Systemic Immune Tuning in Renal Cell Carcinoma: Favorable Prognostic Impact of TGF-β1 mRNA Expression in Peripheral Blood Mononuclear Cells

被引：15

作者：

Busse, Antonia ^{[1
]}

Asemissen, AnneMarie ^{[1
]}

Nonnenmacher, Anika ^{[1
]}

Ochsenreither, Sebastian ^{[1
]}

Fusi, Alberto ^{[1
]}

Braun, Floriane ^{[1
]}

Stather, David ^{[1
]}

Schmittel, Alexander ^{[1
]}

Miller, Kurt ^{[2
]}

Thiel, Eckhard ^{[1
]}

Keilholz, Ulrich ^{[1
]}

机构：

[1] Charite Campus Benjamin Franklin, Dept Med Hematol & Oncol 3, D-12200 Berlin, Germany

[2] Charite Campus Benjamin Franklin, Dept Urol, D-12200 Berlin, Germany

来源：

JOURNAL OF IMMUNOTHERAPY | 2011年 / 34卷 / 01期

关键词：

renal cell carcinoma; regulatory T cells; interleukin-10; transforming growth factor-beta; sorafenib; REGULATORY T-CELLS; GROWTH-FACTOR-BETA; TUMOR MICROENVIRONMENT; SURVIVAL; INTERLEUKIN-10; SUPPRESSION; ACTIVATION; MECHANISMS; FREQUENCY; LYMPHOMA;

D O I：

10.1097/CJI.0b013e3181fb6580

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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)-beta. 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-beta mRNA levels, regulatory T-cell (Treg) counts, and frequencies of IL-10/TGF-beta 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-beta 1 mRNA levels, and frequencies of CD4(+)CD25high/CD3(+) and CD4(+)CD25high FoxP3(+)/CD3(+) Treg cells were significantly higher in mRCC patients compared with healthy individuals. Monocytes were suggested as main producers of IL-10 and TGF-beta. In a multivariate analysis low ECOG score and-surprisingly-high TGF-beta 1 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-beta 1 mRNA expression levels may reflect immune promoting functions of TGF-beta in combined activity with inflammatory cytokines.

引用

页码：113 / 119

页数：7

共 34 条

[1]

Making sense of latent TGFβ activation [J].

Annes, JP ;

Munger, JS ;

Rifkin, DB .

JOURNAL OF CELL SCIENCE, 2003, 116 (02) :217-224

[2]

Increase of CD4+CD25+ regulatory T cells in the peripheral blood of patients with metastatic carcinoma:: a Phase I clinical trial using cyclophosphamide and immunotherapy to eliminate CD4+CD25+ T lymphocytes [J].

Audia, S. ;

Nicolas, A. ;

Cathelin, D. ;

Larmonier, N. ;

Ferrand, C. ;

Foucher, P. ;

Fanton, A. ;

Bergoin, E. ;

Maynadie, M. ;

Arnould, L. ;

Bateman, A. ;

Lorcerie, B. ;

Solary, E. ;

Chauffert, B. ;

Bonnotte, B. .

CLINICAL AND EXPERIMENTAL IMMUNOLOGY, 2007, 150 (03) :523-530

[3]

Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers [J].

Badoual, C ;

Hans, S ;

Rodriguez, J ;

Peyrard, S ;

Klein, C ;

Agueznay, NE ;

Mosseri, V ;

Laccourreye, O ;

Bruneval, P ;

Fridman, WH ;

Brasnu, DF ;

Tartour, E .

CLINICAL CANCER RESEARCH, 2006, 12 (02) :465-472

[4]

DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3+ conventional T cells [J].

Baron, Udo ;

Floess, Stefan ;

Wieczorek, Georg ;

Baumann, Katrin ;

Gruetzkau, Andreas ;

Dong, Jun ;

Thiel, Andreas ;

Boeld, Tina J. ;

Hoffmann, Petra ;

Edinger, Matthias ;

Tuerbachova, Ivana ;

Hamann, Alf ;

Olek, Sven ;

Huehn, Jochen .

EUROPEAN JOURNAL OF IMMUNOLOGY, 2007, 37 (09) :2378-2389

[5]

High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma [J].

Carreras, Joaquim ;

Lopez-Guillermo, Armando ;

Fox, Bridget C. ;

Colomo, Lluis ;

Martinez, Antonio ;

Roncador, Giovanna ;

Montserrat, Emili ;

Campo, Elias ;

Banham, Alison H. .

BLOOD, 2006, 108 (09) :2957-2964

[6]

Characterization of CD4+CD25+ regulatory T cells in patients treated with high-dose interleukin-2 for metastatic melanoma or renal cell carcinoma [J].

Cesana, GC ;

DeRaffele, G ;

Cohen, S ;

Moroziewicz, D ;

Mitcham, J ;

Stoutenburg, J ;

Cheung, K ;

Hesdorffer, C ;

Kim-Schulze, S ;

Kaufman, HL .

JOURNAL OF CLINICAL ONCOLOGY, 2006, 24 (07) :1169-1177

[7]

Requirement for transforming growth factor β1 in controlling T cell apoptosis [J].

Chen, WJ ;

Jin, WW ;

Tian, HS ;

Sicurello, P ;

Frank, M ;

Orenstein, JM ;

Wahl, SM .

JOURNAL OF EXPERIMENTAL MEDICINE, 2001, 194 (04) :439-453

[8]

Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival [J].

Curiel, TJ ;

Coukos, G ;

Zou, LH ;

Alvarez, X ;

Cheng, P ;

Mottram, P ;

Evdemon-Hogan, M ;

Conejo-Garcia, JR ;

Zhang, L ;

Burow, M ;

Zhu, Y ;

Wei, S ;

Kryczek, I ;

Daniel, B ;

Gordon, A ;

Myers, L ;

Lackner, A ;

Disis, ML ;

Knutson, KL ;

Chen, LP ;

Zou, WP .

NATURE MEDICINE, 2004, 10 (09) :942-949

[9]

Sunitinib Reverses Type-1 Immune Suppression and Decreases T-Regulatory Cells in Renal Cell Carcinoma Patients [J].

Finke, James H. ;

Rini, Brian ;

Ireland, Joanna ;

Rayman, Patricia ;

Richmond, Amy ;

Golshayan, Ali ;

Wood, Laura ;

Elson, Paul ;

Garcia, Jorge ;

Dreicer, Robert ;

Bukowski, Ronald .

CLINICAL CANCER RESEARCH, 2008, 14 (20) :6674-6682

[10]

Transforming growth factor β1 inhibits Fas ligand expression and subsequent activation-induced cell death in T cells via downregulation of c-Myc [J].

Genestier, L ;

Kasibhatla, S ;

Brunner, K ;

Green, DR .

JOURNAL OF EXPERIMENTAL MEDICINE, 1999, 189 (02) :231-239

← 1 2 3 4 →