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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

Obese mice have elevated concentrations of the MDSC chemoattractant CCL2 in renal tumors.(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. Homogenates were tested via Multiplex array for CCL2. n = 4–8 mice per group, combined from three experiments. Bars indicate mean +/- sd. * = p < 0.05. (B) Histograms showing intracellular CCL2 for the indicated cell populations. (C) Intracellular CCL2 from pooled DIO versus NW mice for the indicated cell populations, with n = 3–5 mice per group. Bars indicate mean +/- sd. * = p < 0.05.
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pone.0118784.g002: Obese mice have elevated concentrations of the MDSC chemoattractant CCL2 in renal tumors.(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. Homogenates were tested via Multiplex array for CCL2. n = 4–8 mice per group, combined from three experiments. Bars indicate mean +/- sd. * = p < 0.05. (B) Histograms showing intracellular CCL2 for the indicated cell populations. (C) Intracellular CCL2 from pooled DIO versus NW mice for the indicated cell populations, with n = 3–5 mice per group. Bars indicate mean +/- sd. * = p < 0.05.

Mentions: Previous studies have shown that site-specific MDSC accumulation is regulated by cytokines and chemokines. In particular, CCL2 (monocyte chemoattractant protein-1, or MCP-1), TNFα, Interleukin-1β (IL-1β), and IL-6 have been identified as positive mediators of MDSC trafficking and accumulation [28,29]. Given the striking increase in MDSC prevalence in tumors from DIO mice between days 7 and 14, we examined tumor homogenates for the presence of each of the above factors at both time points in DIO and NW mice. Of these factors, only CCL2 showed a significant increase from DIO mice relative to NW mice at day 14 (Fig. 2A and S3 Fig.). As predicted by the lack of tumor growth [22] or MDSC accumulation in contralateral kidneys (Fig. 1), CCL2 concentrations remained low in contralateral kidneys from both DIO and NW mice throughout.


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)

Obese mice have elevated concentrations of the MDSC chemoattractant CCL2 in renal tumors.(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. Homogenates were tested via Multiplex array for CCL2. n = 4–8 mice per group, combined from three experiments. Bars indicate mean +/- sd. * = p < 0.05. (B) Histograms showing intracellular CCL2 for the indicated cell populations. (C) Intracellular CCL2 from pooled DIO versus NW mice for the indicated cell populations, with n = 3–5 mice per group. Bars indicate mean +/- sd. * = p < 0.05.
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Related In: Results  -  Collection

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pone.0118784.g002: Obese mice have elevated concentrations of the MDSC chemoattractant CCL2 in renal tumors.(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. Homogenates were tested via Multiplex array for CCL2. n = 4–8 mice per group, combined from three experiments. Bars indicate mean +/- sd. * = p < 0.05. (B) Histograms showing intracellular CCL2 for the indicated cell populations. (C) Intracellular CCL2 from pooled DIO versus NW mice for the indicated cell populations, with n = 3–5 mice per group. Bars indicate mean +/- sd. * = p < 0.05.
Mentions: Previous studies have shown that site-specific MDSC accumulation is regulated by cytokines and chemokines. In particular, CCL2 (monocyte chemoattractant protein-1, or MCP-1), TNFα, Interleukin-1β (IL-1β), and IL-6 have been identified as positive mediators of MDSC trafficking and accumulation [28,29]. Given the striking increase in MDSC prevalence in tumors from DIO mice between days 7 and 14, we examined tumor homogenates for the presence of each of the above factors at both time points in DIO and NW mice. Of these factors, only CCL2 showed a significant increase from DIO mice relative to NW mice at day 14 (Fig. 2A and S3 Fig.). As predicted by the lack of tumor growth [22] or MDSC accumulation in contralateral kidneys (Fig. 1), CCL2 concentrations remained low in contralateral kidneys from both DIO and NW mice throughout.

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