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
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
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DOI：
10.1016/s0301-472x(99)00089-2
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发表时间：
1999-10-01
影响因子：
2.6
通讯作者：
Miller, JS
中科院分区：
文献类型：
--
作者：
Cooley, S;Burns, LJ;Miller, JS
自体干细胞移植治疗晚期乳腺癌受疾病复发可能性高的限制。在临床试验中，单独使用白细胞介素2 （IL-2）可以在体内扩增自然杀伤细胞（NK），并增加其对乳腺癌细胞系的细胞毒活性，但这种增加是适度的。了解介导NK细胞裂解乳腺癌靶点的机制可能会导致当前免疫治疗策略的改进。Nh;对正常供体或接受皮下IL-2治疗的患者的细胞进行了对五种乳腺癌细胞系的细胞毒性试验。粘附分子和抗体通过Pc受体在NK细胞上相互作用的作用被探索，NK细胞对bl - east癌症靶点的裂解是可变的，部分依赖于通过ICAM-1和CD18的识别。虽然阻断CD2略有降低细胞毒性，但与预期相反，针对CD58 （CD2的配体）的抗体未能阻断杀伤，而是介导与CD58靶密度相关的细胞毒性增加。CD58抗体增强的杀伤不仅依赖于FcR γ III，还依赖于CD2和ICAM-1/CD18。为了进一步阐明这种CD58抗体依赖性细胞毒性（ADCC）的机制，我们测试了另一种抗体。曲妥珠单抗（赫赛汀）是一种针对HER2/neu的人源化抗体，可介导针对所有HER2/neu阳性乳腺癌靶点的强效ADCC。与CD58抗体介导的ADCC不同，Herceptin ADCC受CD2或ICAM-1/CD18阻断抗体的影响最小，这表明其作用机制不同。本研究表明NK细胞裂解乳腺癌靶点涉及多种机制，没有一种靶点具有固有的杀伤抗性，并且ADCC的两种不同机制可以靶向乳腺癌细胞的免疫治疗。(C) 1999国际实验血液学学会。Elsevier Science Inc.出版。
Treatment of advanced breast cancer with autologous stem cell transplantation 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 and increase their cytotoxic activity against breast cancer cell lines, but this increase is modest. Understanding the mechanisms that mediate NK cell lysis of breast cancer targets may lead to improvements of current immunotherapy strategies. Nh; cells from normal donors or patients receiving subcutaneous IL-2 were tested in cytotoxicity assays against five breast cancer cell lines. The role of adhesion molecules and antibodies that interact through Pc receptors on NK cells was explored, NK cell lysis of bl east cancer targets 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 block killing and instead mediated an increased cytotoxicity that correlated with 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 elucidate the mechanism of this CD58 antibody-dependent cellular cytotoxicity (ADCC), another antibody was tested. Trastuzumab (Herceptin), a humanized antibody against HER2/neu, mediated potent ADCC against all the HER2/neu positive breast cancer targets. Unlike CD58 antibody-mediated ADCC, Herceptin ADCC was minimally affected by blocking antibodies to CD2 or ICAM-1/CD18, which suggests a different mechanism of action. This study shows that multiple mechanisms are involved in NK cell lysis of breast cancer targets, that none of the targets are inherently resistant to killing, and that two distinct mechanisms of ADCC can target immunotherapy to breast cancer cells. (C) 1999 International Society for Experimental Hematology. Published by Elsevier Science Inc.