Journal article
Stromal Reprogramming by FAK Inhibition Overcomes Radiation Resistance to Allow for Immune Priming and Response to Checkpoint Blockade
Cancer discovery, Vol.12(12), pp.2774-2799
12/02/2022
DOI: 10.1158/2159-8290.CD-22-0192
PMID: 36165893
Abstract
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 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 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.
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. This article is highlighted in the In This Issue feature, p. 2711.
Details
- Title: Subtitle
- Stromal Reprogramming by FAK Inhibition Overcomes Radiation Resistance to Allow for Immune Priming and Response to Checkpoint Blockade
- Creators
- Varintra E Lander - Washington University in St. LouisJad I Belle - Washington University in St. LouisNatalie L Kingston - Washington University in St. LouisJohn M Herndon - Washington University in St. LouisGraham D Hogg - Washington University in St. LouisXiuting Liu - Washington University in St. LouisLiang-I Kang - Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MissouriBrett L Knolhoff - Washington University in St. LouisSavannah J Bogner - Washington University in St. LouisJohn M Baer - Washington University in St. LouisChong Zuo - Washington University in St. LouisNicholas C Borcherding - Washington University in St. LouisDaniel P Lander - Washington University in St. LouisCedric Mpoy - Washington University in St. LouisJalen Scott - Washington University in St. LouisMichael Zahner - Washington University in St. LouisBuck E Rogers - Washington University in St. LouisJulie K Schwarz - Washington University in St. LouisHyun Kim - Washington University in St. LouisDavid G DeNardo - Washington University in St. Louis
- Resource Type
- Journal article
- Publication Details
- Cancer discovery, Vol.12(12), pp.2774-2799
- DOI
- 10.1158/2159-8290.CD-22-0192
- PMID
- 36165893
- NLM abbreviation
- Cancer Discov
- ISSN
- 2159-8274
- eISSN
- 2159-8290
- Grant note
- R01 CA244938 / NCI NIH HHS F30 CA254087 / NCI NIH HHS R01 CA177670 / NCI NIH HHS R01 CA262506 / NCI NIH HHS R50 CA221675 / NCI NIH HHS UL1 TR002345 / NCATS NIH HHS R01 CA248917 / NCI NIH HHS T32 GM007200 / NIGMS NIH HHS F30 CA243233 / NCI NIH HHS P50 CA196510 / NCI NIH HHS
- Language
- English
- Date published
- 12/02/2022
- Academic Unit
- Orthopedics and Rehabilitation; Otolaryngology
- Record Identifier
- 9985240895502771
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