Intratumoral Bacteria Are Immunosuppressive and Promote Immunotherapy Resistance in Head and Neck Squamous Cell Carcinoma

Authors

Natalie L Silver
Jin Dai
Travis D Kerr
Jessica Altemus
Rekha Garg
Hannah Simmons
Tyler Alban
Laura Noel-Romas
Vladimir Makarov
David J H Shih
Shwetha V Kumar
Akeem Santos
Rehan Akbani
Adam Burgener
Mohammed Dwidar
Neil Gross
Andrew G Sikora
Elias J Sayour
Apollo Stacy
Christian Jobin
Timothy A Chan
Renata Ferrarotto
Daniel J McGrail

Language

English

Publication Date

1-1-2026

Journal

Nature Cancer

DOI

10.1038/s43018-025-01067-1

PMID

41482523

PMCID

PMC12823012

PubMedCentral® Posted Date

1-2-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Despite the promise of immune checkpoint blockade (ICB) in head and neck squamous cell carcinoma (HNSCC), mediators of response are poorly understood. To address this, here we analyzed oropharyngeal HNSCCs treated with neoadjuvant durvalumab (anti-PDL1) alone or in combination with tremelimumab (anti-CTLA4) from the CIAO clinical trial ( NCT03144778 ). We found that only the total abundance of intratumoral bacteria predicted ICB response, which was validated in multiple independent cohorts. High intratumoral bacteria abundance was associated with an immunosuppressive tumor microenvironment, characterized by an accumulation of neutrophils coupled with depletion of T cells and other adaptive immune cells. Experimental elevation or reduction in intratumoral bacteria abundance in orthotopic models of HNSCC in female mice recapitulated immunological associations observed in participant tumors. Increasing intratumoral bacteria abundance was sufficient to induce resistance to anti-PDL1 ICB, irrespective of bacterial species tested. Together, these findings demonstrate that high intratumoral bacteria abundance is a key suppressor of antitumor immunity and promotes immunotherapy resistance.

Keywords

Animals, Squamous Cell Carcinoma of Head and Neck, Humans, Mice, Female, Tumor Microenvironment, Head and Neck Neoplasms, Drug Resistance, Neoplasm, Antibodies, Monoclonal, Immune Checkpoint Inhibitors, Bacteria, Immunotherapy, Head and neck cancer, Tumour immunology, Cancer immunotherapy, Cancer

Published Open-Access

yes

Recommended Citation

Silver, Natalie L; Dai, Jin; Kerr, Travis D; et al., "Intratumoral Bacteria Are Immunosuppressive and Promote Immunotherapy Resistance in Head and Neck Squamous Cell Carcinoma" (2026). Faculty, Staff and Student Publications. 4755.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4755