Down-regulation of PLCgamma2-beta-catenin pathway promotes activation and expansion of myeloid-derived suppressor cells in cancer
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- Down-regulation of PLCgamma2-beta-catenin pathway promotes activation and expansion of myeloid-derived suppressor cells in cancer
- A H Capietto; Seok Ho Kim; D E Sanford; D C Linehan; M Hikida; T Kumosaki; D V Novack; R Faccio
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- Myeloid-derived suppressor cells (MDSCs) favor tumor promotion, mainly by suppressing antitumor T cell responses in many cancers. Although the mechanism of T cell inhibition is established, the pathways leading to MDSC accumulation in bone marrow and secondary lymphoid organs of tumor-bearing hosts remain unclear. We demonstrate that downregulation of PLCγ2 signaling in MDSCs is responsible for their aberrant expansion during tumor progression. PLCγ2-/- MDSCs show stronger immune-suppressive activity against CD8+ T cells than WT MDSCs and potently promote tumor growth when adoptively transferred into WT mice. Mechanistically, PLCγ2-/- MDSCs display reduced β-catenin levels, and restoration of β-catenin expression decreases their expansion and tumor growth. Consistent with a negative role for β-catenin in MDSCs, its deletion in the myeloid population leads to MDSC accumulation and supports tumor progression, whereas expression of β-catenin constitutively active reduces MDSC numbers and protects from tumor growth. Further emphasizing the clinical relevance of these findings, MDSCs isolated from pancreatic cancer patients show reduced p-PLCβ2 and β-catenin levels compared with healthy controls, similar to tumor-bearing mice. Thus, for the first time, we demonstrate that down-regulation of PLCγ2-β-catenin pathway occurs in mice and humans and leads to MDSC-mediated tumor expansion, raising concerns about the efficacy of systemic β-catenin blockade as anti-cancer therapy.
- Rockefeller University Press
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- 1. Journal Articles > Journal Articles
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