HUMAN LUNG-CANCER CELL-LINES EXPRESS CELL-MEMBRANE COMPLEMENT INHIBITORY PROTEINS AND ARE EXTREMELY RESISTANT TO COMPLEMENT-MEDIATED LYSIS - A COMPARISON WITH NORMAL HUMAN RESPIRATORY EPITHELIUM IN-VITRO, AND AN INSIGHT INTO MECHANISM(S) OF RESISTANCE

Human lung cancer expresses cell membrane complement inhibitory protei ns (CIP). We investigated whether human lung cancer cell lines also ex press cell-membrane CIP molecules and whether the biology of CIP molec ules in these cell lines differs from that of CTP in normal human resp iratory epithelium in culture. The cell lines ChaGo K-1 and NCI-H596 w ere compared with normal human nasal epithelium in primary cultures in respect to the level of cell membrane CTP expression of membrane cofa ctor protein (MCP; CD46), decay-accelerating factor (DAF; CD55) and CD 59, in respect to the level of cell resistance to complement-mediated lysis, and in respect to the contribution of cell membrane CIP to cell resistance against complement-mediated lysis. We found, using flow cy tometry, that both human lung cancer cell lines expressed MCP, DAF and CD59, as did normal nasal epithelial cells. However, normal cells sho wed a large subpopulation of low DAF-expressing cells (60% of all cell s) and a smaller subpopulation of high DAF-expressing cells (40%), whi le the lung cancer cell lines showed only one cell population, of high DAF expression. In addition, both lung cancer cell lines expressed hi gher MCP levels, and NCI-H596 cells showed higher levels of CD59. Cell resistance to complement-mediated lysis of both lung cancer cell line s was much higher than that of normal cells. Fifty percent normal huma n serum, under the same concentrations of complement activators, induc ed lysis of less than a mean of 10% of lung cancer cells, while lysing up to a mean of 50% of nasal epithelial cells. Lung cancer cell resis tance to complement was due to its ability to prevent significant acti vation of complement upon its cell membrane, as manifested by a failur e of complement activators to increase cell membrane deposition of C3- related fragments. The exact mechanism for this resistance remains obs cure. Unexpectedly, neutralizing antibodies, anti-MCP and anti-DAF wer e entirely ineffective and anti-CD59 was only slightly effective (18% mean cell lysis) in increasing the susceptibility of the lung cancer c ell lines to complement, while the same antibodies were very effective in facilitating complement-mediated lysis of the normal nasal epithel ial cells (50% mean cell lysis with CD59 MoAb). On the other hand, det achment of DAF and CD59 by phosphatidylinositol-specific phospholipase C (PIPLC) from the lung cancer cell lines abrogated their resistance to lysis. We suggest that the biology of cell membrane CIP molecules i n human lung cancer cell lines is different from that of CLP in normal respiratory epithelial cells. Human lung cancer cell lines are able t o prevent significant complement activation upon its cell membrane and are therefore especially resistant to complement-mediated lysis. Comp lement resistance may serve this common and highly lethal human cancer as an escape mechanism from the body's immunosurveillance and prevent effective immunotherapy with tumour-specific MoAbs.