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+Ly6Clow granulocytic (G)-MDSCs, sparing CD11b+Ly6G−Ly6Chigh 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.

Analyzing One Cell at a TIME: Analysis of Myeloid Cell Contributions in the Tumor Immune Microenvironment

“…A growing body of evidence supports that MDSCs retain some ability to polarize to a cell displaying more characteristics of typical monocytes ( 32 , 33 ). Genetic and pharmacologic methods can promote maturation or polarization in MDSCs, with multiple groups reporting that M-MDSCs can be functionally characterized into not only suppressive states, but also into reactive states ( 32 , 34 , 35 ). Transcriptional programs initiated by c-EBPβ, STAT3, PU.1, IRF8, and RORC1, among others, regulate the suppressive activities of MDSCs ( 36 ).…”

Molecular Regulation of Bone Metastasis Pathogenesis

“…In recent studies, the role of MDSCs in immune escape is a critical role for preventing and decreasing bone metastasis [127, 128]. The strategies of MDSC inhibition was proposed: deactivation, blocking development, and depletion of MDSCs.…”

Comparison of Myeloid Cells in Circulation and in the Tumor Microenvironment of Patients with Colorectal and Breast Cancers

“…Expansion of infiltrating lymphocytes in cancers is often associated with antitumor response and improved clinical outcome [ 9 ]. While cancer treatment strategies like adoptive T cell therapies, which involve transferring in vitro expanded autologous cytotoxic T cells to eradicate tumor cells [ 10 ], aim to elevate the levels of infiltrating lymphocytes, MDSC are recognized as key checkpoint which favor evasion of immune response against tumor and are targeted to reduce their levels in the TME [ 11 ]. High neutrophil to lymphocyte ratio (NLR) has been recognized as a prognostic indicator, associated with patients with advanced stage disease in various malignancies [ 12 ].…”