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