title: Systemic immune tuning in renal cell carcinoma: favorable prognostic impact of TGF-β1 mRNA expression in peripheral blood mononuclear cells.
abstract: Renal cell carcinoma (RCC) can inhibit protective immunity by induction of immunosuppressive cells that produce inhibitory cytokines such as interleukin (IL)-10 and transforming growth factor (TGF)-β. If this immunosuppression influences response to kinase inhibitors such as sorafenib is not known. Therefore, we asked for the prognostic influence of cells with immunosuppressive properties in peripheral blood (pB) in a cohort of metastatic clear cell renal cell carcinoma (mRCC) patients uniformly receiving sorafenib treatment. IL-10 and TGF-β mRNA levels, regulatory T-cell (Treg) counts, and frequencies of IL-10/TGF-β producing mononuclear cell subsets were determined in pB from 46 patients with mRCC before receiving sorafenib treatment. Relationship between established clinical and laboratory prognostic factors and outcome were examined by univariate and multivariate Cox regression analysis. IL-10 and TGF-β1 mRNA levels, and frequencies of CD4(+)CD25high/CD3(+) and CD4(+)CD25highFoxP3(+)/CD3(+)Treg cells were significantly higher in mRCC patients compared with healthy individuals. Monocytes were suggested as main producers of IL-10 and TGF-β. In a multivariate analysis low ECOG score and-surprisingly-high TGF-β1 mRNA levels were independently associated with favorable progression-free survival (P=0.005 and P=0.003, respectively) and overall survival (P=0.001 and P=0.039, respectively). In conclusion, mRCC is associated with an immunosuppressive phenotype in peripheral blood. The positive prognostic influence of high TGF-β1 mRNA expression levels may reflect immune promoting functions of TGF-β in combined activity with inflammatory cytokines.
authors.affiliation: Department of Medicine III (Hematology and Oncology), Charité, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Antonia
authors.initials: A
authors.lastname: Busse
authors.forename: AnneMarie
authors.initials: A
authors.lastname: Asemissen
authors.forename: Anika
authors.initials: A
authors.lastname: Nonnenmacher
authors.forename: Sebastian
authors.initials: S
authors.lastname: Ochsenreither
authors.forename: Alberto
authors.initials: A
authors.lastname: Fusi
authors.forename: Floriane
authors.initials: F
authors.lastname: Braun
authors.forename: David
authors.initials: D
authors.lastname: Stather
authors.forename: Alexander
authors.initials: A
authors.lastname: Schmittel
authors.forename: Kurt
authors.initials: K
authors.lastname: Miller
authors.forename: Eckhard
authors.initials: E
authors.lastname: Thiel
authors.forename: Ulrich
authors.initials: U
authors.lastname: Keilholz
mesh_terms: D000328:Adult; D000368:Aged; D001557:Benzenesulfonates / Q000276:immunology / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000276:immunology; D018572:Disease-Free Survival; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000032:analysis; D015870:Gene Expression; D006801:Humans; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000097:blood; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011379:Prognosis; D011725:Pyridines / Q000276:immunology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077157:Sorafenib; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000097:blood / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D001557:Benzenesulfonates; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D010671:Phenylurea Compounds; D011725:Pyridines; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D009536:Niacinamide; D000077157:Sorafenib