title: Indoleamine 2,3-dioxygenase regulates anti-tumor immunity in lung cancer by metabolic reprogramming of immune cells in the tumor microenvironment.
abstract: Indoleamine 2,3-dioxygenase (IDO) has been implicated in immune evasion by tumors. Upregulation of this tryptophan (Trp)-catabolizing enzyme, in tumor cells and myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment (TME), leads to Trp depletion that impairs cytotoxic T cell responses and survival; however, exact mechanisms remain incompletely understood. We previously reported that a combination therapy of gemcitabine and a superoxide dismutase mimetic promotes anti-tumor immunity in a mouse model of lung cancer by inhibiting MDSCs, enhancing polyfunctional response of CD8+ memory T cells, and extending survival. Here, we show that combination therapy targets IDO signaling, specifically in MDSCs, tumor cells, and CD8+ T cells infiltrating the TME. Deficiency of IDO caused significant reduction in tumor burden, tumor-infiltrating MDSCs, GM-CSF, MDSC survival and infiltration of programmed death receptor-1 (PD-1)-expressing CD8+ T cells compared to controls. IDO-/- MDSCs downregulated nutrient-sensing AMP-activated protein kinase (AMPK) activity, but IDO-/- CD8+ T cells showed AMPK activation associated with enhanced effector function. Our studies provide proof-of-concept for the efficacy of this combination therapy in inhibiting IDO and T cell exhaustion in a syngeneic model of lung cancer and provide mechanistic insights for IDO-dependent metabolic reprogramming of MDSCs that reduces T cell exhaustion and regulates anti-tumor immunity.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Cara C
authors.initials: CC
authors.lastname: Schafer
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Hough
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Anandi
authors.initials: A
authors.lastname: Sawant
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Stefan C
authors.initials: SC
authors.lastname: Grant
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Zmijewski
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Selvarangan
authors.initials: S
authors.lastname: Ponnazhagan
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Jessy S
authors.initials: JS
authors.lastname: Deshane
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004734:Energy Metabolism; D056747:Immunomodulation / Q000235:genetics; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D047368:Tumor Burden; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C529271:EIF2AK4 protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases
keywords: combination therapy; lung cancer; metabolism; myeloid-derived suppressor cells; indoleamine 2,3-dioxygenase