Limits...
AZD1480 delays tumor growth in a melanoma model while enhancing the suppressive activity of myeloid-derived suppressor cells.

Maenhout SK, Du Four S, Corthals J, Neyns B, Thielemans K, Aerts JL - Oncotarget (2014)

Bottom Line: Here we investigated the effects of AZD1480 on the function of different immune cell populations in a melanoma model.Moreover, a significant decrease in the percentage of myeloid-derived suppressor cells (MDSCs) was observed after treatment with AZD1480.The addition of AZD1480 to co-cultures of human MDSCs and T cells does not affect the suppressive activity of MDSCs but it does reduce the IFN-γ secretion and the proliferative capacity of T cells.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular and Cellular Therapy, Department of Immunology-Physiology, Vrije Universiteit Brussel, Brussels, Belgium.

ABSTRACT
AZD1480 is a potent, competitive small-molecule inhibitor of JAK1/2 kinase which inhibits STAT3 phosphorylation and tumor growth. Here we investigated the effects of AZD1480 on the function of different immune cell populations in a melanoma model. When MO4 tumor-bearing mice were treated with AZD1480 we observed a strong inhibition of tumor growth as well as a prolonged survival. Moreover, a significant decrease in the percentage of myeloid-derived suppressor cells (MDSCs) was observed after treatment with AZD1480. However, AZD1480 enhanced the suppressive capacity of murine MDSCs while at the same time impairing the proliferative as well as the IFN-γ secretion capacity of murine T cells. The addition of AZD1480 to co-cultures of human MDSCs and T cells does not affect the suppressive activity of MDSCs but it does reduce the IFN-γ secretion and the proliferative capacity of T cells. We showed that although AZD1480 has the ability to delay the tumor growth of MO4 tumor-bearing mice, this drug has detrimental effects on several aspects of the immune system. These data indicate that systemic targeting of the JAK/STAT pathway by JAK1/2 inhibition can have divergent effects on tumor growth and anti-tumor immune responses.

Show MeSH

Related in: MedlinePlus

In vivo AZD1480 treatment induces profound changes in the immune cell compostion in both the spleen and the tumor microenvironmentMO4 tumor-bearing mice were treated with AZD1480 at 30 mg/kg or vehicle control by oral gavage twice a day for 7 days. Two hours after the last dosing mice were sacrificed and single cell suspensions of spleen and tumor were made. Different immune cell populations were subsequently analysed by flow cytometry. A. Percentage of CD45+CD3+ T cells in the spleen of treated mice. Within the CD45+CD3+ T cells the percentage of CD4+ and CD8+ T cells was determined. B. Percentage of myeloid cells (defined as CD45+CD11b+ cells) in the spleen of treated mice. Within this population the percentage of the different subsets of myeloid-derived suppressor cells (moMDSC: CD45+CD11b+Ly6C+Ly6G− and grMDSC: CD45+CD11b+Ly6G+Ly6Cint) was determined. C. Percentage of CD45+CD3+ T cells in the tumor of treated mice. Within the CD45+CD3+ T cells the percentage of CD4+ and CD8+ T cells was determined. D. Percentage of myeloid cells (defined as CD45+CD11b+ cells) in the tumor of treated mice. Within this population the percentage of the different subsets of myeloid-derived suppressor cells (moMDSC: CD45+CD11b+Ly6C+Ly6G− and grMDSC: CD45+CD11b+Ly6G+Ly6Cint) was determined. Three independent experiments were performed (with each time 3 mice per group) and results are presented as mean ± SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4196164&req=5

Figure 3: In vivo AZD1480 treatment induces profound changes in the immune cell compostion in both the spleen and the tumor microenvironmentMO4 tumor-bearing mice were treated with AZD1480 at 30 mg/kg or vehicle control by oral gavage twice a day for 7 days. Two hours after the last dosing mice were sacrificed and single cell suspensions of spleen and tumor were made. Different immune cell populations were subsequently analysed by flow cytometry. A. Percentage of CD45+CD3+ T cells in the spleen of treated mice. Within the CD45+CD3+ T cells the percentage of CD4+ and CD8+ T cells was determined. B. Percentage of myeloid cells (defined as CD45+CD11b+ cells) in the spleen of treated mice. Within this population the percentage of the different subsets of myeloid-derived suppressor cells (moMDSC: CD45+CD11b+Ly6C+Ly6G− and grMDSC: CD45+CD11b+Ly6G+Ly6Cint) was determined. C. Percentage of CD45+CD3+ T cells in the tumor of treated mice. Within the CD45+CD3+ T cells the percentage of CD4+ and CD8+ T cells was determined. D. Percentage of myeloid cells (defined as CD45+CD11b+ cells) in the tumor of treated mice. Within this population the percentage of the different subsets of myeloid-derived suppressor cells (moMDSC: CD45+CD11b+Ly6C+Ly6G− and grMDSC: CD45+CD11b+Ly6G+Ly6Cint) was determined. Three independent experiments were performed (with each time 3 mice per group) and results are presented as mean ± SEM.

