The effects of radiation therapy (RT) on tumor immunity in PDAC are not well understood. To better understand if RT can prime antigen-specific T cell responses, we analyzed human PDAC tissues and mouse models. In both settings, there was little evidence of RT-induced T cell priming. Using in-vitro systems, we found that tumor stromal components, including fibroblasts and collagen, cooperate to blunt RT efficacy and impair RT-induced interferon signaling. Focal Adhesion Kinase (FAK) inhibition rescued RT efficacy in-vitro and in-vivo, leading to tumor regression, T cell priming, and enhanced long-term survival in PDAC mouse models. Based on these data, we initiated a clinical trial of defactinib in combination with SBRT in PDAC patients (NCT04331041). Analysis of PDAC tissues from these patients showed stromal reprogramming mirroring our findings in GEMMs. Finally, the addition of checkpoint immunotherapy to RT and FAKi in animal models led to complete tumor regression and long-term survival.

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