Glioma-derived M-CSF and IL-34 license M-MDSCs to suppress CD8 + T cells in a NOS-dependent manner.
- Resource Type
- Academic Journal
- Authors
- Takacs GP; Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, FL, 32610, United States.; Garcia JS; Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, FL, 32610, United States.; Hodges CA; Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, FL, 32610, United States.; Kreiger CJ; Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, FL, 32610, United States.; Sherman A; Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, FL, 32610, United States.; Harrison JK; Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, FL, 32610, United States.
- Source
- Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE
- Subject
- Language
- English
Glioblastoma (GBM) is the most common malignant primary brain tumor, resulting in poor survival despite aggressive therapies. GBM is characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME) made up predominantly of infiltrating peripheral immune cells. One significant immune cell type that contributes to glioma immune evasion is a population of immunosuppressive cells, termed myeloid-derived suppressor cells (MDSCs). Previous studies suggest that a subset of myeloid cells, expressing monocytic (M)-MDSC markers and dual expression of chemokine receptors CCR2 and CX3CR1, utilize CCR2 to infiltrate the TME. This study evaluated the mechanism of CCR2 + /CX3CR1 + M-MDSC differentiation and T cell suppressive function in murine glioma models. We determined that bone marrow-derived CCR2 + /CX3CR1 + cells adopt an immune suppressive cell phenotype when cultured with glioma-derived factors. Glioma secreted CSF1R ligands M-CSF and IL-34 were identified as key drivers of M-MDSC differentiation while adenosine and iNOS pathways were implicated in M-MDSC suppression of T cells. Mining a human GBM spatial RNAseq database revealed a variety of different pathways that M-MDSCs utilize to exert their suppressive function that are driven by complex niches within the microenvironment. These data provide a more comprehensive understanding of the mechanism of M-MDSCs in glioblastoma.
Competing Interests: Conflicts of Interest: The authors declare no conflict of interest.