Antibody dependent cell-mediated cytotoxicity

Antibody-dependent cell-mediated cytotoxicity (ADCC) refers to an immune mechanism in which Fc receptor-carrying (CD16) effector cells recognize and specifically kill antibody-coated target cells. Effector cells are mainly NK cells (natural killer cells), but also macrophages, dendritic cells, neutrophils and eosinophils (Wei Wang et al. 2015). ADCC represents a link between the innate and the adaptive immune system.

Four stages and mechanisms leading to antibody-dependent effector-mediated killing of the target cell can be defined as follows:

• recognition of the target cell and the Fc receptor; cross-linking on the surface of the effector cell
• Phosphorylation of activation motifs (ITAMs) on the basis of immune receptor tyrosine by cellular src kinases within the effector cell
• Triggering of three "main downstream signaling pathways" in the effector cell, resulting in polarization and release of the cytotoxic granules
• Killing of the target cell via the perforin / granzyme apoptosis pathway. Perforins penetrate the cell membrane of the target cell and form a pore there. Granzymes are serine proteases that penetrate through these pores into the target cell to hydrolytically cleave intracellular proteins and thereby drive them into apoptosis.

Various laboratory methods exist for determining ADCC (Miller AS et al. 2014). The classical method is the chromium-51 [ 51 Cr] release test. The cytotoxicity of NK cells can be determined by means of a flow cytometry-based cytotoxicity test, among others. In this procedure, the monoclonal antibody trastuzumab, which binds specifically to HER2-positive malignant cells, is used to trigger a defined ADCC (van der Haar Àvila I et al. 2019).

1. Miller AS et al (2014) Methods for measuring antibody-dependent cell-mediated cytotoxicity in vitro. Methods Mol Biol 1134:59-65
2. Wei Wang et al (2015) NK Cell-Mediated Antibody-Dependent Cellular Cytotoxicity in Cancer Immunotherapy. Frontiers in Immunology 6: 368
3. Rogers LM et al (2014) Complement in monoclonal antibody therapy of cancer. Immunologic Research 59: 203-210
4. van der Haar Àvila I et al (2019) Evaluating Antibody-Dependent Cell-Mediated Cytotoxicity by Flow Cytometry. Methods Mol Biol 1913:181-194.