T cells infiltrating melanoma tumors are frequently reactive with differentiation antigens. Consequently, immune escape can occur when melanoma cells dedifferentiate and loose expression of commonly recognized antigens such as MART-1, gp100 or tyrosinase. A change in microenvironment, encountered when transformed melanocytic cells emigrate from the basal layer of the epidermis, may provide the incentive for reduced expression of these target antigens. In the present study, the contribution of IFN-γ exposure to reduced expression of melanosomal antigens was investigated. Immunostaining and FACS analysis of M14 melanoma cells treated with 100-1000 U/ml IFN-γ revealed a >65% suppression of gp100, TRP-1 and MART-1 protein levels. A similar reduction was observed by Northern blotting, suggesting that IFN-γ affects melanosomal gene expression at the transcriptional level. As inflammatory cytokine IFN-γ can simultaneously enhance cell surface expression of HLA molecules, the consequences of IFN-γ exposure for the efficacy of recognition by MART-1-reactive T cells was explored. In spite of elevated MHC class I expression, cytotoxicity towards HLA-matched melanoma cells (but not melanocytes) was reduced by up to 78% by IFN-γ pretreatment, and was restored by addition of MART-1 peptide AAGI-GILTV. This indicates that exposure to IFN-γ can suppress recognition by melanoma-reactive T cells. The actual abundance of IFN-γ in tumor tissue was compared to that in control skin by qRT-PCR, and revealed a 200-fold increase in transcripts within metastatic tumor tissue. Laser capture microdissection and immunohistology localized the majority of IFN-γ-generating T cells to the tumor stroma. Tumor-infiltrating T cells were frequently surrounded by a halo of reduced MART-1 expression, suggesting that IFN-γ generated by activated T cells may interfere with successful recognition of melanoma target cells in vivo. Taken together, these results indicate that IFN-γ may act as a two-edged sword, enhancing inflammatory responses yet hampering effective recognition of melanoma cells.
|Original language||English (US)|
|Journal||Cancer Immunology, Immunotherapy|
|Issue number||SUPPL. 1|
|State||Published - Dec 1 2003|
ASJC Scopus subject areas
- Immunology and Allergy
- Cancer Research