@article{5ab045b247f04952b094d06b477702aa,
title = "Stromal Reprogramming by FAK Inhibition Overcomes Radiation Resistance to Allow for Immune Priming and Response to Checkpoint Blockade",
abstract = "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-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 compo-nents, 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 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 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.",
author = "Lander, {Varintra E.} and Belle, {Jad I.} and Kingston, {Natalie L.} and Herndon, {John M.} and Hogg, {Graham D.} and Xiuting Liu and Kang, {Liang I.} and Knolhoff, {Brett L.} and Bogner, {Savannah J.} and Baer, {John M.} and Chong Zuo and Borcherding, {Nicholas C.} and Lander, {Daniel P.} and Cedric Mpoy and Jalen Scott and Michael Zahner and Rogers, {Buck E.} and Schwarz, {Julie K.} and Hyun Kim and Denardo, {David G.}",
note = "Funding Information: Cell extracts were lysed using (RIPA) lysis buffer (25 mmol/L Tris-HCl pH 7.5, 150 mmol/L NaCl, 1% NP-40, 0.5% DOC, 0.1% SDS) supplemented with protease and phosphatase inhibitors (Roche). Samples were then submitted to the MD Anderson Cancer Center for the RPPA assay. The Functional Proteomics RPPA Core is supported by MD Anderson Cancer Center Support grant # 5 P30 CA016672-40. Funding Information: V.E. Lander was supported by NCI F30CA243233. J.I. Belle was supported by the Canadian Institutes of Health Research Doctoral Foreign Study Award. G.D. Hogg was supported by NCI F30CA254087. L.-I. Kang was supported by NIH 5T32EB021955. J.M. Baer was supported by NIH F31DK122633. J.K. Schwarz was supported by NIH R01CA248917, Siteman Investment Program, and AACR/ Bristol Meyers Squibb Female Investigator Award. H. Kim was supported by NIH R01CA248917. D.G. DeNardo and study costs were supported by NCI R01CA273190, R01CA177670, R01CA262506, R01CA248917, P30CA09184215, P50CA196510, and the BJC Cancer Frontier Fund. We would like to thank Dr. Gregory D. Longmore, Dr. Robert D. Schreiber, and Dr. Sheila A. Stewart for providing reagents and feedback while we were drafting the manuscript. We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital and the Institute of Clinical and Translational Sciences (ICTS) at Washington University in St. Louis, MO. The Siteman Cancer Center is supported in part by NCI Cancer Center Support Grant #P30 CA091842, and the ICTS is funded by the NIH{\textquoteright}s NCATS Clinical and Translational Science Award (CTSA) program grant #UL1 TR002345. We would also like to thank the Washington University Center for Cellular Imaging (WUCCI) supported by the Washington University School of Medicine for imaging experiments, the CHiiPs Immunomonitoring Laboratory for CyTOF experiments, the Flow Cytometry and Fluorescence Activated Cell Sorting Core for sorting and flow cytometry experiments, and the Genome Technology Access Center for scRNA-seq and RNA-seq experiments. We would also like to thank the RPPA Core at MDACC, which is supported by NCI Grant #CA16672 and Dr. Yiling Lu{\textquoteright}s NIH R50 Grant # R50CA221675: Functional Proteomics by RPPA in Cancer. Funding Information: L.-I. Kang reports grants from the NIH during the conduct of the study. J.M. Baer reports grants from the NIH during the conduct of the study. J.K. Schwarz reports receiving NIH grant CA248917 during the conduct of the study, as well as the AACR-Bristol Myers Squibb Female Investigator Grant outside the submitted work. H. Kim reports grants from ViewRay during the conduct of the study, as well as grants and personal fees from Varian outside the submitted work. D.G. DeNardo reports grants from the NIH/NCI during the conduct of the study, as well as grants from Verastem, Bristol Myers Squibb, Pfizer, and PANCAN outside the submitted work. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright} 2022 American Association for Cancer Research.",
year = "2022",
month = dec,
day = "1",
doi = "10.1158/2159-8290.CD-22-0192",
language = "English",
volume = "12",
pages = "2774--2799",
journal = "Cancer Discovery",
issn = "2159-8274",
number = "12",
}