Mentions: The tumor microenvironment is composed of a complex network of immune cells, which can either inhibit or promote tumor growth. Since we observed a significant anti-tumor effect of AZD1480 we wondered whether AZD1480 influences the immune cell composition in the spleen and within the tumor microenvironment. In the spleen of AZD1480 treated mice we observed a significant increase in the percentages of both CD4+ and CD8+ T cells compared to vehicle control treated mice (Figure 3A). While we did not observe differences in the percentage of dendritic cells (DCs), nor in the maturation status of these cells (data not shown), we did observe a significant decrease in the percentage of both monocytic MDSCs (moMDSC; CD11b+Ly6C+Ly6G−) and granulocytic MDSCs (grMDSC; CD11b+Ly6ClowLy6G+; Figure 3B) after treatment with AZD1480. In contrast, within the tumor microenvironment, we observed a significant decrease in the percentage of CD45+ cells (data not shown) when mice were treated with AZD1480. Within the CD45+ cell population we evaluated the presence of T cells, DCs and MDSCs. The percentage of both tumor-infiltrating CD4+ and CD8+ T cells was dramatically decreased in AZD1480 treated mice compared to vehicle treated animals (Figure 3C). The number of tumor-infiltrating DCs was also significantly decreased in AZD1480 treated mice, while the maturation status of these DCs did not differ between AZD1480 treated mice compared to vehicle control treated mice (data not shown). Consistent with the observations in the spleen, we also observed a decrease in the percentage of both moMDSCs and grMDSCs within the tumor microenvironment (Figure 3D) after treatment with AZD1480. These data indicate that AZD1480 treatment has different effects on the immune cell composition of the peripheral lymphoid organs compared to the tumor microenvironment. Thus, whereas we observed an influx of T cells and a reduction of MDSC numbers in the spleen of AZD1480 treated mice, in the tumor the number of both tumor-infiltrating T cells and tumor-infiltrating MDSCs is reduced. A similar reduction was also observed for tumor-infiltrating DC numbers.


AZD1480 delays tumor growth in a melanoma model while enhancing the suppressive activity of myeloid-derived suppressor cells.

Maenhout SK, Du Four S, Corthals J, Neyns B, Thielemans K, Aerts JL - Oncotarget (2014)

In vivo AZD1480 treatment induces profound changes in the immune cell compostion in both the spleen and the tumor microenvironmentMO4 tumor-bearing mice were treated with AZD1480 at 30 mg/kg or vehicle control by oral gavage twice a day for 7 days. Two hours after the last dosing mice were sacrificed and single cell suspensions of spleen and tumor were made. Different immune cell populations were subsequently analysed by flow cytometry. A. Percentage of CD45+CD3+ T cells in the spleen of treated mice. Within the CD45+CD3+ T cells the percentage of CD4+ and CD8+ T cells was determined. B. Percentage of myeloid cells (defined as CD45+CD11b+ cells) in the spleen of treated mice. Within this population the percentage of the different subsets of myeloid-derived suppressor cells (moMDSC: CD45+CD11b+Ly6C+Ly6G− and grMDSC: CD45+CD11b+Ly6G+Ly6Cint) was determined. C. Percentage of CD45+CD3+ T cells in the tumor of treated mice. Within the CD45+CD3+ T cells the percentage of CD4+ and CD8+ T cells was determined. D. Percentage of myeloid cells (defined as CD45+CD11b+ cells) in the tumor of treated mice. Within this population the percentage of the different subsets of myeloid-derived suppressor cells (moMDSC: CD45+CD11b+Ly6C+Ly6G− and grMDSC: CD45+CD11b+Ly6G+Ly6Cint) was determined. Three independent experiments were performed (with each time 3 mice per group) and results are presented as mean ± SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196164&req=5

