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Obesity triggers enhanced MDSC accumulation in murine renal tumors via elevated local production of CCL2.

Hale M, Itani F, Buchta CM, Wald G, Bing M, Norian LA - PLoS ONE (2015)

Bottom Line: Obesity is one of the leading risk factors for developing renal cell carcinoma, an immunogenic tumor that is treated clinically with immunostimulatory therapies.Currently, however, the mechanisms linking obesity with renal cancer incidence are unclear.Thus, our findings suggest that obesity promotes renal tumor progression via development of a robust immunosuppressive environment that is characterized by heightened local and systemic MDSC prevalence.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, The University of Iowa, Iowa City, Iowa, United States of America.

ABSTRACT
Obesity is one of the leading risk factors for developing renal cell carcinoma, an immunogenic tumor that is treated clinically with immunostimulatory therapies. Currently, however, the mechanisms linking obesity with renal cancer incidence are unclear. Using a model of diet-induced obesity, we found that obese BALB/c mice with orthotopic renal tumors had increased total frequencies of myeloid-derived suppressor cells (MDSC) in renal tumors and spleens by d14 post-tumor challenge, relative to lean counterparts. Renal tumors from obese mice had elevated concentrations of the known myeloid cell chemoattractant CCL2, which was produced locally by increased percentages of dendritic cells, macrophages, B cells, and CD45- cells in tumors. MDSC expression of the CCL2 receptor, CCR2, was unaltered by obesity but greater percentages of CCR2+ MDSCs were present in renal tumors from obese mice. Of note, the intracellular arginase levels and per-cell suppressive capacities of tumor-infiltrating and splenic MDSCs were unchanged in obese mice relative to lean controls. Thus, our findings suggest that obesity promotes renal tumor progression via development of a robust immunosuppressive environment that is characterized by heightened local and systemic MDSC prevalence. Targeted intervention of the CCL2/CCR2 pathway may facilitate immune-mediated renal tumor clearance in the obese.

No MeSH data available.


Related in: MedlinePlus

Obesity does not alter the suppressive capacity of MDSC.Tumor-bearing kidneys and spleens from the same mice were harvested between days 21–23. (A) Monocytic (Ly6C+) and granulocytic MDSC (Ly6G+) were sort-purified from each organ, then placed into culture with naive DUC18 T cells and stimulatory splenic DC from tumor-free NW mice. MDSC and stimulatory DC were pulsed with the DUC18 cognate peptide tERK. n = 6–8 mice per group, combined from three experiments. Bars indicate mean +/- sd. * = p < 0.05. TI = tumor-infiltrating: sp = splenic. (B) Bulk tumor and spleen homogenates were surface stained as described in Methods to distinguish monocytic versus granulocytic MDSC subpopulations, then stained intracellularly for arginase-1 expression. Dots indicate results from individual mice. No statistical differences were present in the percentages of arginase+ MDSC subpopulations from like organs in obese versus NW mice.
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pone.0118784.g004: Obesity does not alter the suppressive capacity of MDSC.Tumor-bearing kidneys and spleens from the same mice were harvested between days 21–23. (A) Monocytic (Ly6C+) and granulocytic MDSC (Ly6G+) were sort-purified from each organ, then placed into culture with naive DUC18 T cells and stimulatory splenic DC from tumor-free NW mice. MDSC and stimulatory DC were pulsed with the DUC18 cognate peptide tERK. n = 6–8 mice per group, combined from three experiments. Bars indicate mean +/- sd. * = p < 0.05. TI = tumor-infiltrating: sp = splenic. (B) Bulk tumor and spleen homogenates were surface stained as described in Methods to distinguish monocytic versus granulocytic MDSC subpopulations, then stained intracellularly for arginase-1 expression. Dots indicate results from individual mice. No statistical differences were present in the percentages of arginase+ MDSC subpopulations from like organs in obese versus NW mice.

Mentions: Finally, we asked whether MDSC from DIO mice had an altered suppressive capacity on a per cell basis, relative to MDSC from NW mice. DIO and NW mice were again challenged intra-renally on d0 with Renca cells, then tumors and spleens were harvested between days 21–24 when renal tumors were large and macroscopically visible. Monocytic and granulocytic MDSC subpopulations were sort-purified from both organs and examined for suppressive capacity ex vivo. Granulocytic tumor-infiltrating-MDSC (TI-MDSC) from DIO and NW mice showed nearly identical suppressive capacities ex vivo (Fig. 4A, left panel). Monocytic TI-MDSC from DIO mice showed a trend toward increased suppressive capacity, but this difference was not statistically significant. In addition, we found no differences in the per cell suppressive capacity of splenic Ly6C+ or Ly6G+ MDSCs from tumor-bearing DIO versus NW mice (Fig. 4A, right panel).


