دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: Stromal Reprogramming by FAK Inhibition Overcomes Radiation Resistance to Allow for Immune Priming and Response to Checkpoint Blockade.
المؤلفون: Lander VE; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri., Belle JI; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri., Kingston NL; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri., Herndon JM; Department of Surgery, Washington University School of Medicine, St. Louis, Missouri., Hogg GD; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri., Liu X; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri., Kang LI; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri., Knolhoff BL; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri., Bogner SJ; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri., Baer JM; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri., Zuo C; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri., Borcherding NC; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri., Lander DP; Department of Otolaryngology, Washington University School of Medicine, St. Louis, Missouri., Mpoy C; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri., Scott J; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri., Zahner M; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri., Rogers BE; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri., Schwarz JK; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri.; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri.; Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri., Kim H; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri.; Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri., DeNardo DG; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.; Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
المصدر: Cancer discovery [Cancer Discov] 2022 Dec 02; Vol. 12 (12), pp. 2774-2799.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101561693 Publication Model: Print Cited Medium: Internet ISSN: 2159-8290 (Electronic) Linking ISSN: 21598274 NLM ISO Abbreviation: Cancer Discov Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Philadelphia, PA : American Association for Cancer Research
مواضيع طبية MeSH: Carcinoma, Pancreatic Ductal*/drug therapy , Carcinoma, Pancreatic Ductal*/radiotherapy , Pancreatic Neoplasms*/drug therapy , Pancreatic Neoplasms*/radiotherapy, Mice ; Animals ; Humans ; Focal Adhesion Protein-Tyrosine Kinases ; Immunotherapy ; Tumor Microenvironment ; Cell Line, Tumor
مستخلص: 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.
(©2022 American Association for Cancer Research.)
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معلومات مُعتمدة: F30 CA254087 United States CA NCI NIH HHS; P30 CA016672 United States CA NCI NIH HHS; R01 CA203890 United States CA NCI NIH HHS; R01 CA244938 United States CA NCI NIH HHS; R01 CA248917 United States CA NCI NIH HHS; P30 CA091842 United States CA NCI NIH HHS; P50 CA196510 United States CA NCI NIH HHS; P30 DK052574 United States DK NIDDK NIH HHS; UL1 TR002345 United States TR NCATS NIH HHS; R50 CA221675 United States CA NCI NIH HHS; T32 EB021955 United States EB NIBIB NIH HHS; F31 DK122633 United States DK NIDDK NIH HHS; T32 GM007200 United States GM NIGMS NIH HHS; R01 CA262506 United States CA NCI NIH HHS; F30 CA243233 United States CA NCI NIH HHS; R01 CA177670 United States CA NCI NIH HHS
المشرفين على المادة: EC 2.7.10.2 (Focal Adhesion Protein-Tyrosine Kinases)
تواريخ الأحداث: Date Created: 20220927 Date Completed: 20221205 Latest Revision: 20240607
رمز التحديث: 20240607
مُعرف محوري في PubMed: PMC9722639
DOI: 10.1158/2159-8290.CD-22-0192
PMID: 36165893
قاعدة البيانات: MEDLINE
الوصف
تدمد:2159-8290
DOI:10.1158/2159-8290.CD-22-0192