title: Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors.
abstract: OBJECTIVE
  Glioblastoma (GBM) is the most common form of malignant glioma in adults. Although protected by both the blood-brain and blood-tumor barriers, GBMs are actively infiltrated by T cells. Previous work has shown that IDO, CTLA-4, and PD-L1 are dominant molecular participants in the suppression of GBM immunity. This includes IDO-mediated regulatory T-cell (Treg; CD4(+)CD25(+)FoxP3(+)) accumulation, the interaction of T-cell-expressed, CTLA-4, with dendritic cell-expressed, CD80, as well as the interaction of tumor- and/or macrophage-expressed, PD-L1, with T-cell-expressed, PD-1. The individual inhibition of each pathway has been shown to increase survival in the context of experimental GBM. However, the impact of simultaneously targeting all three pathways in brain tumors has been left unanswered.
  
  
  RESULTS
  In this report, we demonstrate that, when dually challenged, IDO-deficient tumors provide a selectively competitive survival advantage against IDO-competent tumors. Next, we provide novel observations regarding tryptophan catabolic enzyme expression, before showing that the therapeutic inhibition of IDO, CTLA-4, and PD-L1 in a mouse model of well-established glioma maximally decreases tumor-infiltrating Tregs, coincident with a significant increase in T-cell-mediated long-term survival. In fact, 100% of mice bearing intracranial tumors were long-term survivors following triple combination therapy. The expression and/or frequency of T cell expressed CD44, CTLA-4, PD-1, and IFN-γ depended on timing after immunotherapeutic administration.
  
  
  CONCLUSIONS
  Collectively, these data provide strong preclinical evidence that combinatorially targeting immunosuppression in malignant glioma is a strategy that has high potential value for future clinical trials in patients with GBM.
authors.affiliation: The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, Illinois.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Wainwright
authors.affiliation: The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, Illinois.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Chang
authors.affiliation: The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, Illinois.
authors.forename: Mahua
authors.initials: M
authors.lastname: Dey
authors.affiliation: The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, Illinois.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Balyasnikova
authors.affiliation: The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, Illinois.
authors.forename: Chung Kwon
authors.initials: CK
authors.lastname: Kim
authors.affiliation: The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, Illinois.
authors.forename: Alex
authors.initials: A
authors.lastname: Tobias
authors.affiliation: The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, Illinois.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, Illinois.
authors.forename: Julius W
authors.initials: JW
authors.lastname: Kim
authors.affiliation: The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, Illinois.
authors.forename: Jian
authors.initials: J
authors.lastname: Qiao
authors.affiliation: The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, Illinois.
authors.forename: Lingjiao
authors.initials: L
authors.lastname: Zhang
authors.affiliation: The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, Illinois.
authors.forename: Yu
authors.initials: Y
authors.lastname: Han
authors.affiliation: The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, Illinois mlesniak@surgery.bsd.uchicago.edu.
authors.forename: Maciej S
authors.initials: MS
authors.lastname: Lesniak
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors*; D051379:Mice; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D000077204:Temozolomide
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D060908:CTLA-4 Antigen; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D003606:Dacarbazine; D000077204:Temozolomide