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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

DIO mice have enhanced MDSC accumulation in renal tumors and spleens.(A) Flow cytometry gating strategy for MDSCs. (B) Frequencies of combined monocytic and granulocytic MDSC in tumor-bearing kidneys (TK) and tumor-free contralateral kidneys (CK) over time in DIO and NW mice. (C) Frequencies of combined monocytic and granulocytic MDSC in spleens, livers, and adipose stromal cells (ASC) from tumor-bearing mice in panel B. (D) Relative frequencies of granulocytic to monocytic MDSC are shown for the indicated organs at d14 post-tumor challenge. (B-D) For all, n = 4–8 mice/group, combined from three experiments. Bars indicate mean +/- s.d. Boxes indicate range with mean (horizontal bar). * = p < 0.05.
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pone.0118784.g001: DIO mice have enhanced MDSC accumulation in renal tumors and spleens.(A) Flow cytometry gating strategy for MDSCs. (B) Frequencies of combined monocytic and granulocytic MDSC in tumor-bearing kidneys (TK) and tumor-free contralateral kidneys (CK) over time in DIO and NW mice. (C) Frequencies of combined monocytic and granulocytic MDSC in spleens, livers, and adipose stromal cells (ASC) from tumor-bearing mice in panel B. (D) Relative frequencies of granulocytic to monocytic MDSC are shown for the indicated organs at d14 post-tumor challenge. (B-D) For all, n = 4–8 mice/group, combined from three experiments. Bars indicate mean +/- s.d. Boxes indicate range with mean (horizontal bar). * = p < 0.05.

Mentions: Our previous research had found functionally suppressive MDSC from tumor-bearing mice to be CD11cneg [24], thus we gated on CD11cneg/ CD11b+/ I-Ad neg/ Ly6C+ (monocytic) or CD11cneg/ CD11b+/ I-Ad neg/ Ly6G+ (granulocytic) MDSC phenotype cells (Fig. 1A and S1 Fig.). We found no significant differences in the relative MDSC frequency (combined Ly6C+ and Ly6G+ subsets) or MDSC number in the kidney, spleen, liver, or epididymal/renal fat pad adipose stromal cell fraction (ASC) (S1 Fig.). Because this finding was in contrast to a prior report on MDSC accumulation in obese C57BL/6 mice [19], we examined MDSC frequencies in NW or DIO C57BL/6 mice after 8 weeks on diet, as Xia et al. had done. In doing so, we found increased percentages and numbers of MDSC in the spleens of these mice, in agreement with that report (S2 Fig.). However, we found no differences in the expression of CD115 or CD244.2, two proteins described as potential distinguishing markers of granulocytic MDSC versus neutrophils [26], on cells from DIO or NW C57BL/6 mice (S2 Fig.). Thus, in tumor-free mice, the onset of DIO is not universally accompanied by an accumulation of cells possessing an MDSC phenotype, and strain-specific differences exist.


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)

DIO mice have enhanced MDSC accumulation in renal tumors and spleens.(A) Flow cytometry gating strategy for MDSCs. (B) Frequencies of combined monocytic and granulocytic MDSC in tumor-bearing kidneys (TK) and tumor-free contralateral kidneys (CK) over time in DIO and NW mice. (C) Frequencies of combined monocytic and granulocytic MDSC in spleens, livers, and adipose stromal cells (ASC) from tumor-bearing mice in panel B. (D) Relative frequencies of granulocytic to monocytic MDSC are shown for the indicated organs at d14 post-tumor challenge. (B-D) For all, n = 4–8 mice/group, combined from three experiments. Bars indicate mean +/- s.d. Boxes indicate range with mean (horizontal bar). * = p < 0.05.
© Copyright Policy
Related In: Results  -  Collection

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pone.0118784.g001: DIO mice have enhanced MDSC accumulation in renal tumors and spleens.(A) Flow cytometry gating strategy for MDSCs. (B) Frequencies of combined monocytic and granulocytic MDSC in tumor-bearing kidneys (TK) and tumor-free contralateral kidneys (CK) over time in DIO and NW mice. (C) Frequencies of combined monocytic and granulocytic MDSC in spleens, livers, and adipose stromal cells (ASC) from tumor-bearing mice in panel B. (D) Relative frequencies of granulocytic to monocytic MDSC are shown for the indicated organs at d14 post-tumor challenge. (B-D) For all, n = 4–8 mice/group, combined from three experiments. Bars indicate mean +/- s.d. Boxes indicate range with mean (horizontal bar). * = p < 0.05.
Mentions: Our previous research had found functionally suppressive MDSC from tumor-bearing mice to be CD11cneg [24], thus we gated on CD11cneg/ CD11b+/ I-Ad neg/ Ly6C+ (monocytic) or CD11cneg/ CD11b+/ I-Ad neg/ Ly6G+ (granulocytic) MDSC phenotype cells (Fig. 1A and S1 Fig.). We found no significant differences in the relative MDSC frequency (combined Ly6C+ and Ly6G+ subsets) or MDSC number in the kidney, spleen, liver, or epididymal/renal fat pad adipose stromal cell fraction (ASC) (S1 Fig.). Because this finding was in contrast to a prior report on MDSC accumulation in obese C57BL/6 mice [19], we examined MDSC frequencies in NW or DIO C57BL/6 mice after 8 weeks on diet, as Xia et al. had done. In doing so, we found increased percentages and numbers of MDSC in the spleens of these mice, in agreement with that report (S2 Fig.). However, we found no differences in the expression of CD115 or CD244.2, two proteins described as potential distinguishing markers of granulocytic MDSC versus neutrophils [26], on cells from DIO or NW C57BL/6 mice (S2 Fig.). Thus, in tumor-free mice, the onset of DIO is not universally accompanied by an accumulation of cells possessing an MDSC phenotype, and strain-specific differences exist.

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