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Multiple myeloma induces Mcl-1 expression and survival of myeloid-derived suppressor cells.

De Veirman K, Van Ginderachter JA, Lub S, De Beule N, Thielemans K, Bautmans I, Oyajobi BO, De Bruyne E, Menu E, Lemaire M, Van Riet I, Vanderkerken K, Van Valckenborgh E - Oncotarget (2015)

Bottom Line: Interestingly, in vivo MDSC targeting by anti-GR1 antibodies and 5-Fluorouracil resulted in a significant reduced tumor load in 5TMM-diseased mice.Finally, increased Mcl-1 expression was identified as underlying mechanism for MDSC survival.In conclusion, our data demonstrate that soluble factors from MM cells are able to generate MDSC through Mcl-1 upregulation and this cell population can be considered as a possible target in MM disease.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.

ABSTRACT
Myeloid-derived suppressor cells (MDSC) are contributing to an immunosuppressive environment by their ability to inhibit T cell activity and thereby promoting cancer progression. An important feature of the incurable plasma cell malignancy Multiple Myeloma (MM) is immune dysfunction. MDSC were previously identified to be present and active in MM patients, however little is known about the MDSC-inducing and -activating capacity of MM cells. In this study we investigated the effects of the tumor microenvironment on MDSC survival. During MM progression in the 5TMM mouse model, accumulation of MDSC in the bone marrow was observed in early stages of disease development, while circulating myeloid cells were increased at later stages of disease. Interestingly, in vivo MDSC targeting by anti-GR1 antibodies and 5-Fluorouracil resulted in a significant reduced tumor load in 5TMM-diseased mice. In vitro generation of MDSC was demonstrated by increased T cell immunosuppressive capacity and MDSC survival was observed in the presence of MM-conditioned medium. Finally, increased Mcl-1 expression was identified as underlying mechanism for MDSC survival. In conclusion, our data demonstrate that soluble factors from MM cells are able to generate MDSC through Mcl-1 upregulation and this cell population can be considered as a possible target in MM disease.

No MeSH data available.


Related in: MedlinePlus

Effect of Mcl-1 targeting by MIM1 on MDSC survivalA. Murine CD11b+ cells were cultured in 5T33MMvt-CM for 48 h with increasing concentrations of the Mcl-1inhibitor MIM1 (MIM). Viability was measured by CellTiter-Glo and apoptosis by AnnexinV staining (n = 3). B. Human CD11b+ cells were incubated with MIM1 in RPMI8226-CM and LP1-CM for 72 h and analyzed for MDSC markers by FACS (n = 5). * indicates p < 0.05, ** indicate p < 0.01 (Mann–Whitney U-test). Error bars represent the SD.
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Figure 7: Effect of Mcl-1 targeting by MIM1 on MDSC survivalA. Murine CD11b+ cells were cultured in 5T33MMvt-CM for 48 h with increasing concentrations of the Mcl-1inhibitor MIM1 (MIM). Viability was measured by CellTiter-Glo and apoptosis by AnnexinV staining (n = 3). B. Human CD11b+ cells were incubated with MIM1 in RPMI8226-CM and LP1-CM for 72 h and analyzed for MDSC markers by FACS (n = 5). * indicates p < 0.05, ** indicate p < 0.01 (Mann–Whitney U-test). Error bars represent the SD.

Mentions: To verify the role of Mcl-1 in MDSC survival, murine 5T33MMvt-CM-treated CD11b+ cells were incubated with MIM1, a novel Mcl-1 inhibitor [22]. The data clearly showed a decrease in survival, associated with an increase in apoptosis, of the murine CD11b+ cells in presence of MIM1 (Figure 7A). Incubation of human CD11b+ cells in RPMI8226-CM with MIM1 resulted in a slight decrease in the percentage of CD11b+ cells. However, within that population, a significant reduction in the monocytic MDSC subset was observed. MIM1 treatment in presence of LP1-CM resulted in a minor decrease of monocytic MDSC accumulation (Figure 7B). This is in accordance with the absence of Mcl-1 induction by LP1-CM. All these data indicate an important role of Mcl-1 but not pSTAT3 in MDSC survival and accumulation induced by MM soluble factors.


