Document Type
Article
Publication Date
12-15-2025
Abstract
PURPOSE: Immune checkpoint inhibitors (ICI) have demonstrated clinical benefit in head and neck squamous cell carcinoma (HNSCC); however, single-agent efficacy is limited, leaving significant unmet needs. Metformin may synergize with ICIs, offering promise to improve response rates. We leveraged multiomic data from a randomized, presurgical neoadjuvant trial (NCT03618654) evaluating a single infusion of the anti-PD-L1 ICI durvalumab with or without daily, standard dose metformin in previously untreated, nondiabetic patients with HNSCC to understand predictors of response and the effect of combination therapy.
PATIENTS AND METHODS: Clinical, pathologic, and correlative data were analyzed to investigate response and resistance mechanisms. We present an in-depth multiomic analysis of primary tumor specimens to study treatment response/resistance in human papillomavirus-positive HNSCC.
RESULTS: Baseline samples revealed that myofibroblastic cancer-associated fibroblast and extracellular matrix signatures were enriched in durvalumab plus metformin nonresponders, which were localized to the leading tumor edge on spatial transcriptomics. In contrast, baseline responder samples were enriched for the Langerhans-like dendritic cell (DC) state and IFN signatures. Treatment increased intratumoral CD8+ T-cell and IFN signatures and peripheral blood CCL2 levels. Responders demonstrated macrophage and DC enrichment and antigen processing and presentation upregulation. Enrichment of cell cycle-related gene sets, specifically the MYC targets V1 hallmark gene set, correlated with nonresponse.
CONCLUSIONS: Early response and resistance dynamics for durvalumab plus metformin in human papillomavirus-positive HNSCC reveal baseline extracellular matrix-myofibroblastic cancer-associated fibroblast as predictive of nonresponse. In contrast, responders were distinguished by baseline enrichment in the Langerhans-like DC state and posttreatment antigen-presenting gene sets.
Recommended Citation
Llerena, Pablo; Samarah, Hani; Nunes, Kathryn; Lin, Zhao; Bridgham, Kelly; Tekumalla, Sruti; Jain, Amiti; Harshyne, Larry A.; Shukla, Sanket Kumar; Vathiotis, Ioannis; Tuluc, Madalina; Gargano, Stacey; Eisenbrey, John R.; Keith, Scott W; Cognetti, David; Bar-Ad, Voichita; Luginbuhl, Adam J.; Axelrod, Rita S.; Vadigepalli, Rajanikanth; Yang, Hushan; Whitaker-Menezes, Diana; Roche, Megan; Mahoney, My G.; Argiris, Athanassios; Solomides, Charalambos C.; Johnson, MD, Jennifer; Barbirou, Mouadh; Miller, Amanda; South, Andrew P.; Mitra, Ramkrishna; Linnenbach, Alban J; Martinez-Outshoorn, Ubaldo E.; and Curry, Joseph, "Extracellular Matrix-MYCAF Signatures Correlate with Resistance to Neoadjuvant aPD-L1 Immune Checkpoint Inhibition with Durvalumab + Metformin in HPV+ HNSCC" (2025). Department of Otolaryngology - Head and Neck Surgery Faculty Papers. Paper 106.
https://jdc.jefferson.edu/otofp/106
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
PubMed ID
40932382
Language
English
Comments
This article is the author's final published version in Clinical Cancer Research, Volume 31, Issue 24, Pages 5159-5177.
The published version is available at https://doi.org/10.1158/1078-0432.CCR-25-1098. Copyright © 2025 The Author(s).