Dendritic cells as mediators of tumor-induced tolerance in metastatic melanoma.
Escape from immune surveillance is critical for tumor progression in metastatic melanoma. We assessed the function of melanoma-derived dendritic cells (DCs) in patients presenting simultaneously with responding (rM) or progressing (pM) melanoma metastases. These rare coincidences allowed us to compare syngeneically the function of tumor DCs. CD83+ DCs were purified freshly from large responding (rDCs) or progressing (pDCs) metastases following chemoimmunotherapy. rDCs were 5 times more potent inducers of allogeneic T-cell proliferation than the pDCs that were used as control. Phenotypic analysis showed a marked depression of CD86 expression on pDCs. Culture supernatants from pM showed production of Th2-type cytokines [interleukin-10 (IL-10)], whereas a Th1 pattern [IL-2, interferon-gamma (IFN-gamma), IL-12) predominated in rM. The IL-10 detected in progressing metastases was directly derived from melanoma cells. Culture supernatants from metastases applied to DC-supported allo-MLR assays suppressed T-cell responses by 50-75% in the case of pM, but not rM. Finally, in a co-stimulation-dependent anti-CD3 tolerance assay, pDCs (but not rDCs) induced anergy in syngeneic CD4+ T cells. Anergy could be overcome by addition of IL-12 or IL-2. Our results show that melanoma-derived factors convert DC-antigen presenting cell function to tolerance induction against tumor tissue, changing tumor DCs to "silencers" of anti-tumoral immune responses.
Enk
A H
AH
Department of Dermatology, University of Mainz, Germany.
Jonuleit
H
H
Saloga
J
J
Knop
J
J
D015703:Antigens, CD / Q000032:analysis / Q000276:immunology; D000951:Antigens, Neoplasm / Q000032:analysis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D051940:B7-2 Antigen; D002455:Cell Division / Q000276:immunology; D002945:Cisplatin / Q000008:administration & dosage; D016207:Cytokines / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage; D016753:Interleukin-10 / Q000032:analysis; D007376:Interleukin-2 / Q000008:administration & dosage; D008545:Melanoma / Q000276:immunology* / Q000556:secondary / Q000628:therapy; D008562:Membrane Glycoproteins / Q000032:analysis; D009363:Neoplasm Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D019139:Tumor Escape / Q000276:immunology*
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D051940:B7-2 Antigen; C497964:CD86 protein, human; D016207:Cytokines; D016898:Interferon-alpha; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D016753:Interleukin-10; D002945:Cisplatin