Oropharyngeal Cancer Outcomes Correlate With p16 Status, Multinucleation and Immune Infiltration

Authors

David C Wilde
Patricia D Castro
Kaustav Bera
Syeling Lai
Anant Madabhushi
German Corredor
Can Koyuncu
James S Lewis
Cheng Lu
Mitchell J Frederick
Allan M Frederick
Avery E Haugen
Jose P Zevallos
Erich M Sturgis
Justin Shi
Andrew T Huang
David J Hernandez
Heath D Skinner
Jan O Kemnade
Wendong Yu
Andrew G Sikora
Vlad C Sandulache

Publication Date

8-1-2022

Journal

Modern Pathology

DOI

10.1038/s41379-022-01024-8

PMID

35184149

PMCID

PMC10391519

PubMedCentral® Posted Date

8-1-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Cyclin-Dependent Kinase Inhibitor p16, Head and Neck Neoplasms, Humans, Oropharyngeal Neoplasms, Papillomaviridae, Papillomavirus Infections, Precision Medicine, Prognosis, Squamous Cell Carcinoma of Head and Neck

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.