Metastatic Melanoma Secreted IL-10 Down-Regulates CD1 Molecules on Dendritic Cells in Metastatic Tumor Lesions

Abstract

CD1 molecules are expressed by antigen-presenting cells such as dendritic cells and mediate primary immune responses to lipids and glycolipids which have been shown to be expressed by various tumors. Glycolipids are expressed by melanoma cells but, despite their immunogenicity, no efficient spontaneous immune responses are elicited. As IL-10 has previously been shown to down-regulate CD1a on dendritic cells and is known to be expressed by various melanoma cell lines, we investigated if melanoma-derived IL-10 could down-regulate CD1 molecule expression on dendritic cells as a possible way to circumvent immune recognition. We found that CD1a, CD1b, CD1c, and CD1d were significantly down-regulated on dendritic cells in metastatic (n ‫؍‬ 10) but not in primary melanoma lesions (n ‫؍‬ 10). We further detected significantly higher IL-10 protein levels in metastatic than in primary melanomas. Moreover, supernatants from metastatic melanomas were significantly more effective in down-regulating CD1 molecules on dendritic cells than supernatants from primary melanoma cultures. This effect was blocked using a neutralizing IL-10 antibody in a dose dependent manner. Our findings suggest that metastatic but not primary melanomas can down-regulate CD1 molecules on infiltrating dendritic cells by secreting IL-10 which may represent a novel way to escape the immune response directed against the tumor. CD1 molecules are cell surface glycoproteins and represent a non-classical, non-polymorphic antigen-presenting system which is distantly related to major histocompatibility complex (MHC) class I and class II molecules. While MHC molecules form complexes with peptides, the CD1 system presents lipids and glycolipids of self and foreign origin.

Galectin-3 Expression Correlates with Apoptosis of Tumor-Associated Lymphocytes in Human Melanoma Biopsies

“…8,35 In the whole, only ϳ23% of the TALs were found to be apoptotic, independent of the cause. The viability of most TALs would explain why they may be expanded from tumor biopsies and give rise to CD8 ϩ /CD4 ϩ populations that, when reinfused to the patient, are able to induce clinical regressions.…”

“…Thus, the tumor relies on several mechanisms of immune escape such as down-regulation of major histocompatibility complex context molecules, insufficient antigen expression, 5 and production of local immunosuppressive factors, such as Fas ligand 6,7 or interleukin-10. 8 We and others have recently demonstrated in experimental melanoma that galectin-1 (gal-1) may also contribute to tumor immune escape. 9 Galectins are carbohydrate-binding proteins that share a constant recognition domain for ␤-galactosides and are involved in cell adhesion, migration, differentiation, angiogenesis, proliferation, mRNA splicing, and apoptosis.…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…Indeed, tumors have been shown to escape the anti-tumor immune responses by generating an immunosuppressed tumor microenvironment. Tumors often produce soluble immunosuppressive factors, such as TGFβ [13,68,69], VEGF [69,70], IL-10 [69,71], iNOS [72,73], PGE 2 [74,75], and gangliosides [76,77], that act on neutrophils and other tumor infiltrating immune cells. Often, progressive immunosuppression is observed at advanced tumor stages, which is partially mediated by tumor-infiltrating immunosuppressive immune cells such as regulatory T (Treg) cells, Th17 cells, regulatory dendritic cells, TAMs, TANs and MDSCs.…”

Reovirus Virotherapy Overrides Tumor Antigen Presentation Evasion and Promotes Protective Antitumor Immunity

“…Some of the well-recognized tumor immune evasion mechanisms include failure of tumor antigen recognition (4-6), modulation of MHC molecule expression (7,8), improper activation of antigen-presenting cells (APC; refs. 1, 9), failure of lymphocyte homing (1,10), and production of immunosuppressive cytokines (11,12). These immunologic abnormalities associated with the tumor microenvironment either inhibit the priming of antitumor adaptive immunity (1) or tolerize tumor-specific CD4 (13,14) and CD8 (15,16) T cells.…”