Extracellular Matrix–MYCAF Signatures Correlate with Resistance to Neoadjuvant aPD-L1 Immune Checkpoint Inhibition with Durvalumab + Metformin in HPV+ HNSCC

作者：Pablo Llerena, Hani Samarah, Kathryn L. Nunes, Zhao Lin, Kelly Bridgham, Sruti Tekumalla, Amiti Jain, Larry A. Harshyne, Sanket K. Shukla, Ioannis A. Vathiotis, Madalina Tuluc, Stacey Gargano, John Robert Eisenbrey, Scott W. Keith, David M. Cognetti, Voichita Bar‐Ad, Adam Luginbuhl, Rita Susan Axelrod, Rajanikanth Vadigepalli, Hushan Yang, Diana Whitaker‐Menezes, Megan E. Roche, My G Mahoney, Athanassios E. Argiris, Charalambos Solomides, Jennifer Maria Johnson, Mouadh Barbirou, Amanda A. Miller, Andrew P. South, Ramkrishna Mitra, Alban J. Linnenbach, Ubaldo Martinez‐Outschoorn, Joseph Curry · 发表于：Clinical Cancer Research · 年份：2025 · DOI：10.1158/1078-0432.ccr-25-1098 · 被引用次数：6 · 研究领域：Metabolism, Diabetes, and Cancer、Immune cells in cancer、Cancer Immunotherapy and Biomarkers

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 cyc...