FAP+ cells restrict antibody drug delivery and promote an immunosuppressive environment in head and neck squamous cell carcinoma.

Background Antibody-based therapies (such as anti-EGFR and anti-PD1/L1 agents) have altered the landscape of cancer treatment to improve patient outcomes in formerly unresponsive tumor types. However, this robust response is not ubiquitous for all patients or cancer subtypes. Head and neck squamous cell carcinoma continues to have reduced response in many patient populations regardless of target expression (e.g. EGFR or PDL1). The role of microenvironmental proteins, such as fibroblast activation protein (FAP), may hold the key to improving antibody drug delivery and efficacy. We explore the role of FAP in restricting antibody drug therapies and the subsequent impact of targeting FAP to improve immunotherapy response. Methods Our study uses fluorescently- labeled panitumumab (anti-EGFR) to dissect the impact of FAP on drug delivery in HNSCC patients. Through spatial transcriptomic analysis on these patient samples, we explored the effects of FAP expression on another highly relevant subset of antibody-based drugs- immunotherapy. Based on our patient findings, we used a flank syngeneic mouse model to corroborate the role of FAP in responsive (MOC1) and unresponsive (MOC2) tumor types. Our work culminated in a therapeutic proof-of concept using combination anti-FAP therapy with anti-PDL1. Results Our patient samples revealed that high FAP areas had significantly reduced panitumumab compared to regions with lower FAP expression. Furthermore, depth of penetration within tumor nest was reduced in high FAP areas. Our spatial transcriptomic analysis segmented by FAP, PanCK (tumor), and CD31 (vasculature) showed reduced immunotherapy responsiveness (via TIDE scores) in FAP segments. We confirmed that high-FAP expression was associated with reduced immunotherapy (anti-PDL1) response in our MOC2 tumor-bearing model. We also saw reduced anti-PDL1 drug delivery within MOC2 tumors. However, concurrent administration of an anti-FAP monoclonal antibody improved anti-PDL1 response and overall survival. The administration of anti-FAP agents simultaneously enhanced CD8 T cell infiltration while inducing collagen reorganization (both mechanisms previously linked to improved cancer therapeutic efficacy). Conclusion Our study used human and in vivo data to support a clinically implementable approach for improving antibody-based drug efficacy and response. These findings suggest targeting FAP improves drug penetration and alters the microenvironment to result in higher drug efficacy.