Multiple myeloma induces Mcl-1 expression and survival of myeloid-derived suppressor cells.

De Veirman K, Van Ginderachter JA, Lub S, De Beule N, Thielemans K, Bautmans I, Oyajobi BO, De Bruyne E, Menu E, Lemaire M, Van Riet I, Vanderkerken K, Van Valckenborgh E - Oncotarget (2015)

Effect of Mcl-1 targeting by MIM1 on MDSC survivalA. Murine CD11b+ cells were cultured in 5T33MMvt-CM for 48 h with increasing concentrations of the Mcl-1inhibitor MIM1 (MIM). Viability was measured by CellTiter-Glo and apoptosis by AnnexinV staining (n = 3). B. Human CD11b+ cells were incubated with MIM1 in RPMI8226-CM and LP1-CM for 72 h and analyzed for MDSC markers by FACS (n = 5). * indicates p < 0.05, ** indicate p < 0.01 (Mann–Whitney U-test). Error bars represent the SD.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496373&req=5

Figure 7: Effect of Mcl-1 targeting by MIM1 on MDSC survivalA. Murine CD11b+ cells were cultured in 5T33MMvt-CM for 48 h with increasing concentrations of the Mcl-1inhibitor MIM1 (MIM). Viability was measured by CellTiter-Glo and apoptosis by AnnexinV staining (n = 3). B. Human CD11b+ cells were incubated with MIM1 in RPMI8226-CM and LP1-CM for 72 h and analyzed for MDSC markers by FACS (n = 5). * indicates p < 0.05, ** indicate p < 0.01 (Mann–Whitney U-test). Error bars represent the SD.
Mentions: To verify the role of Mcl-1 in MDSC survival, murine 5T33MMvt-CM-treated CD11b+ cells were incubated with MIM1, a novel Mcl-1 inhibitor [22]. The data clearly showed a decrease in survival, associated with an increase in apoptosis, of the murine CD11b+ cells in presence of MIM1 (Figure 7A). Incubation of human CD11b+ cells in RPMI8226-CM with MIM1 resulted in a slight decrease in the percentage of CD11b+ cells. However, within that population, a significant reduction in the monocytic MDSC subset was observed. MIM1 treatment in presence of LP1-CM resulted in a minor decrease of monocytic MDSC accumulation (Figure 7B). This is in accordance with the absence of Mcl-1 induction by LP1-CM. All these data indicate an important role of Mcl-1 but not pSTAT3 in MDSC survival and accumulation induced by MM soluble factors.

Bottom Line: Interestingly, in vivo MDSC targeting by anti-GR1 antibodies and 5-Fluorouracil resulted in a significant reduced tumor load in 5TMM-diseased mice.Finally, increased Mcl-1 expression was identified as underlying mechanism for MDSC survival.In conclusion, our data demonstrate that soluble factors from MM cells are able to generate MDSC through Mcl-1 upregulation and this cell population can be considered as a possible target in MM disease.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.

ABSTRACT
Myeloid-derived suppressor cells (MDSC) are contributing to an immunosuppressive environment by their ability to inhibit T cell activity and thereby promoting cancer progression. An important feature of the incurable plasma cell malignancy Multiple Myeloma (MM) is immune dysfunction. MDSC were previously identified to be present and active in MM patients, however little is known about the MDSC-inducing and -activating capacity of MM cells. In this study we investigated the effects of the tumor microenvironment on MDSC survival. During MM progression in the 5TMM mouse model, accumulation of MDSC in the bone marrow was observed in early stages of disease development, while circulating myeloid cells were increased at later stages of disease. Interestingly, in vivo MDSC targeting by anti-GR1 antibodies and 5-Fluorouracil resulted in a significant reduced tumor load in 5TMM-diseased mice. In vitro generation of MDSC was demonstrated by increased T cell immunosuppressive capacity and MDSC survival was observed in the presence of MM-conditioned medium. Finally, increased Mcl-1 expression was identified as underlying mechanism for MDSC survival. In conclusion, our data demonstrate that soluble factors from MM cells are able to generate MDSC through Mcl-1 upregulation and this cell population can be considered as a possible target in MM disease.

No MeSH data available.


Related in: MedlinePlus