Figure 3: In vivo AZD1480 treatment induces profound changes in the immune cell compostion in both the spleen and the tumor microenvironmentMO4 tumor-bearing mice were treated with AZD1480 at 30 mg/kg or vehicle control by oral gavage twice a day for 7 days. Two hours after the last dosing mice were sacrificed and single cell suspensions of spleen and tumor were made. Different immune cell populations were subsequently analysed by flow cytometry. A. Percentage of CD45+CD3+ T cells in the spleen of treated mice. Within the CD45+CD3+ T cells the percentage of CD4+ and CD8+ T cells was determined. B. Percentage of myeloid cells (defined as CD45+CD11b+ cells) in the spleen of treated mice. Within this population the percentage of the different subsets of myeloid-derived suppressor cells (moMDSC: CD45+CD11b+Ly6C+Ly6G− and grMDSC: CD45+CD11b+Ly6G+Ly6Cint) was determined. C. Percentage of CD45+CD3+ T cells in the tumor of treated mice. Within the CD45+CD3+ T cells the percentage of CD4+ and CD8+ T cells was determined. D. Percentage of myeloid cells (defined as CD45+CD11b+ cells) in the tumor of treated mice. Within this population the percentage of the different subsets of myeloid-derived suppressor cells (moMDSC: CD45+CD11b+Ly6C+Ly6G− and grMDSC: CD45+CD11b+Ly6G+Ly6Cint) was determined. Three independent experiments were performed (with each time 3 mice per group) and results are presented as mean ± SEM.
Mentions: The tumor microenvironment is composed of a complex network of immune cells, which can either inhibit or promote tumor growth. Since we observed a significant anti-tumor effect of AZD1480 we wondered whether AZD1480 influences the immune cell composition in the spleen and within the tumor microenvironment. In the spleen of AZD1480 treated mice we observed a significant increase in the percentages of both CD4+ and CD8+ T cells compared to vehicle control treated mice (Figure 3A). While we did not observe differences in the percentage of dendritic cells (DCs), nor in the maturation status of these cells (data not shown), we did observe a significant decrease in the percentage of both monocytic MDSCs (moMDSC; CD11b+Ly6C+Ly6G−) and granulocytic MDSCs (grMDSC; CD11b+Ly6ClowLy6G+; Figure 3B) after treatment with AZD1480. In contrast, within the tumor microenvironment, we observed a significant decrease in the percentage of CD45+ cells (data not shown) when mice were treated with AZD1480. Within the CD45+ cell population we evaluated the presence of T cells, DCs and MDSCs. The percentage of both tumor-infiltrating CD4+ and CD8+ T cells was dramatically decreased in AZD1480 treated mice compared to vehicle treated animals (Figure 3C). The number of tumor-infiltrating DCs was also significantly decreased in AZD1480 treated mice, while the maturation status of these DCs did not differ between AZD1480 treated mice compared to vehicle control treated mice (data not shown). Consistent with the observations in the spleen, we also observed a decrease in the percentage of both moMDSCs and grMDSCs within the tumor microenvironment (Figure 3D) after treatment with AZD1480. These data indicate that AZD1480 treatment has different effects on the immune cell composition of the peripheral lymphoid organs compared to the tumor microenvironment. Thus, whereas we observed an influx of T cells and a reduction of MDSC numbers in the spleen of AZD1480 treated mice, in the tumor the number of both tumor-infiltrating T cells and tumor-infiltrating MDSCs is reduced. A similar reduction was also observed for tumor-infiltrating DC numbers.

Bottom Line: Here we investigated the effects of AZD1480 on the function of different immune cell populations in a melanoma model.Moreover, a significant decrease in the percentage of myeloid-derived suppressor cells (MDSCs) was observed after treatment with AZD1480.The addition of AZD1480 to co-cultures of human MDSCs and T cells does not affect the suppressive activity of MDSCs but it does reduce the IFN-γ secretion and the proliferative capacity of T cells.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular and Cellular Therapy, Department of Immunology-Physiology, Vrije Universiteit Brussel, Brussels, Belgium.

ABSTRACT
AZD1480 is a potent, competitive small-molecule inhibitor of JAK1/2 kinase which inhibits STAT3 phosphorylation and tumor growth. Here we investigated the effects of AZD1480 on the function of different immune cell populations in a melanoma model. When MO4 tumor-bearing mice were treated with AZD1480 we observed a strong inhibition of tumor growth as well as a prolonged survival. Moreover, a significant decrease in the percentage of myeloid-derived suppressor cells (MDSCs) was observed after treatment with AZD1480. However, AZD1480 enhanced the suppressive capacity of murine MDSCs while at the same time impairing the proliferative as well as the IFN-γ secretion capacity of murine T cells. The addition of AZD1480 to co-cultures of human MDSCs and T cells does not affect the suppressive activity of MDSCs but it does reduce the IFN-γ secretion and the proliferative capacity of T cells. We showed that although AZD1480 has the ability to delay the tumor growth of MO4 tumor-bearing mice, this drug has detrimental effects on several aspects of the immune system. These data indicate that systemic targeting of the JAK/STAT pathway by JAK1/2 inhibition can have divergent effects on tumor growth and anti-tumor immune responses.

Show MeSH
Related in: MedlinePlus