Immunosuppressive dendritic and regulatory T cells are upregulated in melanoma patients.
BACKGROUND
Immunologic therapies for melanoma rarely succeed, suggesting a persistent counter-regulatory immune modulation. Regulatory T cells (T(regs)) and plasmacytoid subpopulations of dendritic cells (pDCs) inhibit the immune response. We hypothesize that melanoma upregulates T(regs )and subpopulations of immunosuppressive dendritic cells (DCs).


METHODS
Peripheral blood mononuclear cells (PBMCs) were obtained from healthy controls, stage I and stage IV melanoma patients. T(regs )were identified as CD4+ and CD25(hi). Dendritic cells were identified using a DC cocktail of antibodies including CD11c+ myeloid dendritic cells (mDCs) and CD123+ pDCs. Serum transforming growth factor-beta (TGF-beta), interleukin-4 (IL-4) and interleukin-10 (IL-10) levels were determined by enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed using analysis of variance (ANOVA).


RESULTS
Stage IV melanoma patients had a doubling of regulatory T cells compared to both normal subjects and stage I melanoma patients. There was a significantly higher number of DCs in all melanoma patients compared to normal subjects. Stage I melanoma patients had a significantly higher number of pDCs than normal subjects, and all melanoma patients had a higher concentration of mDCs than controls. Serum IL-4 and IL-10 were not detectable but serum TGF-beta levels were significantly higher in stage I and stage IV melanoma patients compared to normal controls.


CONCLUSIONS
Advanced melanoma is associated with increased numbers of circulating dendritic cells and regulatory T cells. These data suggest that melanoma induces immunosuppressive DCs and regulatory T cells in the systemic circulation.
McCarter
Martin D
MD
Department of Surgery, University of Colorado at Denver Health Sciences Center, Denver, CO 80262, USA. martin.mccarter@uchsc.edu
Baumgartner
Joel
J
Escobar
Guillermo A
GA
Richter
Donald
D
Lewis
Karl
K
Robinson
William
W
Wilson
Cara
C
Palmer
Brent E
BE
Gonzalez
Rene
R
D000368:Aged; D015704:CD4 Antigens / Q000097:blood; D003713:Dendritic Cells / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D016753:Interleukin-10 / Q000097:blood; D053645:Interleukin-2 Receptor alpha Subunit / Q000097:blood; D053650:Interleukin-3 Receptor alpha Subunit / Q000097:blood; D015847:Interleukin-4 / Q000097:blood; D018655:Lymphocyte Count; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000097:blood; D019139:Tumor Escape / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology
D015704:CD4 Antigens; D053645:Interleukin-2 Receptor alpha Subunit; D053650:Interleukin-3 Receptor alpha Subunit; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D015847:Interleukin-4