Tumor Microenvironment Governs the Prognostic Landscape of Immunotherapy for Head and Neck Squamous Cell Carcinoma: A Computational Model-Guided Analysis

Authors

Priyan Bhattacharya, Thomas Jefferson UniversityFollow
Alban J Linnenbach, Thomas Jefferson UniversityFollow
Andrew P. South, Thomas Jefferson UniversityFollow
Ubaldo E. Martinez-Outshoorn, Thomas Jefferson UniversityFollow
Joseph M. Curry, Thomas Jefferson UniversityFollow
Jennifer M. Johnson, Thomas Jefferson UniversityFollow
Larry A. Harshyne, Thomas Jefferson UniversityFollow
Mỹ G. Mahoney, Thomas Jefferson UniversityFollow
Adam J. Luginbuhl, Thomas Jefferson UniversityFollow
Rajanikanth Vadigepalli, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

6-3-2025

Comments

This article is the author's final published version in PLOS Computational Biology, Volume 21, June 2025, e1013127.

The published version is available at https://doi.org/10.1371/journal.pcbi.1013127.

Copyright © 2025 Bhattacharya et al.

Abstract

Immune checkpoint inhibition (ICI) has emerged as a critical treatment strategy for squamous cell carcinoma of the head and neck (HNSCC) that halts the immune escape of the tumor cells. Increasing evidence suggests that the onset, progression, and lack of/no response of HNSCC to ICI are emergent properties arising from the interactions within the tumor microenvironment (TME). Deciphering how the diversity of cellular and molecular interactions leads to distinct HNSCC TME subtypes subsequently governing the ICI response remains largely unexplored. We developed a cellular-molecular model of the HNSCC TME that incorporates multiple cell types, cellular states, and transitions, and molecularly mediated paracrine interactions. Simulation across the selected parameter space of the HNSCC TME network shows that distinct mechanistic balances within the TME give rise to the five clinically observed TME subtypes such as immune/non-fibrotic, immune/fibrotic, fibrotic only and immune/fibrotic desert. We predict that the cancer-associated fibroblast, beyond a critical proliferation rate, drastically worsens the ICI response by hampering the accessibility of the CD8 + killer T cells to the tumor cells. Our analysis reveals that while an Interleukin-2 (IL-2) + ICI combination therapy may improve response in the immune desert scenario, Osteopontin (OPN) and Leukemia Inhibition Factor (LIF) knockout with ICI yields the best response in a fibro-dominated scenario. Further, we predict Interleukin-8 (IL-8), and lactate can serve as crucial biomarkers for ICI-resistant HNSCC phenotypes. Overall, we provide an integrated quantitative framework that explains a wide range of TME-mediated resistance mechanisms for HNSCC and predicts TME subtype-specific targets that can lead to an improved ICI outcome.

Recommended Citation

Bhattacharya, Priyan; Linnenbach, Alban J; South, Andrew P.; Martinez-Outshoorn, Ubaldo E.; Curry, Joseph M.; Johnson, Jennifer M.; Harshyne, Larry A.; Mahoney, Mỹ G.; Luginbuhl, Adam J.; and Vadigepalli, Rajanikanth, "Tumor Microenvironment Governs the Prognostic Landscape of Immunotherapy for Head and Neck Squamous Cell Carcinoma: A Computational Model-Guided Analysis" (2025). Department of Otolaryngology - Head and Neck Surgery Faculty Papers. Paper 86.
https://jdc.jefferson.edu/otofp/86

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

40460357

Language

English