Extracellular Matrix-MYCAF Signatures Correlate with Resistance to Neoadjuvant aPD-L1 Immune Checkpoint Inhibition with Durvalumab + Metformin in HPV+ HNSCC
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…
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Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 2 of 5 (High · randomized trial). Randomized trials of a reasonable size are the strongest single-study design.
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