دورية أكاديمية
Stromal Reprogramming by FAK Inhibition Overcomes Radiation Resistance to Allow for Immune Priming and Response to Checkpoint Blockade.
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.) |
References: | Clin Cancer Res. 2016 Dec 1;22(23):5851-5863. (PMID: 27220963) Nat Rev Mol Cell Biol. 2005 Jan;6(1):56-68. (PMID: 15688067) Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20212-7. (PMID: 24277834) N Engl J Med. 2004 Mar 18;350(12):1200-10. (PMID: 15028824) Cell. 2015 Jan 15;160(1-2):324-38. (PMID: 25557080) Oncogenesis. 2015 May 18;4:e148. (PMID: 25985209) Sci Adv. 2020 Sep 11;6(37):. (PMID: 32917705) Cancer Cell. 2014 Jun 16;25(6):719-34. (PMID: 24856586) Gastroenterology. 2016 Jun;150(7):1659-1672.e5. (PMID: 26946344) F1000Res. 2018 Dec 13;7:. (PMID: 30613390) Innovation (Camb). 2021 Jul 01;2(3):100141. (PMID: 34557778) Cancer Res. 2008 Jun 1;68(11):4398-405. (PMID: 18519702) Cancer Discov. 2019 Feb;9(2):282-301. (PMID: 30366930) Nat Protoc. 2009;4(11):1670-80. (PMID: 19876027) Clin Cancer Res. 2005 Jan 15;11(2 Pt 1):743-50. (PMID: 15701864) J Cell Physiol. 2013 Jul;228(7):1601-9. (PMID: 23359252) Int J Radiat Oncol Biol Phys. 2008 Aug 1;71(5):1591-9. (PMID: 18640502) Nat Rev Cancer. 2021 May;21(5):313-324. (PMID: 33731845) Cancer Res. 2008 Feb 1;68(3):918-26. (PMID: 18245495) EBioMedicine. 2020 Mar;53:102655. (PMID: 32139179) Nat Med. 2007 Aug;13(8):992-7. (PMID: 17676052) Int J Gastrointest Cancer. 2003;34(2-3):121-8. (PMID: 15361645) Cancer Cell. 2021 Apr 12;39(4):548-565.e6. (PMID: 33667385) J Exp Med. 2017 Mar 6;214(3):579-596. (PMID: 28232471) Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18490-5. (PMID: 19001271) Cancer Cell. 2005 May;7(5):469-83. (PMID: 15894267) Cancer Cell. 2020 Mar 16;37(3):289-307.e9. (PMID: 32183949) Mol Cancer Ther. 2011 Nov;10(11):2135-45. (PMID: 21903606) Cancer Discov. 2019 Aug;9(8):1102-1123. (PMID: 31197017) Nat Rev Gastroenterol Hepatol. 2020 Mar;17(3):153-168. (PMID: 32005945) Gut. 2017 Jan;66(1):124-136. (PMID: 27402485) Ann Surg Oncol. 2011 Dec;18(13):3601-7. (PMID: 21947697) Int J Radiat Oncol Biol Phys. 2005 Nov 1;63(3):901-10. (PMID: 16199320) Genome Biol. 2019 Dec 23;20(1):296. (PMID: 31870423) Nat Methods. 2019 Dec;16(12):1289-1296. (PMID: 31740819) Nat Med. 2016 Aug;22(8):851-60. (PMID: 27376576) Nat Med. 2016 May;22(5):497-505. (PMID: 27089513) Cancers (Basel). 2020 Feb 19;12(2):. (PMID: 32092952) Am J Respir Crit Care Med. 2008 Jan 1;177(1):82-90. (PMID: 17916808) World J Gastrointest Oncol. 2020 Feb 15;12(2):173-181. (PMID: 32104548) Nature. 2014 Oct 2;514(7520):112-6. (PMID: 25079333) Cancer Discov. 2020 Feb;10(2):232-253. (PMID: 31699795) Sci Rep. 2016 Jan 14;6:19276. (PMID: 26763945) Physiol Rev. 2021 Jan 1;101(1):147-176. (PMID: 32466724) Cancer Cell. 2021 Sep 13;39(9):1227-1244.e20. (PMID: 34297917) J Clin Invest. 