title: Therapeutic targeting of myeloid-derived suppressor cells involves a novel mechanism mediated by clusterin.
abstract: Myeloid-derived suppressor cells (MDSCs) constitute a key checkpoint that impedes tumor immunity against cancer. Chemotherapeutic intervention of MDSCs has gained ground as a strategy for cancer therapy but its mechanism remains obscure.We report here a unique mechanism by which monocytic (M)-MDSCs are spared, allowing them to polarize towards M1 macrophages for reactivation of immunity against breast cancer. We first demonstrated that curcumin, like docetaxel (DTX), can selectively target CD11b(+)Ly6G(+)Ly6C(low) granulocytic (G)-MDSCs, sparing CD11b(+)Ly6G(-)Ly6C(high) M-MDSCs, with reduced tumor burden in 4T1-Neu tumor-bearing mice. Curcumin treatment polarized surviving M-MDSCs toward CCR7(+) Dectin-1(-)M1 cells, accompanied by IFN-γ production and cytolytic function in T cells. Selective M-MDSC chemoresistence to curcumin and DTX was mediated by secretory/cytoplasmic clusterin (sCLU). sCLU functions by trapping Bax from mitochondrial translocation, preventing the apoptotic cascade. Importantly, sCLU was only found in M-MDSCs but not in G-MDSCs. Knockdown of sCLU in M-MDSCs and RAW264.7 macrophages was found to reverse their natural chemoresistance. Clinically, breast cancer patients possess sCLU expression only in mature CD68(+) macrophages but not in immature CD33(+) immunosuppressive myeloid cells infiltrating the tumors. We thus made the seminal discovery that sCLU expression in M-MDSCs accounts for positive immunomodulation by chemotherapeutic agents.
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Junmin
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Donatelli
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Gilvary
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Melba M
authors.initials: MM
authors.lastname: Tejera
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Erika A
authors.initials: EA
authors.lastname: Eksioglu
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Xianghong
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pathology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Domenico
authors.initials: D
authors.lastname: Coppola
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Wei
authors.affiliation: Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Julie Y
authors.initials: JY
authors.lastname: Djeu
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D039481:CD11b Antigen / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051152:Clusterin / Q000378:metabolism*; D003474:Curcumin / Q000008:administration & dosage* / Q000494:pharmacology; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D000072737:Myeloid-Derived Suppressor Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D000067996:RAW 264.7 Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D000950:Antigens, Ly; D000970:Antineoplastic Agents; D039481:CD11b Antigen; C495243:Clu protein, mouse; D051152:Clusterin; C000611649:IFNG protein, mouse; C494192:Ly-6C antigen, mouse; C480309:Ly6G antigen, mouse; D007371:Interferon-gamma; D003474:Curcumin