Targeting the glucose metabolism of myeloid-derived suppressor cells (MDSCs) to stimulate cancer immunity.

MDSCs;myeloid;glucose metabolism

Jaspreet Grewal

University:University of Louisville

Department:Pharmacology and Toxicology

关键词: MDSCs;    myeloid;    glucose metabolism;   

Others  :  https://ir.library.louisville.edu/cgi/viewcontent.cgi?article=3787&context=etd

美国|英语

来源: The Universite of Louisville's Institutional Repository

【 摘 要 】

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.