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Interferon-gamma reduces melanosomal antigen expression and recognition of melanoma cells by cytotoxic T cells.
- Source :
-
The American journal of pathology [Am J Pathol] 2002 Feb; Vol. 160 (2), pp. 521-8. - Publication Year :
- 2002
-
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.
- Subjects :
- Antigens, Neoplasm genetics
Antigens, Neoplasm immunology
Cell Separation
Flow Cytometry
Humans
Immunohistochemistry
Interferon-gamma genetics
MART-1 Antigen
Melanoma pathology
Microscopy methods
Neoplasm Proteins genetics
Neoplasm Proteins metabolism
T-Lymphocytes, Cytotoxic immunology
Tumor Cells, Cultured
Antigens, Neoplasm metabolism
Interferon-gamma metabolism
Melanoma immunology
T-Lymphocytes, Cytotoxic metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0002-9440
- Volume :
- 160
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The American journal of pathology
- Publication Type :
- Academic Journal
- Accession number :
- 11839572
- Full Text :
- https://doi.org/10.1016/s0002-9440(10)64871-7