Skip to main page content
U.S. flag

An official website of the United States government

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Jul-Sep;9(3):292-300.
doi: 10.3109/1547691X.2011.642418. Epub 2012 Jan 28.

Paclitaxel promotes differentiation of myeloid-derived suppressor cells into dendritic cells in vitro in a TLR4-independent manner

Tillmann Michels  1 , Galina V Shurin, Hiam Naiditch, Alexandra Sevko, Viktor Umansky, Michael R Shurin
Affiliations

Paclitaxel promotes differentiation of myeloid-derived suppressor cells into dendritic cells in vitro in a TLR4-independent manner

Tillmann Michels et al. J Immunotoxicol. 2012 Jul-Sep.

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.

PubMed Disclaimer

Conflict of interest statement

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Figures

Figure 1
Figure 1
Phenotype of ex vivo generated MDSC. MDSC were cultured for 5 days and stained for (a) CD11b, Gr-1, and (b and c) a sub-type marker Ly6C, as described in the Materials and methods. Data from one representative staining are shown. Similar results were obtained in five independent experiments.
Figure 2
Figure 2
Paclitaxel does not block the generation of MDSC ex vivo. MDSC cultures were treated with 1 nM paclitaxel on Day 1 and compared with untreated cells on Day 5. (a) Data from one representative CD11b/Gr-1 staining are shown. (b) The results of three independent experiments are shown as the means (± SEM).
Figure 3
Figure 3
Paclitaxel fails to induce apoptosis in MDSC. MDSC were treated with different concentrations of paclitaxel or medium alone (control) for 24 h and Annexin V/PI staining was used to measure the percentage of apoptotic cells (a, b), whereas trypan blue staining was used to measure live cell numbers (c), as described in the Materials and methods. Data from one representative Annexin V/PI staining are shown (a). The results of three independent experiments are shown (b, c) as the means ± SEM. * p < 0.05 vs control. (See colour version of this figure online at www.informahealthcare.com/imt)
Figure 4
Figure 4
Paclitaxel stimulates differentiation of MDSC into DC. (a) MDSC cultures were treated with 1 nM paclitaxel and the amount of CD11c+ DC was assessed after 24–72 h by FACScan, as described in Materials and methods. Results from four independent experiments are shown as the mean (± SEM). (b) Additional phenotyping of DC revealed that they express MHC Class II molecules and low levels of CD86 and CD40. (c) CD11c+ DC were isolated from paclitaxel-treated MDSC cultures using magnetic beads (DC) and co-cultured with ConA-activated syngeneic splenocytes (T-cells/ConA). DC-depleted MDSC served as a control (MDSC). T-cell proliferation was assessed by [3H]-thymidine incorporation and express as count per minute (cpm). * p < 0.05 vs corresponding control (a) or ConA-stimulated T-cell proliferation (c). (See colour version of this figure online at www.informahealthcare.com/imt)
Figure 5
Figure 5
Paclitaxel induces differentiation of MDSC into DC in TLR4-independent manner. MDSC cultures were prepared from the bone marrow cells obtained from wild-type (WT) and TLR4−/− mice and cultured with GM-CSF alone or GM-CSF + IL-6. At Day 5, cells were treated with 1 nM paclitaxel for 72 h and DC were assessed by FACScan as CD11c+ cells co-expressing CD86, CD80, CD40, and MHC Class II and expressed as the means (± SEM) (n = 3). * p < 0.05 vs corresponding control.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Almand B, Clark JI, Nikitina E, van Beynen J, English NR, Knight SC, Carbone DP, Gabrilovich DI. Increased production of immature myeloid cells in cancer patients: A mechanism of immunosuppression in cancer. J Immunol. 2001;166:678–689. - PubMed
    1. Apetoh L, Vegran F, Ladoire S, Ghiringhelli F. Restoration of anti-tumor immunity through selective inhibition of myeloid derived suppressor cells by anti-cancer therapies. Curr Mol Med. 2011;11:365–372. - PubMed
    1. Balkir L, Tourkova IL, Makarenkova VP, Shurin GV, Robbins PD, Yin XM, Chatta G, Shurin MR. Comparative analysis of dendritic cells transduced with different anti-apoptotic molecules: Sensitivity to tumor-induced apoptosis. J Gene Med. 2004;6:537–544. - PubMed
    1. Byrd-Leifer CA, Block EF, Takeda K, Akira S, Ding A. The role of MyD88 and TLR4 in the LPS-mimetic activity of Taxol. Eur J Immunol. 2001;31:2448–2457. - PubMed
    1. Chan OT, Yang LX. The immunological effects of taxanes. Cancer Immunol Immunother. 2000;49:181–185. - PMC - PubMed

Publication types

LinkOut - more resources