Downregulation of the constitutive tapasin expression in human tumor cells of distinct origin and its transcriptional upregulation by cytokines.
Human tumor cells frequently exhibit abnormalities in the major histocompatibility complex (MHC) class I surface expression which can be due to structural alterations and/or dysregulation of various components of the MHC class I antigen processing machinery, such as HLA class I heavy and light chains, the peptide transporter and the proteasome subunits. Although several cofactors critical for proper MHC class I assembly have been identified, their contribution to the immune escape phenotype of tumor cells has not been analyzed. In order to determine whether tapasin deficits are an integral part of immune escape mechanisms of human tumors, we studied the constitutive and cytokine-regulated expression pattern of tapasin in malignant cells of distinct histology. Heterogeneous and reduced expression levels of tapasin were found in small-cell lung carcinoma, pancreatic carcinoma, colon carcinoma, head an neck squamous cell carcinoma and renal cell carcinoma cell lines. Tapasin downregulation was also prominent in surgically removed tumor lesions when compared to normal controls. The impaired tapasin expression is often associated with low MHC class I cell surface expression. In addition, various cytokines, including interferon (IFN)-alpha, IFN-gamma, tumor necrosis factor (TNF)-alpha and interleukin (IL)-4, but not granulocyte-macrophage colony stimulating factor (GM-CSF), transcriptionally upregulate to a distinct extent and in a time-dependent manner tapasin expression in tumor cells. Thus, deficient tapasin expression appears to be a frequent event in human tumor cells. Its restoration by cytokines further suggests that impaired tapasin expression in tumors is rather due to dysregulation than to structural alterations.
Seliger
B
B
The Johannes Gutenberg-University, IIIrd Department of Internal Medicine, Mainz, Germany. B.Seliger@3-med.klinik.uni-mainz.de
Schreiber
K
K
Delp
K
K
Meissner
M
M
Hammers
S
S
Reichert
T
T
Pawlischko
K
K
Tampé
R
R
Huber
C
C
D017920:Antiporters / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D016207:Cytokines / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D006680:HLA Antigens / Q000096:biosynthesis / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis* / Q000235:genetics; D026901:Membrane Transport Proteins; D009369:Neoplasms / Q000235:genetics / Q000276:immunology*; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000276:immunology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
D017920:Antiporters; D016207:Cytokines; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D007136:Immunoglobulins; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; C107762:tapasin