@article{91641286ac6c49ae9eea3c08f7488d7a,
title = "Oropharyngeal cancer outcomes correlate with p16 status, multinucleation and immune infiltration",
abstract = "Oropharyngeal squamous cell carcinoma (OPSCC), largely fueled by the human papillomavirus (HPV), has a complex biological and immunologic phenotype. Although HPV/p16 status can be used to stratify OPSCC patients as a function of survival, it remains unclear what drives an improved treatment response in HPV-associated OPSCC and whether targetable biomarkers exist that can inform a precision oncology approach. We analyzed OPSCC patients treated between 2000 and 2016 and correlated locoregional control (LRC), disease-free survival (DFS) and overall survival (OS) with conventional clinical parameters, risk parameters generated using deep-learning algorithms trained to quantify tumor-infiltrating lymphocytes (TILs) (OP-TIL) and multinucleated tumor cells (MuNI) and targeted transcriptomics. P16 was a dominant determinant of LRC, DFS and OS, but tobacco exposure, OP-TIL and MuNI risk features correlated with clinical outcomes independent of p16 status and the combination of p16, OP-TIL and MuNI generated a better stratification of OPSCC risk compared to individual parameters. Differential gene expression (DEG) analysis demonstrated overlap between MuNI and OP-TIL and identified genes involved in DNA repair, oxidative stress response and tumor immunity as the most prominent correlates with survival. Alteration of inflammatory/immune pathways correlated strongly with all risk features and oncologic outcomes. This suggests that development of OPSCC consists of an intersection between multiple required and permissive oncogenic and immunologic events which may be mechanistically linked. The strong relationship between tumor immunity and oncologic outcomes in OPSCC regardless of HPV status may provide opportunities for further biomarker development and precision oncology approaches incorporating immune checkpoint inhibitors for maximal anti-tumor efficacy.",
author = "Wilde, {David C.} and Castro, {Patricia D.} and Kaustav Bera and Syeling Lai and Anant Madabhushi and German Corredor and Can Koyuncu and Lewis, {James S.} and Cheng Lu and Frederick, {Mitchell J.} and Frederick, {Allan M.} and Haugen, {Avery E.} and Zevallos, {Jose P.} and Sturgis, {Erich M.} and Justin Shi and Huang, {Andrew T.} and Hernandez, {David J.} and Skinner, {Heath D.} and Kemnade, {Jan O.} and Wendong Yu and Sikora, {Andrew G.} and Sandulache, {Vlad C.}",
note = "Funding Information: There are no competing interests or conflicts of interest directly related to this work. A.M. is an equity holder in Elucid Bioimaging and in Inspirata Inc. In addition he has served as a scientific advisory board member for Inspirata Inc, Astrazeneca, Bristol Meyers-Squibb and Merck. Currently he serves on the advisory board of Aiforia Inc and currently consults for Caris, Roche and Aiforia. He also has sponsored research agreements with Philips, AstraZeneca, Boehringer-Ingelheim and Bristol Meyers-Squibb. His technology has been licensed to Elucid Bioimaging. He is also involved in a NIH U24 grant with PathCore Inc, and 3 different R01 grants with Inspirata Inc. J.P.Z. is founder, equity shareholder, and chair of the board for Droplet Biosciences (Cambridge, MA), equity shareholder in Summit Biolabs (Aurora, CO), and a consultant for Merck. Funding Information: This material is the result of work supported with resources and the use of facilities of the Michael E. DeBakey VA Medical Center and was specifically supported by an institutional pilot grant (V.C.S). A.G.S. has received support from the Department of Veterans Affairs Million Veteran Program (BX004183-01A1) and the National Institutes of Health (U01DE028233). This work was supported by a Career Development Award to V.C.S. from the Veterans Administration Clinical Science Research and Development division (1IK2CX001953). A.M.{\textquoteright}s work is supported from grants supported by the National Cancer Institute under award numbers 1U24CA199374-01, R01CA249992-01A1, R01CA202752-01A1, R01CA208236-01A1, R01CA216579-01A1, R01CA220581-01A1, R01CA257612-01A1, 1U01CA239055-01, 1U01CA248226-01, 1U54CA254566-01, National Heart, Lung and Blood Institute 1R01HL15127701A1, R01HL15807101A1, National Institute of Biomedical Imaging and Bioengineering 1R43EB028736-01, National Center for Research Resources under award number 1 C06 RR12463-01 VA Merit Review Award IBX004121A from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the Office of the Assistant Secretary of Defense for Health Affairs, through the Breast Cancer Research Program (W81XWH-19-1-0668), the Prostate Cancer Research Program (W81XWH-15-1-0558, W81XWH-20-1-0851), the Lung Cancer Research Program (W81XWH-18-1-0440, W81XWH-20-1-0595), the Peer Reviewed Cancer Research Program (W81XWH-18-1-0404, W81XWH-21-1-0345), the Kidney Precision Medicine Project (KPMP) Glue Grant, the Ohio Third Frontier Technology Validation Fund, the Clinical and Translational Science Collaborative of Cleveland (UL1TR0002548) from the National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health and NIH roadmap for Medical Research, The Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering at Case Western Reserve University. Sponsored research agreements from Bristol Myers-Squibb, Boehringer-Ingelheim, and Astrazeneca. H.D.S. is supported by R01CA168485-06. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.",
year = "2022",
doi = "10.1038/s41379-022-01024-8",
language = "English",
journal = "Modern Pathology",
issn = "0893-3952",
}