Paclitaxel promotes differentiation of myeloid-derived suppressor cells into dendritic cellsin vitroin a TLR4-independent manner

Abstract

Myeloid cells play a key role in the outcome of anti-tumor immunity and response to anti-cancer therapy, since in the tumor microenvironment they may exert both stimulatory and inhibitory pressures on the proliferative, angiogenic, metastatic, and immunomodulating potential of tumor cells. Therefore, understanding the mechanisms of myeloid regulatory cell differentiation is critical for developing strategies for the therapeutic reversal of myeloid derived suppressor cell (MDSC) accumulation in the tumor-bearing hosts. Here, using an in vitro model system, several potential mechanisms of the direct effect of paclitaxel on MDSC were tested, which might be responsible for the anti-tumor potential of low-dose paclitaxel therapy in mice. It was hypothesized that a decreased level of MDSC in vivo after paclitaxel administration might be due to (i) the blockage of MDSC generation, (ii) an induction of MDSC apoptosis, or (iii) the stimulation of MDSC differentiation. The results revealed that paclitaxel in ultra-low concentrations neither increased MDSC apoptosis nor blocked MDSC generation, but stimulated MDSC differentiation towards dendritic cells. This effect of paclitaxel was TLR4-independent since it was not diminished in cell cultures originated from TLR4−/− mice. These results support a new concept that certain chemotherapeutic agents in ultra-low non-cytotoxic doses may suppress tumor progression by targeting several cell populations in the tumor microenvironment, including MDSC.

Tumor Microenvironment and Myeloid-Derived Suppressor Cells

“…MDSCs have been shown to differentiate into mature macrophages, DCs or granulocytes upon the administration of all-trans-retinoic acid (ATRA) [28,102] or ultra-low noncytotoxic doses of paclitaxel [103]. Although retinoic acid receptors (RARs and RXRs) are known to be expressed on various cell types, receptors RARα and RXRα were detected predominantly on myeloid cells [104].…”

“…These changes were associated with a partial recovery of tumorspecific T cell responses that were resulted in profound antimelanoma effects indicated by a delayed tumor growth and prolonged animal survival (V.U.,A.S., unpublished results). To decipher the molecular mechanisms of MDSC inhibition under ultra-low paclitaxel treatment, MDSCs were generated in vitro from the bone marrow precursors and treated paclitaxel at ultra-low, nanomolar concentrations [103]. Under these conditions, paclitaxel failed to impair the MDSC generation from bone marrow precursors or to stimulate MDSC apoptosis, whereas the differentiation of these cells towards DCs was found to be significantly stimulated in the toll-like receptor 4-independent way.…”

A New Approach to Cancer Therapy: The Tumor Microenvironment as Target

“…Hence, injection of tumor cells in combination with CD11b + Gr1 + cells in mice prompt tumor growth [249]. Accordingly, depletion of Gr1 + cells in tumor-bearing mice leads to delayed tumor growth, suggesting MDSC as potential targets for anti-cancer therapy [250][251][252][253][254][255][256]. A report by Youn and colleagues indicated that CD11b + Gr1 + cells from naïve tumor-free mice are not immune suppressive [243].…”

Breaking immunotolerance of tumors: A new perspective for dendritic cell therapy

“…For example, both in vitro and in animal models, all trans-retinoid acid (ATRA) has been used to induce MDSC differentiation into mature myeloid cells (Kusmartsev et al 2008;Mirza et al, 2006). More recently, paclitaxel (at ultra-low non-cytotoxic doses) was shown to stimulate differentiation of MDSC into DC (Michels et al, 2012). Another method to reduce MDSC counts was the use of cytostatic agents like gemcitabine; in a mouse model, this drug was shown to reduce GR-1 þ /CD11b þ MDSC levels (Le et al, 2009;Suzuki et al, 2005).…”