Integrin receptors on tumor cells facilitate NK cell‐mediated antibody‐dependent cytotoxicity

NK cells that mediate ADCC play an important role in tumor‐specific immunity. We have examined factors limiting specific lysis of tumor cells by CD16.NK‐92 cells induced by CNTO 95LF antibodies recognizing αV integrins that are overexpressed on many tumor cells. Although all tested tumor cells were killed by CD16.NK‐92 effectors in the presence of the antibodies, the killing of target cells with a low level of ICAM‐1 expression revealed a dramatic decrease in their specific lysis at high antibody concentration, revealing a dose limiting effect. A similar effect was also observed with primary human NK cells. The effect was erased after IFN‐γ treatment of tumor cells resulting in upregulation of ICAM‐1. Furthermore, killing of the same tumor cells induced by Herceptin antibody was significantly impaired in the presence of CNTO 95Ala‐Ala antibody variant that blocks αV integrins but is incapable of binding to CD16. These data suggest that αV integrins on tumor cells could compensate for the loss of ICAM‐1 molecules, thereby facilitating ADCC by NK cells. Thus, NK cells could exercise cytolytic activity against ICAM‐1 deficient tumor cells in the absence of proinflammatory cytokines, emphasizing the importance of NK cells in tumor‐specific immunity at early stages of cancer.