Neoadjuvant PD-L1/TGF-β blockade can rapidly disrupt the tumor stroma in head and neck cancer patients.
15 affiliations
- 1Equipe Leader Fondation ARC, INSERM U932, Immunity and Cancer, Institut Curie, PSL University, Paris, France.
- 2Surgical Oncology Department, Institut Curie, Paris, France.
- 3Department of Biostatistics, Centre Lacassagne, Nice, France.
- 4Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
- 5Department of Pathology and
- 6Single Cell Initiative, Institut Curie, Paris, France.
- 7Department of Drug Development and Innovation (D3i), Institut Curie, Paris & Saint-Cloud, INSERM U900 Research Unit, Paris-Saclay University, Orsay, France.
- 8Institut de Cancérologie de Lorraine, Vandœuvre-lès-Nancy, France.
- 9GenoSplice, Paris, France.
- 10Inserm U1331, Institut Curie, PSL University, Paris, France.
- 11Institut Hospitalo Universitaire PRISM, National PRecISion Medicine Center in Oncology, Gustave Roussy, Paris, France.
- 12Department of Genetics, Institut Curie, Paris, France.
- 13Unicancer, Le Kremlin-Bicêtre, France.
- 14Section on Translational Tumor Immunology, National Institute on Deafness and Other Communication Disorders, and
- 15Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Abstract
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).
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BibTeX
@article{hoffmann2026neoadjuvant,
title = {{Neoadjuvant PD-L1/TGF-β blockade can rapidly disrupt the tumor stroma in head and neck cancer patients.}},
author = {Caroline Hoffmann and Jan-Timon Werle and Philémon Sirven and Mamy Andrianteranagna and Jocelyn Gal and Wiem Lassoued and Jerzy Klijanienko and Jeremy Mesple and Benjamin Demaille and Abdenour Abbas and Valentine Gauthier and Kyra J.E. Borgman and Isabelle Puisieux and Serena Janho dit Hreich and Olivier Choussy and Gregoire Marret and Sonia Lameiras and Nathalie Badois and Antoine Dubray-Vautrin and Gilles Dolivet and Lionnel Geoffrois and Renaud Leclère and Wail Zeitouni and Noemie Robil and Jane Merlevede and Altynbek Zhubanchaliyev and Maud Kamal and Ivan Bieche and Laure Monard and Clotilde Simon and Delphine Louis and Clint T. Allen and Arun Rajan and James L. Gulley and Maude Guillot-Delost and Christophe Le Tourneau and Hélène Salmon},
journal = {The Journal of clinical investigation},
year = {2026},
month = nov,
doi = {10.1172/jci198718},
url = {https://europepmc.org/article/MED/42969228},
note = {CC BY},
}
RIS
TY - JOUR
TI - Neoadjuvant PD-L1/TGF-β blockade can rapidly disrupt the tumor stroma in head and neck cancer patients.
AU - Caroline Hoffmann
AU - Jan-Timon Werle
AU - Philémon Sirven
AU - Mamy Andrianteranagna
AU - Jocelyn Gal
AU - Wiem Lassoued
AU - Jerzy Klijanienko
AU - Jeremy Mesple
AU - Benjamin Demaille
AU - Abdenour Abbas
AU - Valentine Gauthier
AU - Kyra J.E. Borgman
AU - Isabelle Puisieux
AU - Serena Janho dit Hreich
AU - Olivier Choussy
AU - Gregoire Marret
AU - Sonia Lameiras
AU - Nathalie Badois
AU - Antoine Dubray-Vautrin
AU - Gilles Dolivet
AU - Lionnel Geoffrois
AU - Renaud Leclère
AU - Wail Zeitouni
AU - Noemie Robil
AU - Jane Merlevede
AU - Altynbek Zhubanchaliyev
AU - Maud Kamal
AU - Ivan Bieche
AU - Laure Monard
AU - Clotilde Simon
AU - Delphine Louis
AU - Clint T. Allen
AU - Arun Rajan
AU - James L. Gulley
AU - Maude Guillot-Delost
AU - Christophe Le Tourneau
AU - Hélène Salmon
PY - 2026
DA - 2026/11/02
JO - The Journal of clinical investigation
DO - 10.1172/jci198718
UR - https://europepmc.org/article/MED/42969228
AB - 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).
SN - 0021-9738
SN - 1558-8238
ER -