Dendritic cells as mediators of tumor-induced tolerance in metastatic melanoma

✍ Scribed by Alexander H. Enk; Helmut Jonuleit; Joachim Saloga; Jürgen Knop

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: French
• Weight: 150 KB
• Volume: 73
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/(sici)1097-0215(19971104)73:3<309::aid-ijc1>3.0.co;2-3

✦ Synopsis

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-␥ (IFN-␥), 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 melanomaderived factors convert DC-antigen presenting cell function to tolerance induction against tumor tissue, changing tumor DCs to ''silencers'' of anti-tumoral immune responses.