent was received from all patients and the study was conducted in accordance with the Declaration of Helsinki. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All the data presented in this manuscript are available