title: CpG-mediated modulation of MDSC contributes to the efficacy of Ad5-TRAIL therapy against renal cell carcinoma.
abstract: Tumor progression occurs through the modulation of a number of physiological parameters, including the development of immunosuppressive mechanisms to prevent immune detection and response. Among these immune evasion mechanisms, the mobilization of myeloid-derived suppressor cells (MDSC) is a major contributor to the suppression of antitumor T-cell immunity. Patients with renal cell carcinoma (RCC) show increased MDSC, and methods are being explored clinically to reduce the prevalence of MDSC and/or inhibit their function. In the present study, we investigated the relationship between MDSC and the therapeutic potential of a TRAIL-encoding recombinant adenovirus (Ad5-TRAIL) in combination with CpG-containing oligodeoxynucleotides (Ad5-TRAIL/CpG) in an orthotopic mouse model of RCC. This immunotherapy effectively clears renal (Renca) tumors and enhances survival, despite the presence of a high frequency of MDSC in the spleens and primary tumor-bearing kidneys at the time of treatment. Subsequent analyses revealed that the CpG component of the immunotherapy was responsible for decreasing the frequency of MDSC in Renca-bearing mice; further, treatment with CpG modulated the phenotype and function of MDSC that remained after immunotherapy and correlated with an increased T-cell response. Interestingly, the CpG-dependent alterations in MDSC frequency and function did not occur in tumor-bearing mice complicated with diet-induced obesity. Collectively, these data suggest that in addition to its adjuvant properties, CpG also enhances antitumor responses by altering the number and function of MDSC.
authors.affiliation: Department of Urology, University of Minnesota, 3-125 CCRB, 2231 6th St. SE, Minneapolis, MN, 55455, USA.
authors.forename: Britnie R
authors.initials: BR
authors.lastname: James
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Anderson
authors.forename: Erik L
authors.initials: EL
authors.lastname: Brincks
authors.forename: Tamara A
authors.initials: TA
authors.lastname: Kucaba
authors.forename: Lyse A
authors.initials: LA
authors.lastname: Norian
authors.forename: David
authors.initials: D
authors.lastname: Masopust
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Griffith
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D007167:Immunotherapy / Q000379:methods*; D007668:Kidney / Q000378:metabolism; D007680:Kidney Neoplasms / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000166:cytology; D009765:Obesity; D009838:Oligodeoxyribonucleotides / Q000276:immunology*; D009841:Oligonucleotides; D010641:Phenotype; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*
chemical_list: C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D009841:Oligonucleotides; D053221:TNF-Related Apoptosis-Inducing Ligand