title: Down-regulation of PLCγ2-β-catenin pathway promotes activation and expansion of myeloid-derived suppressor cells in cancer.
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 down-regulation 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-PLCγ2 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.
authors.affiliation: Department of Orthopedics, 2 Department of Surgery, 3 Department of Medicine, Washington University School of Medicine, St. Louis, MO.
authors.forename: Aude-Hélène
authors.initials: AH
authors.lastname: Capietto
authors.forename: Seokho
authors.initials: S
authors.lastname: Kim
authors.forename: Dominic E
authors.initials: DE
authors.lastname: Sanford
authors.forename: David C
authors.initials: DC
authors.lastname: Linehan
authors.forename: Masaki
authors.initials: M
authors.lastname: Hikida
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kumosaki
authors.forename: Deborah V
authors.initials: DV
authors.lastname: Novack
authors.forename: Roberta
authors.initials: R
authors.lastname: Faccio
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000378:metabolism* / Q000473:pathology*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051966:Phospholipase C gamma / Q000172:deficiency / Q000378:metabolism*; D055550:Protein Stability; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051176:beta Catenin; D051966:Phospholipase C gamma