Interferon-γ Reduces Melanosomal Antigen Expression and Recognition of Melanoma Cells by Cytotoxic T Cells

Abstract

In malignant melanoma, tumor-infiltrating lymphocytes are frequently reactive with melanosomal antigens. Achieving complete remissions by peptide therapy is frequently hampered by metastases evading immune recognition. The tumor microenvironment seems to favor reduced expression of target antigens by melanoma cells. Among candidate factors, interferon-gamma (IFN-gamma) (10(2) to 10(3) U/ml) suppressed expression of antigens MART-1, TRP-1, and gp100 by M14 melanoma cells as shown by immunohistology and fluorescence-activated cell sorting analysis, reducing MART-1 expression by >65%. Northern blot analysis revealed that reduced expression was regulated at the transcriptional level, demonstrating a 79% reduction in MART-1 transcript abundance after 32 hours of IFN-gamma treatment. To evaluate consequences of IFN-gamma exposure for immune recognition, MART-1-responsive T cells were reacted with pretreated HLA-matched melanoma cells. Cytotoxicity was reduced up to 78% by IFN-gamma pretreatment, and was restored by addition of MART-1 peptide AAGIGILTV for 2 hours. Examination of melanoma lesions by quantitative reverse transcriptase-polymerase chain reaction revealed up to 188-fold more abundant IFN-gamma transcripts when compared to control skin. Laser capture microdissection and immunohistology localized most IFN-gamma-producing T cells to the tumor stroma. Reduced MART-1 expression was frequently observed in adjacent tumor cells. Consequently, IFN-gamma may enhance inflammatory responses yet hamper effective recognition of melanoma cells.

Enhancement of Human Melanoma Antigen Expression by IFN-β

“…More recently, both IFN-␣ and IFN-␥ have been shown to be effective in inducing class I HLA, but with limited effectiveness for Ag induction (39). Furthermore, IFN-␥ sometimes down-regulates Ag expression (40), consistent with our own results.…”

“…Despite its superior stimulation of HLA class I Ag expression (16), IFN-␥ is a poor inducer of melanocytic Ags (Ref. 39 and this work), and may even repress Ag expression in some tumors (40). Our own experience has shown that stimulation of A375 cells with IFN-␥ fails to elicit the enhanced cytotoxicity induced by IFN-␤.…”

IFN-γ signaling maintains skin pigmentation homeostasis through regulation of melanosome maturation

“…Of the pigmentation genes, DCT showed a drastic decrease of around 80%. Similar observations were also reported during the course of another study (17,18). TYRP1 and TYR were decreased to a lesser extent across different primary cultures treated with IFN-γ ( Fig.…”

Interleukins 1α and 1β secreted by some melanoma cell lines strongly reduce expression of MITF‐M and melanocyte differentiation antigens

“…21,22,34,35 According to our results, this reduction most likely originates from the downregulation of transcription factor MITF-M by these cytokines. We provide the first evidence that IL-1a and IL-1b are additional cytokines that reduce the expression of MITF-M.…”

“…In a previous study, IFN-c was shown to reduce by up to 78% the cytotoxicity of anti-Melan-A/MART-1 26-35 CTL, despite the stimulatory effect of IFN-c on MHC class I expression and antigen presentation. 22 This reduction is most likely due to the induction of the immunoproteasome, which does not process the Melan-A/MART-1 [26][27][28][29][30][31][32][33][34][35] peptide. 42 Data of a recent study suggest that IL-1b is not able to induce the immunoproteasome.…”