Neoadjuvant PD-L1/TGF-β blockade can rapidly disrupt the tumor stroma in head and neck cancer patients

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Abstract

BACKGROUND TGF-β drives fibroblast activation in cancer and is a resistance biomarker to PD-1/PD-L1 blockade.METHODS Focusing 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.RESULTS After 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.CONCLUSION While 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 REGISTRATION ClinicalTrials.gov NCT04428047.FUNDING Merck 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, Jan-Timon Werle, Philémon Sirven, Mamy Andrianteranagna, Jocelyn Gal, Wiem Lassoued, Jerzy Klijanienko, Jeremy Mesple, Benjamin Demaille, Abdenour Abbas, Valentine Gauthier, Kyra J.E. Borgman, Isabelle Puisieux, Serena Janho dit Hreich, Olivier Choussy, Gregoire Marret, Sonia Lameiras, Nathalie Badois, Antoine Dubray-Vautrin, Gilles Dolivet, Lionnel Geoffrois, Renaud Leclère, Wail Zeitouni, Noemie Robil, Jane Merlevede, Altynbek Zhubanchaliyev, Maud Kamal, Ivan Bieche, Laure Monard, Clotilde Simon, Delphine Louis, Clint T. Allen, Arun Rajan, James L. Gulley, Maude Guillot-Delost, Christophe Le Tourneau, Hélène Salmon