2007 May;117(5):1305-13. (PMID: 17415413) Cancer Discov. 2022 Jun 2;12(6):1580-1597. (PMID: 35348629) Cancers (Basel). 2020 Oct 11;12(10):. (PMID: 33050580) Cancer Discov. 2022 Feb;12(2):484-501. (PMID: 34548310) Clin Cancer Res. 2020 Sep 15;26(18):4814-4822. (PMID: 32554514) Cancer Res. 2011 May 15;71(10):3453-8. (PMID: 21558392) Nat Rev Clin Oncol. 2021 Dec;18(12):792-804. (PMID: 34489603) Cancer Discov. 2021 Feb;11(2):446-479. (PMID: 33127842) Nat Rev Clin Oncol. 2018 Jun;15(6):366-381. (PMID: 29651130) J Surg Oncol. 2013 Jan;107(1):86-96. (PMID: 22532174) Gastrointest Cancer Res. 2009 Jan;3(1):20-8. (PMID: 19343134) J Immunother Cancer. 2016 Mar 15;4:14. (PMID: 26981244) J Natl Cancer Inst. 2007 Oct 3;99(19):1441-54. (PMID: 17895480) J Immunol. 2012 Jul 15;189(2):558-66. (PMID: 22685313) J Clin Invest. 2016 Nov 1;126(11):4140-4156. (PMID: 27701147) N Engl J Med. 2015 Jul 2;373(1):23-34. (PMID: 26027431) Nat Rev Cancer. 2014 Sep;14(9):598-610. (PMID: 25098269) Cancer Lett. 2006 Oct 8;242(1):11-9. (PMID: 16448744) Clin Cancer Res. 2012 Aug 15;18(16):4266-76. (PMID: 22896693) N Engl J Med. 2018 May 31;378(22):2078-2092. (PMID: 29658856) Cell Struct Funct. 1996 Oct;21(5):445-50. (PMID: 9118254) Blood. 2009 Jul 16;114(3):589-95. (PMID: 19349616) World J Gastroenterol. 2018 Nov 21;24(43):4846-4861. (PMID: 30487695) Lancet. 2004 Mar 27;363(9414):1049-57. (PMID: 15051286) N Engl J Med. 2015 Jun 25;372(26):2521-32. (PMID: 25891173) Pancreas. 2004 Oct;29(3):179-87. (PMID: 15367883) Oncogene. 2006 Mar 2;25(9):1378-90. (PMID: 16247454) JAMA Oncol. 2019 Oct 01;5(10):1431-1438. (PMID: 31318392) Biophys J. 2016 May 10;110(9):2106-19. (PMID: 27166818) Sci Rep. 2017 Aug 30;7(1):10093. (PMID: 28855644) Cancer Immunol Immunother. 2017 Aug;66(8):1037-1048. (PMID: 28451791) JCI Insight. 2017 Oct 5;2(19):. (PMID: 28978805) Cell. 2015 Sep 24;163(1):160-73. (PMID: 26406376) Int J Cancer. 2009 May 15;124(10):2468-77. (PMID: 19165865) Cell Rep. 2017 Apr 4;19(1):203-217. (PMID: 28380359) Gut. 2014 Nov;63(11):1769-81. (PMID: 24555999) Br J Cancer. 2009 Jul 7;101(1):91-7. (PMID: 19491897) Front Oncol. 2012 Dec 17;2:191. (PMID: 23251903) Cancer Res. 2000 May 1;60(9):2497-503. (PMID: 10811131) Cancer Res. 2006 Feb 1;66(3):1526-35. (PMID: 16452209) Clin Cancer Res. 2015 Aug 1;21(15):3561-8. (PMID: 25695692) Front Oncol. 2019 Dec 06;9:1376. (PMID: 31867279) Front Oncol. 2014 Jan 21;4:1. (PMID: 24478982) J Gastrointest Oncol. 2018 Dec;9(6):1014-1026. (PMID: 30603120) World J Gastroenterol. 2015 Aug 21;21(31):9297-316. (PMID: 26309356) Mol Cancer. 2019 Jan 21;18(1):14. (PMID: 30665410) Front Mol Biosci. 2014 Nov 17;1:24. (PMID: 25988165) Cell Rep. 2019 Oct 8;29(2):406-421.e5. (PMID: 31597100) |
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 |
تدمد: | 2159-8290 |
---|---|
DOI: | 10.1158/2159-8290.CD-22-0192 |