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Title 

Down-regulation of PLCgamma2-beta-catenin pathway promotes activation and expansion of myeloid-derived suppressor cells in cancer

Authors 

A H CapiettoSeok Ho KimD E SanfordD C LinehanM HikidaT KumosakiD V NovackR Faccio

Publisher 

Rockefeller University Press

Issue Date 

2013

Citation 

Journal of Experimental Medicine, vol. 210, no. 11, pp. 2257-2271

Abstract 

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.

ISSN 

0022-1007

Link 

http://dx.doi.org/10.1084/jem.20130281

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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