Neoadjuvant PD-L1/TGF-β blockade can rapidly disrupt the tumor stroma in head and neck cancer patients
BACKGROUNDTGF-β drives fibroblast activation in cancer and is a resistance biomarker to PD-1/PD-L1 blockade.METHODSFocusing on the tumor stroma, we characterized the impact of neoadjuvant treatment with bintrafusp alfa (BA), a dual PD-L1 and TGF-β inhibitor, in a window-of-opportunity study with 6 patients with head and neck squamous cell carcinoma (HNSCC). Tumor biopsies before treatment and 3 weeks after therapy were analyzed using scRNA-seq, imaging, and spatial transcriptomics.RESULTSAfter treatment, we observed significantly decreased levels of activated LRRC15+ cancer-associated fibroblasts (CAFs), remodeled stromal architecture with reduced collagen I and XII content, and increased CD8+ T cell infiltration in immune-excluded tumors. These changes were independently confirmed in an additional neoadjuvant BA-treated cohort of 6 patients with HNSCC. The drastic CAF and stromal compartment reduction observed indicated a fibroblast depletion rather than a fibroblast polarization shift.CONCLUSIONWhile our final clinical cohort does not allow assessment of the treatment effect, this study demonstrated that targeting TGF-β in patients can disrupt the tumor stroma within a short time frame. Further trials and novel biomarkers are now needed to select patients who could benefit.TRIAL REGISTRATIONClinicalTrials.gov NCT04428047.FUNDINGMerck KGaA, ARC Emerging Leaders in Oncology, ANR-10-IDEX-0001-02 PSL, Centre d'Investigation Clinique IGR-Curie 1428, Site de Recherche Intégrée sur le Cancer (INCa-DGOS-Inserm-ITMO cancer_18000), French Government "Investissements d'Avenir" program, France 2030 program, Fondation pour la Recherche Médicale, Marie Skłodowska-Curie grant agreement 847718, Cooperative Research and Development Agreement with EMD Serono, and NIH (ZIA BC 010666).
Authors
- Caroline Hoffmann (ORCID: https://orcid.org/0000-0002-4430-3439)
- Jan-Timon Werle (ORCID: https://orcid.org/0009-0005-6078-9116)
- Philémon Sirven (ORCID: https://orcid.org/0000-0002-1179-4972)
- Mamy Jean De Dieu Andrianteranagna (ORCID: https://orcid.org/0000-0001-6782-7449)
- Hélène Salmon (ORCID: https://orcid.org/0000-0002-2253-3807)
- Jérémy Mesple (ORCID: https://orcid.org/0000-0003-2537-3463)
- Ivan Bièche (ORCID: https://orcid.org/0000-0002-2430-5429)
- Noémie Robil (ORCID: https://orcid.org/0000-0002-3918-1406)
- Wiem Lassoued (ORCID: https://orcid.org/0009-0004-5742-6982)
- Grégoire Marret (ORCID: https://orcid.org/0000-0003-4525-7777)
- Benjamin Demaille (ORCID: https://orcid.org/0000-0003-3626-1985)
- Delphine Louis
- Altynbek Zhubanchaliyev (ORCID: https://orcid.org/0000-0001-7469-4613)
- Wail Zeitouni
- Sonia Lameiras (ORCID: https://orcid.org/0000-0001-8996-8488)
- Nathalie Badois (ORCID: https://orcid.org/0000-0002-8157-3366)
- Christophe Le Tourneau (ORCID: https://orcid.org/0000-0001-9772-4686)
- Gilles Dolivet (ORCID: https://orcid.org/0000-0003-3765-4051)
- Abdenour Abbas (ORCID: https://orcid.org/0000-0003-2372-4530)
- Renaud Leclère (ORCID: https://orcid.org/0000-0001-8737-6817)
- James L. Gulley (ORCID: https://orcid.org/0000-0002-6569-2912)
- Clint Tanner Allen (ORCID: https://orcid.org/0000-0001-6586-5804)
- Isabelle Puisieux (ORCID: https://orcid.org/0000-0002-2710-4905)
- Maude Guillot‐Delost (ORCID: https://orcid.org/0000-0002-2603-719X)
- Kyra J. E. Borgman (ORCID: https://orcid.org/0000-0001-7898-2911)
- Jocelyn Gal (ORCID: https://orcid.org/0000-0002-1802-118X)
- Lionnel Geoffrois
- Antoine Dubray‐Vautrin (ORCID: https://orcid.org/0000-0001-5792-8430)
- Clotilde Simon
- Arun Rajan (ORCID: https://orcid.org/0000-0003-2776-3385)
- Jane Merlevede (ORCID: https://orcid.org/0009-0000-0192-756X)
- Jerzy Klijanienko (ORCID: https://orcid.org/0000-0001-9706-7241)
- Laure Monard (ORCID: https://orcid.org/0000-0001-6731-1450)
- Olivier Choussy (ORCID: https://orcid.org/0000-0002-8597-8424)
- Maud Kamal
- Valentine Gauthier
- Serena Janho dit Hreich
Institutions
- National Institutes of Health (US)
- Inserm (FR)
- Université Paris Sciences et Lettres (FR)
- Institut Gustave Roussy (FR)
- Institut de Cancérologie de Lorraine (FR)
- Immunité et Cancer (FR)
- National Cancer Institute (US)
- UniCancer Group (FR)
- Center for Cancer Research (US)
- Centre Antoine Lacassagne (FR)
- National Institute on Deafness and Other Communication Disorders (US)
- Institut Curie (FR)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2026-11-01
- DOI
- https://doi.org/10.1172/jci198718
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- European Commission
- NIH Clinical Center