Date on Master's Thesis/Doctoral Dissertation

5-2017

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, PhD

Committee Chair

Chesney, Jason

Committee Co-Chair (if applicable)

Yaddanapudi, Kavitha

Committee Member

Clem, Brian

Committee Member

Siskind, Leah

Committee Member

Salter, Russell

Author's Keywords

MDSCs; myeloid; glucose metabolism

Abstract

Myeloid derived suppressor cells (MDSCs) are a heterogeneous group of immature myeloid cells that are significantly increased in cancer patients and correlate with higher stage and poor prognosis. MDSCs negatively modulate anti-tumor immunity, suppress T cell activity, promote angiogenesis and increase the risk of metastasis. In this study, we report that monocytic-MDSCs (M-MDSCs) but polymorphonuclear-MDSCs (PMN-MDSCs) over-express 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatases 3 (PFKFB3), an important regulator of glycolysis. Furthermore in the melanoma model, M-MDSCs but not PMN-MDSCs suppressed T cell function which correlated with PFKFB3 over-expression and increased rate of glycolysis. PFKFB3 inhibition with the first-in-class small molecule inhibitor, PFK-158 reversed M-MDSC mediated T cell suppression and decreased the expression of arginase 1 and inducible nitric oxide synthase (iNOS) both in vitro and in vivo. In addition, both in B16-F10 tumor-bearing mice and patients enrolled in Phase 1 clinical trial, PFKFB3 inhibition resulted in decrease in M-MDSC frequency and increase in effector T cell populations. In this first-of-a-kind study, we present strong evidence for targeting metabolic profile of M-MDSCs to modulate their immune suppressive phenotype. This study provides the basis to study PFK-158 as an immunomodulatory agent in combination with immune checkpoint blockade therapies to improve T cell activity and anti-tumor responses.

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