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- W4362546543 abstract "<div>Abstract<p>The effects of radiotherapy (RT) on tumor immunity in pancreatic ductal adenocarcinoma (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 <i>in vitro</i> 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 <i>in vitro</i> and <i>in vivo</i>, 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.</p>Significance:<p>Checkpoint immunotherapeutics have not been effective in PDAC, even when combined 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 checkpoint immunotherapy.</p><p><i><a href=https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-12-12-ITI target=_blank>This article is highlighted in the In This Issue feature, p. 2711</a></i></p></div>" @default.
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- W4362546543 date "2023-04-04" @default.
- W4362546543 modified "2023-09-25" @default.
- W4362546543 title "Data from Stromal Reprogramming by FAK Inhibition Overcomes Radiation Resistance to Allow for Immune Priming and Response to Checkpoint Blockade" @default.
- W4362546543 doi "https://doi.org/10.1158/2159-8290.c.6549747.v1" @default.
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