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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

Equivalent surface expression of CCR2 on MDSCs from DIO and NW mice.(A) DIO and NW mice were challenged as in Fig. 1. Tumor-bearing kidneys (TK) or tumor-free contralateral kidneys (CK) were harvested at the times indicated. Histograms show representative surface expression of CCR2 on Ly6C+ or Ly6G+ MDSC from DIO or NW mice. Open histograms = isotype control; shaded histograms = CCR2 staining. (B) Pooled data showing the % of MDSCs that express CCR2 in tumor-bearing kidneys (TK) and contralateral kidneys (CK). Gating on Ly6C+ or Ly6G+ MDSC shows strong and equivalent expression of CCR2 on MDSC subpopulations from DIO and NW mice. (C) Increased overall frequencies of CCR2+ MDSC from both Ly6C+ and Ly6G+ subsets when calculated as a percentage of total live cells within tumor-bearing kidneys. For B and C, n = 4–6 mice per group from two experiments. Bars indicate mean +/- sd. * = p < 0.05.
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pone.0118784.g003: Equivalent surface expression of CCR2 on MDSCs from DIO and NW mice.(A) DIO and NW mice were challenged as in Fig. 1. Tumor-bearing kidneys (TK) or tumor-free contralateral kidneys (CK) were harvested at the times indicated. Histograms show representative surface expression of CCR2 on Ly6C+ or Ly6G+ MDSC from DIO or NW mice. Open histograms = isotype control; shaded histograms = CCR2 staining. (B) Pooled data showing the % of MDSCs that express CCR2 in tumor-bearing kidneys (TK) and contralateral kidneys (CK). Gating on Ly6C+ or Ly6G+ MDSC shows strong and equivalent expression of CCR2 on MDSC subpopulations from DIO and NW mice. (C) Increased overall frequencies of CCR2+ MDSC from both Ly6C+ and Ly6G+ subsets when calculated as a percentage of total live cells within tumor-bearing kidneys. For B and C, n = 4–6 mice per group from two experiments. Bars indicate mean +/- sd. * = p < 0.05.

Mentions: The increased percentages of MDSCs in renal tumors of obese mice may result from up-regulation of the CCL2 receptor, CCR2, in addition to elevated local concentrations of CCL2 protein. We therefore examined CCR2 expression on MDSCs from tumor-bearing kidneys and tumor-free contralateral kidneys at d14 post-tumor challenge, as both CCL2 protein and MDSC accumulation were elevated at this time point (Fig. 2). We again gated on Ly6C+ monocytic or Ly6G+ granulocytic MDSC subpopulations (as in Fig. 1A) and examined surface CCR2 expression (Fig. 3). CCR2 protein was found on both subsets of MDSC from tumor-bearing kidneys in DIO and NW mice, with no change in the intensity of CCR2 staining (Fig. 3A). Equivalent percentages of monocytic and granulocytic MDSC expressed CCR2 in DIO and NW mice in both tumor-bearing and contralateral kidneys (Fig. 3B). However, when percentages of CCR2+ MDSCs as a fraction of the total live cells present were calculated, we again found significant increases in the overall frequency of both monocytic and granulocytic CCR2+ MDSC in tumor-bearing kidneys from DIO mice (Fig. 3C). Tumor-free contralateral kidneys contained few MDSCs (note scale change), and DIO mice had reduced percentages of CCR2+ monocytic MDSC as compared to NW counterparts (Fig. 3C). We conclude that the increased percentages of MDSCs within renal tumors from obese mice are due primarily to elevated local production of the myeloid chemoattractant CCL2, and not changes in expression of CCR2.


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)

Equivalent surface expression of CCR2 on MDSCs from DIO and NW mice.(A) DIO and NW mice were challenged as in Fig. 1. Tumor-bearing kidneys (TK) or tumor-free contralateral kidneys (CK) were harvested at the times indicated. Histograms show representative surface expression of CCR2 on Ly6C+ or Ly6G+ MDSC from DIO or NW mice. Open histograms = isotype control; shaded histograms = CCR2 staining. (B) Pooled data showing the % of MDSCs that express CCR2 in tumor-bearing kidneys (TK) and contralateral kidneys (CK). Gating on Ly6C+ or Ly6G+ MDSC shows strong and equivalent expression of CCR2 on MDSC subpopulations from DIO and NW mice. (C) Increased overall frequencies of CCR2+ MDSC from both Ly6C+ and Ly6G+ subsets when calculated as a percentage of total live cells within tumor-bearing kidneys. For B and C, n = 4–6 mice per group from two experiments. Bars indicate mean +/- sd. * = p < 0.05.
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Related In: Results  -  Collection

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pone.0118784.g003: Equivalent surface expression of CCR2 on MDSCs from DIO and NW mice.(A) DIO and NW mice were challenged as in Fig. 1. Tumor-bearing kidneys (TK) or tumor-free contralateral kidneys (CK) were harvested at the times indicated. Histograms show representative surface expression of CCR2 on Ly6C+ or Ly6G+ MDSC from DIO or NW mice. Open histograms = isotype control; shaded histograms = CCR2 staining. (B) Pooled data showing the % of MDSCs that express CCR2 in tumor-bearing kidneys (TK) and contralateral kidneys (CK). Gating on Ly6C+ or Ly6G+ MDSC shows strong and equivalent expression of CCR2 on MDSC subpopulations from DIO and NW mice. (C) Increased overall frequencies of CCR2+ MDSC from both Ly6C+ and Ly6G+ subsets when calculated as a percentage of total live cells within tumor-bearing kidneys. For B and C, n = 4–6 mice per group from two experiments. Bars indicate mean +/- sd. * = p < 0.05.
Mentions: The increased percentages of MDSCs in renal tumors of obese mice may result from up-regulation of the CCL2 receptor, CCR2, in addition to elevated local concentrations of CCL2 protein. We therefore examined CCR2 expression on MDSCs from tumor-bearing kidneys and tumor-free contralateral kidneys at d14 post-tumor challenge, as both CCL2 protein and MDSC accumulation were elevated at this time point (Fig. 2). We again gated on Ly6C+ monocytic or Ly6G+ granulocytic MDSC subpopulations (as in Fig. 1A) and examined surface CCR2 expression (Fig. 3). CCR2 protein was found on both subsets of MDSC from tumor-bearing kidneys in DIO and NW mice, with no change in the intensity of CCR2 staining (Fig. 3A). Equivalent percentages of monocytic and granulocytic MDSC expressed CCR2 in DIO and NW mice in both tumor-bearing and contralateral kidneys (Fig. 3B). However, when percentages of CCR2+ MDSCs as a fraction of the total live cells present were calculated, we again found significant increases in the overall frequency of both monocytic and granulocytic CCR2+ MDSC in tumor-bearing kidneys from DIO mice (Fig. 3C). Tumor-free contralateral kidneys contained few MDSCs (note scale change), and DIO mice had reduced percentages of CCR2+ monocytic MDSC as compared to NW counterparts (Fig. 3C). We conclude that the increased percentages of MDSCs within renal tumors from obese mice are due primarily to elevated local production of the myeloid chemoattractant CCL2, and not changes in expression of CCR2.

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