All ETDs from UAB

Advisory Committee Chair

Jessy S Deshane

Advisory Committee Members

Donald J Buchsbaum

Douglas R Hurst

Selvarangan Ponnazhagan

Theresa V Strong

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Overcoming cancer cell immune escape represents a fundamental obstacle in the treatment of cancer. Indoleamine 2,3-dioxygenase (IDO)-expressing myeloid-derived suppressor cells (MDSCs) are known to induce oxidative stress and alter amino acid metabolism within the tumor microenvironment (TME). The tryptophan (Trp)-catabolizing action of IDO not only promotes T cell tolerance and evasion but is also associated with impaired quality of life in cancer patients. We have previously demonstrated that a novel combination therapy, consisting of MDSC-depleting gemcitabine and a superoxide dismutase mimetic, prolonged survival of tumor-bearing mice by enhancing CD8+ memory T cell metabolism. We identify that combination therapy inhibits IDO in the TME and clarify the signaling mechanisms by which IDO inhibition impacts cellular metabolic signaling, particularly in the major cell subsets infiltrating the TME. These studies utilize a murine lung cancer model implanted with Lewis lung carcinoma cells (LLCs) into wild type (WT) and IDO-/- mice. Compared to WT controls, IDO-/- mice exhibit reduced tumor burden and MDSC infiltration into the TME. In bone marrow-differentiated MDSCs, IDO-/- MDSCs have enhanced apoptosis, suggesting that their survival in tumor-bearing hosts is impaired. Interestingly, IDO-/- CD8+ and CD4+ T cells have lower expression of exhaustion marker PD-1. Analyses of MDSCs, CD8+ T cells, and LLCs from the TME demonstrate a unique role for nutrient-sensing AMP-activated protein kinase (AMPK) activation in IDO-/- CD8+ T cells, coinciding with elevated IFN-γ and lactate production, and AMPK downregulation in IDO-/- MDSCs. WT mice receiving combination therapy downregulate IDO signaling within immune suppressive MDSCs and LLCs, allowing CD8+ T cells to re-establish effector function. These studies clarify the role of host-derived IDO and provide mechanistic evidence that inhibition of IDO, by either genetic deficiency or therapeutic intervention, modulates cross-talk and metabolic signaling networks between cellular components of the TME to improve anti-tumor immunity for lung cancer.

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