Obesity triggers enhanced MDSC accumulation in murine renal tumors via elevated local production of CCL2.

Hale M, Itani F, Buchta CM, Wald G, Bing M, Norian LA - PLoS ONE (2015)

Obesity does not alter the suppressive capacity of MDSC.Tumor-bearing kidneys and spleens from the same mice were harvested between days 21–23. (A) Monocytic (Ly6C+) and granulocytic MDSC (Ly6G+) were sort-purified from each organ, then placed into culture with naive DUC18 T cells and stimulatory splenic DC from tumor-free NW mice. MDSC and stimulatory DC were pulsed with the DUC18 cognate peptide tERK. n = 6–8 mice per group, combined from three experiments. Bars indicate mean +/- sd. * = p < 0.05. TI = tumor-infiltrating: sp = splenic. (B) Bulk tumor and spleen homogenates were surface stained as described in Methods to distinguish monocytic versus granulocytic MDSC subpopulations, then stained intracellularly for arginase-1 expression. Dots indicate results from individual mice. No statistical differences were present in the percentages of arginase+ MDSC subpopulations from like organs in obese versus NW mice.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4358922&req=5

pone.0118784.g004: Obesity does not alter the suppressive capacity of MDSC.Tumor-bearing kidneys and spleens from the same mice were harvested between days 21–23. (A) Monocytic (Ly6C+) and granulocytic MDSC (Ly6G+) were sort-purified from each organ, then placed into culture with naive DUC18 T cells and stimulatory splenic DC from tumor-free NW mice. MDSC and stimulatory DC were pulsed with the DUC18 cognate peptide tERK. n = 6–8 mice per group, combined from three experiments. Bars indicate mean +/- sd. * = p < 0.05. TI = tumor-infiltrating: sp = splenic. (B) Bulk tumor and spleen homogenates were surface stained as described in Methods to distinguish monocytic versus granulocytic MDSC subpopulations, then stained intracellularly for arginase-1 expression. Dots indicate results from individual mice. No statistical differences were present in the percentages of arginase+ MDSC subpopulations from like organs in obese versus NW mice.
Mentions: Finally, we asked whether MDSC from DIO mice had an altered suppressive capacity on a per cell basis, relative to MDSC from NW mice. DIO and NW mice were again challenged intra-renally on d0 with Renca cells, then tumors and spleens were harvested between days 21–24 when renal tumors were large and macroscopically visible. Monocytic and granulocytic MDSC subpopulations were sort-purified from both organs and examined for suppressive capacity ex vivo. Granulocytic tumor-infiltrating-MDSC (TI-MDSC) from DIO and NW mice showed nearly identical suppressive capacities ex vivo (Fig. 4A, left panel). Monocytic TI-MDSC from DIO mice showed a trend toward increased suppressive capacity, but this difference was not statistically significant. In addition, we found no differences in the per cell suppressive capacity of splenic Ly6C+ or Ly6G+ MDSCs from tumor-bearing DIO versus NW mice (Fig. 4A, right panel).

Bottom Line: Obesity is one of the leading risk factors for developing renal cell carcinoma, an immunogenic tumor that is treated clinically with immunostimulatory therapies.Currently, however, the mechanisms linking obesity with renal cancer incidence are unclear.Thus, our findings suggest that obesity promotes renal tumor progression via development of a robust immunosuppressive environment that is characterized by heightened local and systemic MDSC prevalence.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, The University of Iowa, Iowa City, Iowa, United States of America.

ABSTRACT
Obesity is one of the leading risk factors for developing renal cell carcinoma, an immunogenic tumor that is treated clinically with immunostimulatory therapies. Currently, however, the mechanisms linking obesity with renal cancer incidence are unclear. Using a model of diet-induced obesity, we found that obese BALB/c mice with orthotopic renal tumors had increased total frequencies of myeloid-derived suppressor cells (MDSC) in renal tumors and spleens by d14 post-tumor challenge, relative to lean counterparts. Renal tumors from obese mice had elevated concentrations of the known myeloid cell chemoattractant CCL2, which was produced locally by increased percentages of dendritic cells, macrophages, B cells, and CD45- cells in tumors. MDSC expression of the CCL2 receptor, CCR2, was unaltered by obesity but greater percentages of CCR2+ MDSCs were present in renal tumors from obese mice. Of note, the intracellular arginase levels and per-cell suppressive capacities of tumor-infiltrating and splenic MDSCs were unchanged in obese mice relative to lean controls. Thus, our findings suggest that obesity promotes renal tumor progression via development of a robust immunosuppressive environment that is characterized by heightened local and systemic MDSC prevalence. Targeted intervention of the CCL2/CCR2 pathway may facilitate immune-mediated renal tumor clearance in the obese.

No MeSH data available.


Related in: MedlinePlus