Extracellular Matrix-MYCAF Signatures Correlate with Resistance to Neoadjuvant aPD-L1 Immune Checkpoint Inhibition with Durvalumab + Metformin in HPV+ HNSCC.
Publication/Presentation 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.
Volume
31
Issue
24
First Page
5159
Last Page
5177
ISSN
1557-3265
Published In/Presented At
Llerena, P., Samarah, H., Nunes, K., Lin, Z., Bridgham, K., Tekumalla, S., Jain, A., Harshyne, L., Shukla, S. K., Vathiotis, I., Tuluc, M., Gargano, S., Eisenbrey, J. R., Keith, S., Cognetti, D. M., Bar-Ad, V. C., Luginbuhl, A. J., Axelrod, R., Vadigepalli, R., Yang, H., … Curry, J. M. (2025). Extracellular Matrix-MYCAF Signatures Correlate with Resistance to Neoadjuvant aPD-L1 Immune Checkpoint Inhibition with Durvalumab + Metformin in HPV+ HNSCC. Clinical cancer research : an official journal of the American Association for Cancer Research, 31(24), 5159–5177. https://doi.org/10.1158/1078-0432.CCR-25-1098
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
40932382
Department(s)
Administration and Leadership
Document Type
Article