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.
Highlights
The metabolic state and activities of the immune cells comprising the tumor microenvironment (TME) influences the proliferative and invasive capacity of tumor cells
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 myeloid-derived suppressor cells (MDSCs), enhancing polyfunctional response of CD8+ memory T cells, and extending survival
We previously demonstrated the effectiveness of a combination therapy of gemcitabine (GEM) and a superoxide dismutase mimetic (SOD) in reducing tumor infiltrating MDSCs and Tregs, while enhancing the quantity and quality of cytotoxic CD8+ T cell response in the TME, in a murine model of lung cancer [15]
Summary
The metabolic state and activities of the immune cells comprising the tumor microenvironment (TME) influences the proliferative and invasive capacity of tumor cells. IDO overexpression, in both hematopoietic and nonhematopoietic compartments [2], can alter metabolic properties of immune and tumor cells to promote tumor progression [3]. Does IDO activation deplete essential Trp from the TME, but it causes accumulation of Kyn which generates a tumor-promoting environment by converting naïve CD4+ T cell development into regulatory T cells (Tregs) that facilitate tolerance to tumors and counteract anti-tumor immune cells [1, 7]. In addition to IDO, upregulation of programmed death ligand-1 and its engagement with the inhibitory receptor programmed death receptor-1 (PD-1) have been identified as immune inhibitory mechanisms that downregulate active T cell responses [8, 9]
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