Oncotarget

Research Papers:

Indoleamine 2,3-dioxygenase regulates anti-tumor immunity in lung cancer by metabolic reprogramming of immune cells in the tumor microenvironment

Cara C. Schafer, Yong Wang, Kenneth P. Hough, Anandi Sawant, Stefan C. Grant, Victor J. Thannickal, Jaroslaw Zmijewski, Selvarangan Ponnazhagan and Jessy S. Deshane _

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Oncotarget. 2016; 7:75407-75424. https://doi.org/10.18632/oncotarget.12249

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Abstract

Cara C. Schafer1, Yong Wang1, Kenneth P. Hough1, Anandi Sawant2, Stefan C. Grant1, Victor J. Thannickal1, Jaroslaw Zmijewski1, Selvarangan Ponnazhagan2, Jessy S. Deshane1

1Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

2Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

Correspondence to:

Jessy S. Deshane, email: treena@uab.edu

Keywords: indoleamine 2,3-dioxygenase, myeloid-derived suppressor cells, lung cancer, metabolism, combination therapy

Received: March 01, 2016    Accepted: September 13, 2016    Published: September 26, 2016

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.


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