Regulation of the Prostate Cancer Tumor Microenvironment
Technical Report,15 Mar 2011,14 Mar 2017
University of California Los Angeles United States
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The role of innate immunity in prostate cancer tumorigenesis is unclear. We hypothesis that innate immune pathways contribute to programming the inflammatory component of the tumor microenvironment and that activation of these pathways may selectively skew this immune composition and alter tumor growth. Pattern recognition receptors such as Toll-like receptors TLRs are key signaling molecules that regulate innate and adaptive immune responses in the presence of pathogens and endogenous ligands. We have generated and characterized TRAMP Tg- x MyD88-- mice. We showed that de novo prostate cancers in absence of MyD88 develop higher grade adenocarcinomas than wild-type controls at 30 weeks of age. Analysis of tumor infiltrating cells revealed increased infiltration of macrophage lineage cells, characterized as myeloid-derived suppressor cells MDSCs, and decreased CD8 T lymphocytes and NK cells. We have shown that MyD88plays in intrinsic role in the differentiation of MDSCs, with the absence of MyD88 biasing development towards the granulocytic subtype. MyD88-deficient MDSCs have an increased migration in response to the endogenous ligand S100A9,suggesting a role of MyD88 in governing MDSC homeostasis that can be leveraged as an anti-tumor therapy.
- Medicine and Medical Research