Citation: Miranda-Galvis, M.; Carneiro Soares, C.; Moretto Carnielli, C.; Ramalho Buttura, J.; Sales de Sá, R.; Kaminagakura, E.; Marchi, F.A.; Paes Leme, A.F.; Lópes Pinto, C.A.; Santos-Silva, A.R.; et al. New Insights into the Impact of Human Papillomavirus on Oral Cancer in Young Patients: Proteomic Approach Reveals a Novel Role for S100A8. Cells 2023, 12, 1323. https://doi.org/ 10.3390/cells12091323 Academic Editor: Guohui Sun Received: 8 March 2023 Revised: 29 April 2023 Accepted: 2 May 2023 Published: 5 May 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). cells Article New Insights into the Impact of Human Papillomavirus on Oral Cancer in Young Patients: Proteomic Approach Reveals a Novel Role for S100A8 Marisol Miranda-Galvis 1,2 , Carolina Carneiro Soares 2,3 , Carolina Moretto Carnielli 4 , Jaqueline Ramalho Buttura 5 , Raisa Sales de Sá 2 , Estela Kaminagakura 6 , Fabio Albuquerque Marchi 7,8 , Adriana Franco Paes Leme 4 , Clóvis A. Lópes Pinto 9 , Alan Roger Santos-Silva 2 , Rogerio Moraes Castilho 1,10 , Luiz Paulo Kowalski 11,12 and Cristiane Helena Squarize 1,10, * 1 Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA; mgalvis@augusta.edu (M.M.-G.); rcastilh@umich.edu (R.M.C.) 2 Oral Diagnosis Department, Piracicaba Dental School, University of Campinas (UNICAMP), Piracicaba 13414-903, SP, Brazil; carol_ccsm@hotmail.com (C.C.S.); raisadesa@hotmail.com (R.S.d.S.); alanroge@unicamp.br (A.R.S.-S.) 3 Department of Microbiology, Immune Biology, and Genetics, Center for Molecular Biology, University of Vienna, 1030 Vienna, Austria 4 Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas 13083-970, SP, Brazil; carolina.carnielli@lnbio.cnpem.br (C.M.C.); adriana.paesleme@lnbio.cnpem.br (A.F.P.L.) 5 Laboratory of Bioinformatics and Computational Biology, A.C.Camargo Cancer Center (CIPE), São Paulo 01508-010, SP, Brazil; jaquelineramalho0@gmail.com 6 Department of Bioscience and Oral Diagnosis, Science and Technology Institute, University of São Paulo State (UNESP), São José dos Campos 01049-010, SP, Brazil; estela.tango@unesp.br 7 Center for Translational Research in Oncology, Cancer Institute of the State of São Paulo (ICESP), São Paulo 01246-000, SP, Brazil; fabio.marchi@hc.fm.usp.br 8 Comprehensive Center for Precision Oncology, University of São Paulo, São Paulo 05508-900, SP, Brazil 9 Department of Anatomic Pathology, A.C.Camargo Cancer Center, São Paulo 01509-001, SP, Brazil; coipinto@uol.com.br 10 Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA 11 Head and Neck Surgery Department, Medical School, University of São Paulo, São Paulo 05508-900, SP, Brazil; lp_kowalski@uol.com.br 12 Department of Head and Neck Surgery and Otorhinolaryngology, A.C.Camargo Cancer Center, São Paulo 01509-001, SP, Brazil * Correspondence: csquariz@umich.edu Abstract: Human papillomavirus (HPV) infection has recently been linked to a subset of cancers affecting the oral cavity. However, the molecular mechanisms underlying HPV-driven oral squamous cell carcinoma (OSCC) onset and progression are poorly understood. Methods: We performed MS-based proteomics profiling based on HPV status in OSCC in young patients, following biological characterization and cell assays to explore the proteome functional landscape. Results: Thirty-nine proteins are differentially abundant between HPV (+) and HPV (−) OSCC. Among them, COPS3, DYHC1, and S100A8 are unfavorable for tumor recurrence and survival, in contrast to A2M and Serpine1, low levels of which show an association with better DFS. Remarkably, S100A8 is considered an independent prognostic factor for lower survival rates, and at high levels, it alters tumor-associated immune profiling, showing a lower proportion of M1 macrophages and dendritic cells. HPV (+) OSCC also displayed the pathogen-associated patterns receptor that, when activated, triggered the S100A8 and NFκB inflammatory responses. Conclusion: HPV (+) OSCC has a peculiar microenvironment pattern distinctive from HPV (−), involving the expression of pathogen-associated pattern receptors, S100A8 overexpression, and NFκB activation and responses, which has important consequences in prognosis and may guide therapeutic decisions. Cells 2023, 12, 1323. https://doi.org/10.3390/cells12091323 https://www.mdpi.com/journal/cells