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

Int J Cancer. 1997 Nov 4;73(3):309-16. doi: 10.1002/(sici)1097-0215(19971104)73:3<309::aid-ijc1>3.0.co;2-3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / analysis
  • Antigens, CD / immunology
  • Antigens, Neoplasm / analysis
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • B7-2 Antigen
  • Cell Division / immunology
  • Cisplatin / administration & dosage
  • Cytokines / pharmacology
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Humans
  • Interferon-alpha / administration & dosage
  • Interleukin-10 / analysis
  • Interleukin-2 / administration & dosage
  • Melanoma / immunology*
  • Melanoma / secondary
  • Melanoma / therapy
  • Membrane Glycoproteins / analysis
  • Neoplasm Proteins / pharmacology
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • Tumor Escape / immunology*

Substances

  • Antigens, CD
  • Antigens, Neoplasm
  • B7-2 Antigen
  • CD86 protein, human
  • Cytokines
  • Interferon-alpha
  • Interleukin-2
  • Membrane Glycoproteins
  • Neoplasm Proteins
  • Interleukin-10
  • Cisplatin