Date of Award

2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Pharmacology

First Advisor

Dmitry I. Gabrilovich

Abstract

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of pathologically activated immature myeloid cells that expand and accumulate in cancer, and are categorized as M-MDSC or PMN-MDSC. The role of MDSC to suppress T-cell activation and proliferation in the tumor microenvironment has been clarified over the past 15 years. Our lab has previously demonstrated that an inflammatory environment can lead to the expansion of “MDSC-like” cells that lack immunosuppressive capability. However, the role of these MDSC-like cells in cancer has not been elucidated. First, we hypothesized that PMN-MDSC-like cells will develop in relatively low inflammatory conditions, such as the early stages of tumor development. Next, we hypothesized that because bona fide PMN-MDSC must migrate into tissues to exert their immunosuppressive effects, PMN-MDSC-like cells that lack immunosuppressive capability will exhibit altered migratory behavior. Finally, because many immune cells undergo metabolic reprogramming to meet the energetic demands of their functionality, we hypothesized that PMN-MDSC-like cells would alter their metabolic profile compared to na�ve PMN and bona fide PMN-MDSC. We have demonstrated that PMN-MDSC-like cells develop in the early stages of tumor development and in transgenic models, but not in the late stages of tumor development or in transplantable models. Moreover, we have found that PMN-MDSC-like cells spontaneously migrate 2-3 fold more than na�ve PMN, and that this motility is characterized by increased speed, persistence time, mean squared displacement and an overall increased random motility coefficient. We demonstrated that PMN-MDSC-like cell spontaneous migration is dependent upon pannexin-1 hemichannel-mediated ATP release, autocrine ATP signaling through the P2X1 purinergic receptor, and increased pMLC2 levels. Additionally, we have shown that PMN-MDSC-like cells increase cell surface expression of the glucose transporter Glut1. Finally, we have shown that, in comparison to na�ve PMN and bona fide PMN-MDSC, PMN-MDSC-like cells increase their glycolytic rate to meet the energetic demands of their altered migratory behavior. Collectively, these studies have shed insight on the development of bona fide PMN-MDSC in cancer, and have suggested a role for PMN-MDSC-like cells in pre-metastatic niche development.

Embargoed

Available to all on Tuesday, June 16, 2020

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