Therapeutic targeting of myeloid-derived suppressor cells involves a novel mechanism mediated by clusterin
Junmin Zhou1, Sarah S Donatelli1, Danielle L Gilvary1
1Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
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.
Insights
Chemotherapy spares monocytic myeloid-derived suppressor cells (M-MDSCs) by secreting clusterin (sCLU), enabling them to become anti-tumor M1 macrophages. This mechanism enhances cancer immunity against breast cancer.
Area of Science:
- Immunology
- Cancer Biology
- Pharmacology
Background:
- Myeloid-derived suppressor cells (MDSCs) are crucial in suppressing anti-tumor immunity.
- Chemotherapeutic strategies targeting MDSCs show promise but their mechanisms require elucidation.
Purpose of the Study:
- To uncover the mechanism by which certain chemotherapeutic agents modulate MDSCs for cancer therapy.
- To investigate the role of monocytic MDSCs (M-MDSCs) in mediating anti-tumor immunity post-chemotherapy.
Main Methods:
- Selective targeting of granulocytic (G)-MDSCs versus M-MDSCs using curcumin and docetaxel (DTX) in a 4T1-Neu mouse model.
- Analysis of M-MDSC polarization, cytokine production (IFN-γ), and T cell function.
- Investigation of secretory/cytoplasmic clusterin (sCLU) role in M-MDSC chemoresistance via Bax inhibition.
- Assessment of sCLU expression in breast cancer patient tumor-infiltrating myeloid cells.
Main Results:
- Curcumin and DTX selectively depleted G-MDSCs, sparing M-MDSCs, leading to reduced tumor burden.
- Surviving M-MDSCs polarized into M1 macrophages, enhancing T cell-mediated anti-tumor immunity.
- Secretory/cytoplasmic clusterin (sCLU) mediated chemoresistance in M-MDSCs by inhibiting Bax-dependent apoptosis.
- sCLU was detected in M-MDSCs but not G-MDSCs, and its knockdown reversed chemoresistance.
- Clinical samples showed sCLU expression in mature macrophages, not immature immunosuppressive myeloid cells.
Conclusions:
- Selective chemoresistance of M-MDSCs to agents like curcumin and DTX is mediated by sCLU.
- sCLU facilitates M-MDSC polarization to M1 macrophages, promoting anti-tumor immunity.
- sCLU expression in M-MDSCs represents a novel mechanism for positive immunomodulation by chemotherapy in breast cancer.
