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

Abstract

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.

Integrins Influence the Size and Dynamics of Signaling Microclusters in a Pyk2-dependent Manner

“…SKBR3 cells have a low level of ICAM-1 that serves as a ligand for ␤ 2 integrins on CD16.NK-92 cells (7). We have shown that treatment of SKBR3 with IFN-␥ for 48 h results in significant up-regulation of cell-surface ICAM-1 molecules but not Her2/neu receptor (7).…”

“…Herceptin, humanized antibody against human HER2/neu used in this study have been previously described (7,9). Hybridomas producing mouse blocking antibody TS1/18 specific for human CD18 (␤ 2 integrin chain), mouse non-blocking TS2/4 antibody against human CD11a (␣ L integrin chain), mouse blocking antibody R6.5 specific for human ICAM-1, and mouse 3G8 antibody specific for human CD16 were purchased from ATCC.…”

“…Cells, Antibodies, and Chemicals-The human NK-92 cell line transduced to express Fc␥RIIIa receptor (176V allele of CD16 that binds to the antibody Fc fragment with high affinity) has been described in detail elsewhere (7,8). The human breast cancer cell line SKBR3 was supplied by ATCC.…”

“…To unravel the mechanism by which integrins influence activating receptor-mediated signaling in cytotoxic lymphocytes and facilitates cytolytic granule delivery to target cells, we took advantage of well characterized CD16.NK-92 cytolytic effectors that express several integrin receptors, whose binding to ICAM-1 and/or other ligands influence cytolytic activity of these cells (7). We exploited tumor target cells with varying levels of ICAM-1 expression and have found that changes in the ICAM-1 level significantly influence the kinetics of CD16.NK-92 cell degranulation and the rate of target cell lysis in ADCC.…”

IL-18 Is Involved in Eosinophil-Mediated Tumoricidal Activity against a Colon Carcinoma Cell Line by Upregulating LFA-1 and ICAM-1

“…Thus, JAM-A-JAM-A binding may also have been involved in our celladhesion assay. ICAM-1 is both a cell surface glycoprotein that belongs to the Ig superfamily and a costimulatory molecule that provides signals to cytotoxic T lymphocytes and NK cells (46,47). Increasing evidence suggests that ICAM-1 plays a functional role on the tumor cell surface.…”