title: Obesity triggers enhanced MDSC accumulation in murine renal tumors via elevated local production of CCL2.
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.
authors.affiliation: Department of Urology, The University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Malika
authors.initials: M
authors.lastname: Hale
authors.affiliation: Interdisciplinary Graduate Program in Immunology, The University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Farah
authors.initials: F
authors.lastname: Itani
authors.affiliation: Department of Urology, The University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Buchta
authors.affiliation: Department of Urology, The University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Gal
authors.initials: G
authors.lastname: Wald
authors.affiliation: Department of Urology, The University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Megan
authors.initials: M
authors.lastname: Bing
authors.affiliation: Department of Urology, The University of Iowa, Iowa City, Iowa, United States of America; Interdisciplinary Graduate Program in Immunology, The University of Iowa, Iowa City, Iowa, United States of America; Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa, United States of America; Fraternal Order of Eagles Diabetes Research Center, The University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Lyse A
authors.initials: LA
authors.lastname: Norian
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D007167:Immunotherapy; D007680:Kidney Neoplasms / Q000150:complications / Q000276:immunology* / Q000378:metabolism* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000166:cytology* / Q000276:immunology*; D009765:Obesity / Q000150:complications / Q000276:immunology*; D013045:Species Specificity; D013154:Spleen / Q000276:immunology
chemical_list: D018932:Chemokine CCL2