Integrative Genomic Analysis Reveals Low T-Cell Infiltration As the Primary Feature of Tobacco Use in HPV-Positive Oropharyngeal Cancer

Authors

Benjamin M Wahle
Paul Zolkind
Ricardo J Ramirez
Zachary L Skidmore
Sydney R Anderson
Angela Mazul
D Neil Hayes
Vlad C Sandulache
Wade L Thorstad
Douglas Adkins
Obi L Griffith
Malachi Griffith
Jose P Zevallos

Publication Date

5-20-2022

Journal

iScience

DOI

10.1016/j.isci.2022.104216

PMID

35494251

PMCID

10.1016/j.isci.2022.104216

PubMedCentral® Posted Date

4-6-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Oncology, Immunology, Genomics

Abstract

Although tobacco use is an independent adverse prognostic feature in HPV(+) oropharyngeal squamous cell carcinoma (OPSCC), the biologic features associated with tobacco use have not been systematically investigated. We characterized genomic and immunologic features associated with tobacco use through whole exome sequencing, mRNA hybridization, and immunohistochemical staining in 47 HPV(+) OPSCC tumors. Low expression of transcripts in a T cell-inflamed gene expression profile (TGEP) was associated with tobacco use at diagnosis and lower overall and disease-free survival. Tobacco use was associated with an increased proportion of T > C substitutions and a lower proportion of expected mutational signatures, but not with increases in mutational burden or recurrent oncogenic mutations. Our findings suggest that rather than increased mutational burden, tobacco's primary and clinically relevant association in HPV(+) OPSCC is immunosuppression of the tumor immune microenvironment. Quantitative assays of T cell infiltration merit further study as prognostic markers in HPV(+) OPSCC.