Cooley S, Burns L J, Repka T, Miller J S
Department of Medicine, University of Minnesota Cancer Center, Minneapolis 55455, USA.
Exp Hematol. 1999 Oct;27(10):1533-41. doi: 10.1016/s0301-472x(99)00089-2.
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. NK 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 Fc receptors on NK cells was explored. NK cell lysis of breast 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 FcRgammaIII 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.
自体干细胞移植治疗晚期乳腺癌受到疾病复发高概率的限制。在临床试验中，单独使用白细胞介素2（IL-2）可在体内扩增自然杀伤（NK）细胞，并增加其对乳腺癌细胞系的细胞毒性活性，但这种增加幅度较小。了解介导NK细胞对乳腺癌靶细胞裂解的机制可能会改善当前的免疫治疗策略。对来自正常供体或接受皮下IL-2治疗患者的NK细胞进行了针对五种乳腺癌细胞系的细胞毒性试验。探讨了粘附分子以及通过NK细胞上的Fc受体相互作用的抗体的作用。NK细胞对乳腺癌靶细胞的裂解具有变异性，并且部分依赖于通过细胞间粘附分子1（ICAM-1）和CD18的识别。虽然阻断CD2会略微降低细胞毒性，但与预期相反，一种针对CD58（CD2的配体）的抗体未能阻断杀伤作用，反而介导了细胞毒性增加，且这种增加与CD58的靶密度相关。CD58抗体增强的杀伤作用不仅依赖于FcRγIII，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，测试了另一种抗体。曲妥珠单抗（赫赛汀），一种针对HER2/neu的人源化抗体，介导了对所有HER2/neu阳性乳腺癌靶细胞的强效ADCC。与CD58抗体介导的ADCC不同，赫赛汀介导的ADCC受CD2或ICAM-1/CD18阻断抗体的影响极小，这表明其作用机制不同。本研究表明，NK细胞对乳腺癌靶细胞的裂解涉及多种机制，没有一个靶细胞具有固有的抗杀伤性，并且两种不同的ADCC机制可将免疫治疗靶向乳腺癌细胞。
