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Indoleamine 2,3-dioxygenase regulates anti-tumor immunity in lung cancer by metabolic reprogramming of immune cells in the tumor microenvironment
| Content Provider | Semantic Scholar |
|---|---|
| Author | Schafer, Cara C. Wang, Yong Hough, Kenneth P. Sawant, Anandi B. Grant, Stefan C. Thannickal, Victor J. Zmijewski, Jaroslaw W. Ponnazhagan, Selvarangan Deshane, Jessy S. |
| Copyright Year | 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. |
| Starting Page | 75407 |
| Ending Page | 75424 |
| Page Count | 18 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://www.oncotarget.com/index.php?journal=oncotarget&op=download&page=article&path%5B%5D=12249&path%5B%5D=38782 |
| PubMed reference number | 27705910v1 |
| Alternate Webpage(s) | https://doi.org/10.18632/oncotarget.12249 |
| DOI | 10.18632/oncotarget.12249 |
| Journal | Oncotarget |
| Volume Number | 7 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Carcinoma of lung Gentamicins Indoleamine-Pyrrole 2,3,-Dioxygenase Infiltration Inhibition Leukemia, B-Cell Metabolic Process, Cellular Myeloid-Derived Suppressor Cells Neoplasms Protein Kinases Reprogram Superoxides Tryptophan Tumor Burden Tumor Immunity Tumor Microenvironment gemcitabine |
| Content Type | Text |
| Resource Type | Article |
