Natural killer cell cytotoxicity of breast cancer targets is enhanced by two distinct mechanisms of antibody-dependent cellular cytotoxicity against LFA-3 and HER2/neu

Treatment of advanced breast cancer with autologous stem cell transplantati on is limited by a high probability of disease relapse. In clinical trials, interleukin 2 (IL-2) alone can expand natural killer (NK) cells in vivo an d increase their cytotoxic activity against breast cancer cell lines, but t his increase is modest. Understanding the mechanisms that mediate NK cell l ysis of breast cancer targets may lead to improvements of current immunothe rapy strategies. Nh; cells from normal donors or patients receiving subcuta neous IL-2 were tested in cytotoxicity assays against five breast cancer ce ll lines. The role of adhesion molecules and antibodies that interact throu gh Pc receptors on NK cells was explored, NK cell lysis of bl east cancer t argets is variable and is partially dependent on recognition through ICAM-1 and CD18, While blocking CD2 slightly decreased cytotoxicity, contrary to expectations, an antibody against CD58 (the ligand for CD2), failed to bloc k killing and instead mediated an increased cytotoxicity that correlated wi th target density of CD58, The CD58 antibody-enhanced killing was dependent not only on FcR gamma III but also on CD2 and ICAM-1/CD18. To further eluc idate the mechanism of this CD58 antibody-dependent cellular cytotoxicity ( ADCC), another antibody was tested. Trastuzumab (Herceptin), a humanized an tibody against HER2/neu, mediated potent ADCC against all the HER2/neu posi tive breast cancer targets. Unlike CD58 antibody-mediated ADCC, Herceptin A DCC was minimally affected by blocking antibodies to CD2 or ICAM-1/CD18, wh ich suggests a different mechanism of action. This study shows that multipl e mechanisms are involved in NK cell lysis of breast cancer targets, that n one of the targets are inherently resistant to killing, and that two distin ct mechanisms of ADCC can target immunotherapy to breast cancer cells. (C) 1999 International Society for Experimental Hematology. Published by Elsevi er Science Inc.