Stromal reprogramming by FAK inhibition overcomes radiation resistance to allow for immune priming and response to checkpoint blockade
Open accessPublished version of a preprint
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. 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. This article is highlighted in the In This Issue feature, p. 2711
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FAK is hyperactivated in pancreatic cancer cells and is an important driver of fibrosis and immune suppression in the TME.
“Focal adhesion kinase (FAK), hyperactivated in pancreatic cancer cells, is an important driver of fibrosis and immune suppression in the TME174”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [174]
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References 95 · Cited by 114
Research works printed but not linked: 1
- [30]Ohlund D, Handly-Santana A, Biffi G, Elyada E, Almeida AS, Ponz-Sarvise M, Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med 2017; 214(3): 579– 96 doi 10.1084/jem.20162024. 28232471 PMC5339682 · DOI · Paper page
- Authors
- Lander, V. E., Belle, J. I., Kingston, N. L., Herndon, J. M., Hogg, G. D., Liu, X., Kang, L.-I., Knolhoff, B. L., Bogner, S. J., Baer, J. M., Zuo, C., Borcherding, N. C., Lander, D. P., Mpoy, C., Scott, J., Zahner, M., Rogers, B. E., Schwarz, J. K., Kim, H., & DeNardo, D. G.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Kim, Hyun
- DeNardo, David G.
- ORCID
- Lander, Varintra E.
- Belle, Jad I.
- Kingston, Natalie L.
- Herndon, John M.
- Hogg, Graham D.
- Liu, Xiuting
- Kang, Liang-I
- Knolhoff, Brett L.
- Bogner, Savannah J.
- Baer, John M.
- Zuo, Chong
- Borcherding, Nicholas C.
- Lander, Daniel P.
- Mpoy, Cedric
- Scott, Jalen
- Zahner, Michael
- Rogers, Buck E.
- Schwarz, Julie K.
- Kim, Hyun
- DeNardo, David G.
- Venue
- Cancer Discovery
- Published
- 2022-09-27
- Volume
- 12
- Issue
- 12
- Pages
- 2774-2799
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC9722639
- OpenAlex
- W4297263588
- Cited by
- 114
- References
- 95
- Citations by year
- 2026: 29 · 2025: 30 · 2024: 40 · 2023: 15
- FWCI
- 8.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (F30CA243233, R01CA248917, R01CA273190, R01CA177670, R01CA262506)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Keywords
- focal adhesion kinase inhibition, defactinib, radiotherapy resistance, pancreatic ductal adenocarcinoma, tumor stroma, T cell priming, immune checkpoint blockade, interferon signaling, tumor fibroblasts, collagen, stereotactic body radiotherapy, combination immunotherapy
- MeSH terms
- Animals, Humans, Immunotherapy, Pancreatic Neoplasms, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Mice, Focal Adhesion Protein-Tyrosine Kinases, Tumor Microenvironment
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