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

Abstract

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.