Date on Master's Thesis/Doctoral Dissertation

1-2020

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Microbiology and Immunology

Degree Program

Microbiology and Immunology, PhD

Committee Chair

Yan, Jun

Committee Co-Chair (if applicable)

Yolcu, Esma

Committee Member

Bodduluri, Haribabu

Committee Member

Shirwan, Haval

Committee Member

Zhang, Huang-ge

Author's Keywords

exosomes; PD-L1; pre-metastatic niche; metabolism; lactate

Abstract

The formation of a pre-metastatic niche is a fundamental requirement for primary tumor metastasis. One of the defining characteristics of a pre-metastatic niche is infiltration of immunosuppressive macrophages. However, how these macrophages acquire their immunosuppressive phenotype remains largely unexplored. Here, we demonstrate that tumor-derived exosomes (TDE) polarize macrophages towards an immunosuppressive phenotype characterized by increased PD-L1 expression through NF-kB-dependent metabolic reprogramming in mice and humans. While NF-κB has previously been shown to act as a direct transcription factor for PD-L1, we report a novel mechanism where TDE-induced NF-κB activation drives PD-L1 expression by augmenting the glycolytic capacity of macrophages through two separate pathways. First, NF-κB increases glucose uptake into macrophages via a HIF-1α/GLUT-1-dependent mechanism. Secondly, elevated NOS2-dependent nitric oxide inhibits mitochondrial oxidative phosphorylation resulting in an increased conversion of pyruvate to lactate. Lactate then feeds back on NF-κB further increasing PD-L1 expression. Analysis of metastasis negative draining lymph nodes of non-small cell lung cancer patients revealed that macrophage PD-L1 expression positively correlates with expression levels of GLUT-1 and exosomal release genes YKT6 and TSG101 from primary tumors. Collectively, our study provides a novel mechanism by which macrophages within a pre-metastatic niche acquire their immunosuppressive phenotype and identifies an important link between exosomes, metabolism, and metastasis.

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