The indoleamine 2,3-dioxygenase pathway controls complement-dependent enhancement of chemo-radiation therapy against murine glioblastoma

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• 作者：Minghui Li (7) (8) (9)
  Aaron R Bolduc (10) (7) (8)
  Md Nasrul Hoda (11) (15)
  Denise N Gamble (7) (8)
  Sarah-Bianca Dolisca (9)
  Anna K Bolduc (7) (8)
  Kelly Hoang (9)
  Claire Ashley (9)
  David McCall (7) (8)
  Amyn M Rojiani (12) (7)
  Bernard L Maria (11) (13) (7) (9)
  Olivier Rixe (14) (7)
  Tobey J MacDonald (16)
  Peter S Heeger (17) (18)
  Andrew L Mellor (14) (7) (8)
  David H Munn (7) (8) (9)
  Theodore S Johnson (7) (8) (9)
  
  7. GRU Cancer Center ; Georgia Regents University ; Augusta ; Georgia ; 30912 ; USA
  8. Program in Cancer immunology ; Inflammation and Tolerance (CIT) ; Georgia Regents University ; Augusta ; GA ; USA
  9. Medical College of Georgia Department of Pediatrics ; Georgia Regents University ; 1120 Fifteenth Street ; Augusta ; GA ; CN-4141A ; USA
  10. Department of Surgery ; Georgia Regents University ; Augusta ; GA ; USA
  11. Department of Neurology ; Georgia Regents University ; Augusta ; GA ; USA
  15. College of Allied Health Sciences Department of Medical Laboratory ; Imaging & Radiologic Sciences ; Georgia Regents University ; Augusta ; GA ; 30912 ; USA
  12. Department of Pathology ; Georgia Regents University ; Augusta ; GA ; USA
  13. Department of Neurosurgery ; Georgia Regents University ; Augusta ; GA ; USA
  14. Department of Medicine ; Georgia Regents University ; Augusta ; GA ; USA
  16. Aflac Cancer & Blood Disorders Center ; Children鈥檚 Healthcare of Atlanta ; Emory University School of Medicine ; Atlanta ; GA ; 30322 ; USA
  17. Department of Medicine ; Division of Nephrology ; The Immunology Institute ; New York ; NY ; 10025 ; USA
  18. Recanati-Miller Transplant Institute ; Icahn School of Medicine at Mount Sinai ; New York ; NY ; 10025 ; USA
  
• 关键词：IDO ; Indoleamine ; Complement ; Tumor ; Immunotherapy ; Chemotherapy ; Radiation therapy ; Indoximod ; Glioblastoma ; NLG919
• 刊名：Journal for Immunotherapy of Cancer
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：2
• 期：1
• 全文大小：3,327 KB
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• 刊物主题：Oncology;
• 出版者：BioMed Central
• ISSN：2051-1426

文摘

Background Indoleamine 2,3-dioxygenase (IDO) is an enzyme with immune-suppressive properties that is commonly exploited by tumors to evade immune destruction. Anti-tumor T cell responses can be initiated in solid tumors, but are immediately suppressed by compensatory upregulation of immunological checkpoints, including IDO. In addition to these known effects on the adaptive immune system, we previously showed widespread, T cell-dependent complement deposition during allogeneic fetal rejection upon maternal treatment with IDO-blockade. We hypothesized that IDO protects glioblastoma from the full effects of chemo-radiation therapy by preventing vascular activation and complement-dependent tumor destruction. Methods To test this hypothesis, we utilized a syngeneic orthotopic glioblastoma model in which GL261 glioblastoma tumor cells were stereotactically implanted into the right frontal lobes of syngeneic mice. These mice were treated with IDO-blocking drugs in combination with chemotherapy and radiation therapy. Results Pharmacologic inhibition of IDO synergized with chemo-radiation therapy to prolong survival in mice bearing intracranial glioblastoma tumors. We now show that pharmacologic or genetic inhibition of IDO allowed chemo-radiation to trigger widespread complement deposition at sites of tumor growth. Chemotherapy treatment alone resulted in collections of perivascular leukocytes within tumors, but no complement deposition. Adding IDO-blockade led to upregulation of VCAM-1 on vascular endothelium within the tumor microenvironment, and further adding radiation in the presence of IDO-blockade led to widespread deposition of complement. Mice genetically deficient in complement component C3 lost all of the synergistic effects of IDO-blockade on chemo-radiation-induced survival. Conclusions Together these findings identify a novel mechanistic link between IDO and complement, and implicate complement as a major downstream effector mechanism for the beneficial effect of IDO-blockade after chemo-radiation therapy. We speculate that this represents a fundamental pathway by which the tumor regulates intratumoral vascular activation and protects itself from immune-mediated tumor destruction.