Stromal Reprogramming by FAK Inhibition Overcomes Radiation Resistance to Allow for Immune Priming and Response to Checkpoint Blockade

The effects of radiotherapy (RT) on tumor immunity in pancreatic ductal adenocarci-noma (PDAC) are not well understood. To better understand if RT can prime antigen-specifi c 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 compo-nents, including fi broblasts and collagen, cooperate to blunt RT effi cacy and impair RT-induced interferon signaling. Focal adhesion kinase (FAK) inhibition rescued RT effi cacy 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 stereotactic body RT in patients with PDAC (NCT04331041). Analysis of PDAC tissues from these patients showed stromal reprogramming mirroring our findings in genetically engineered mouse models. Finally, the addition of checkpoint immunotherapy to RT and FAK inhibition in animal models led to complete tumor regression and long-term survival.SIGNIFICANCE: Checkpoint immunotherapeutics have not been effective in PDAC, even when com-bined with RT. One possible explanation is that RT fails to prime T-cell responses in PDAC. Here, we show that FAK inhibition allows RT to prime tumor immunity and unlock responsiveness to check-point immunotherapy.

Automated summary

The effects of radiotherapy on tumor immunity in pancreatic ductal adenocarcinoma are not well understood. In this study, FAK inhibition was found to prime tumor immunity and unlock responsiveness to checkpoint immunotherapy in combination with radiotherapy.