A Novel Chemoimmunomodulating Property of Docetaxel: Suppression of Myeloid-Derived Suppressor Cells in Tumor Bearers

Abstract

Purpose Myeloid-derived suppressor cells (MDSC) accumulate in tumor-bearing hosts and are associated with immune suppression. To date, there have only been few studies that evaluate the direct effect of chemotherapeutic agents on MDSCs. Agents that inhibit MDSCs may be useful in the treatment of patients with various cancers. Experimental Design We investigated the in vivo effects of docetaxel on immune function in 4T1-Neu mammary tumor-bearing mice to examine if a favorable immunomodulatory effect accompanies tumor suppression. Primary focus was on the differentiation status of MDSCs and their ability to modulate T-cell responses. Results Docetaxel administration significantly inhibited tumor growth in 4T1-Neu tumor-bearing mice and considerably decreased MDSC proportion in the spleen. The treatment also selectively increased CTL responses. Docetaxel-pretreated MDSCs cocultured with OT-II splenocytes in the presence of OVA323–339 showed OT-II–specific CD4 activation and expansion in vitro. In characterizing the phenotype of MDSCs for M1 (CCR7) and M2 [mannose receptor (CD206)] markers, MDSCs from untreated tumor bearers were primarily MR+ with few CCR7+ cells. Docetaxel treatment polarized MDSCs toward an M1-like phenotype, resulting in 40% of MDSCs expressing CCR7 in vivo and in vitro, and macrophage differentiation markers such as MHC class II, CD11c, and CD86 were upregulated. Interestingly, docetaxel induced cell death selectively in MR+ MDSCs while sparing the M1-like phenotype. Finally, inhibition of signal transducer and activator of transcription 3 may in part be responsible for the observed results. Conclusions These findings suggest potential clinical benefit for the addition of docetaxel to current immunotherapeutic protocols.

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

“…88 Docetaxel, another antimicrotubule agent, was shown to polarize MDSCs toward an M1-like phenotype, and to selectively kill MDSCs while sparing the M1-like cells. 89 Recently, 5-FU has been shown to selectively induce MDSC apoptosis in vitro and in vivo, 49,90 resulting in enhanced IFN-g secretion by tumor-infiltrating CD8 T-cells and T-cell-mediated antitumor responses in vivo. 90 Suppressor cells adopt various means to inhibit the antitumor activity of effector lymphocytes.…”

Cancer‐promoting tumor‐associated macrophages: New vistas and open questions

“…[13,15]), or depletion of angiogenic monocyte subsets [48,49]. Moreover, the influence of selected chemotherapeutic agents on the viability and function of myelomonocytic cells may contribute to or be a critical component of the agents' anti-tumor activity [9,50,51]. Thus, the current understanding of TAM biology opens up different and alternative strategies to target these cells, although the careful definition of the immunobiology of the context in different tumors, as noted in the previous section, may be required for successful therapeutic exploitation.…”

The blood mMDSC to DC ratio is a sensitive and easy to assess independent predictive factor for epithelial ovarian cancer survival

“…This shows the importance of functional assessments of myeloid cell types and explains why deletion of CD33- dnMDSC by gemcitabine did not have an impact on the survival. Interestingly, docetaxel has also been reported to eliminate MDSC in mice 34 and the change in mMDSC from baseline to the third treatment cycle was prognostic for survival in metastatic castration-resistant prostate cancer, 35 suggesting that docetaxel may eliminate the right MDSC type in patients, albeit that this chemotherapy is not frequently used in patients with EOC.…”