CD44 stimulation down-regulates Fas expression and Fas-mediated apoptosis of lung cancer cells.
Cytotoxic T lymphocytes (CTL) play a major role in the rejection of tumor cells, but tumor rejection does not always occur in vivo, indicating that defects in anti-tumor immune responses may be common. We here document a novel function for CD44--using lung cancer cells, we showed that stimulation of CD44 reduced Fas expression and Fas-mediated apoptosis: (i) lung cancer cells expressed high levels of CD44; (ii) engagement of CD44 on the cells by a specific antibody or fragmented hyaluronan reduced Fas expression; (iii) CD44 cross-linking reduced Fas-mediated apoptosis; (iv) stimulation of CD44 on lung cancer cells decreased IFN-gamma production by autologous CTL; and (v) CD44 stimulation prevented killing of lung cancer cells by autologous CTL. Based on these findings, we postulate a new concept--that interaction of CD44 on lung cancer cells with fragments of extracellular hyaluronan present in the surrounding extracellular matrix reduces Fas expression as well as Fas-mediated apoptosis of cancer cells. This leads to reduced susceptibility of the cells to CTL-mediated cytotoxicity through the Fas-Fas ligand pathway.
Yasuda
M
M
Second Department of Surgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan.
Tanaka
Y
Y
Fujii
K
K
Yasumoto
K
K
D017209:Apoptosis; D003602:Cytotoxicity, Immunologic; D015536:Down-Regulation; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000276:immunology; D007108:Immune Tolerance; D007152:Immunologic Capping; D007371:Interferon-gamma; D008175:Lung Neoplasms / Q000276:immunology*; D018448:Models, Immunological; D014407:Tumor Cells, Cultured; D019139:Tumor Escape / Q000276:immunology*; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
D018960:Hyaluronan Receptors; D019014:fas Receptor; D007371:Interferon-gamma; D006820:Hyaluronic Acid