The Immunological Organ Environment Dictates the Molecular and Cellular Pathways of Cytotoxic Antibody Activity.

Cytotoxic immunoglobulin G antibodies are an essential component of therapeutic approaches aimed at depleting self-reactive or malignant cells. More recent evidence suggests that the tissue in which the target cell resides influences the underlying molecular and cellular pathways responsible for cytotoxic antibody activity. By studying cytotoxic IgG activity directed against natural killer cells in primary and secondary immunological organs, we show that distinct organ-specific effector pathways are responsible for target cell depletion. While in the bone marrow, the classical complement pathway and the high-affinity Fcγ-receptor I expressed on organ-resident macrophages were both involved in removing opsonized target cells; in the spleen and blood, all activating FcγRs but not the classical complement pathway were critical for target cell killing. Our study suggests that future strategies aimed at optimizing overall cytotoxic antibody activity may need to consider organ-specific pathways to achieve a maximal therapeutic effect.

Tumor location determines tissue-specific recruitment of tumor-associated macrophages and antibody-dependent immunotherapy response.

Despite recent advances in activating immune cells to target tumors, the presence of some immune cells, such as tumor-associated macrophages (TAMs) or tumor-associated neutrophils (TANs), may promote rather than inhibit tumor growth. However, it remains unclear how antibody-dependent tumor immunotherapies, such as cytotoxic or checkpoint control antibodies, affect different TAM or TAN populations, which abundantly express activating Fcγ receptors. In this study, we show that the tissue environment determines which cellular effector pathways are responsible for antibody-dependent tumor immunotherapy. Although TAMs derived from Ly6Chigh monocytes recruited by the CCL2-CCR2 axis were critical for tumor immunotherapy of skin tumors, the destruction of lung tumors was CCL2-independent and required the presence of colony-stimulating factor 2-dependent tissue-resident macrophages. Our findings suggest that TAMs may have a dual role not only in promoting tumor growth in certain tissue environments on the one hand but also in contributing to tumor cell destruction during antibody-mediated immunotherapy on the other hand.

bIgG time for large eaters: monocytes and macrophages as effector and target cells of antibody-mediated immune activation and repression.

The mononuclear phagocytic system consists of a great variety of cell subsets localized throughout the body in immunological and non-immunological tissues. While one of their prime tasks is to detect, phagocytose, and kill intruding microorganisms, they are also involved in maintaining tissue homeostasis and immune tolerance toward self through removal of dying cells. Furthermore, monocytes and macrophages have been recognized to play a critical role for mediating immunoglobulin G (IgG)-dependent effector functions, including target cell depletion, tissue inflammation, and immunomodulation. For this, monocyte and macrophage populations are equipped with a complex set of Fc-receptors, enabling them to directly interact with pro- or anti-inflammatory IgG preparations. In this review, we will summarize the most recent findings, supporting a central role of monocytes and macrophages for pro- and anti-inflammatory IgG activity.

FcγR dependent mechanisms of cytotoxic, agonistic, and neutralizing antibody activities.

Given the widespread use of antibodies of the immunoglobulin G (IgG) class as cytotoxic, immunomodulatory, and neutralizing agents in the therapy of malignant, infectious, and autoimmune diseases, understanding the molecular and cellular mechanisms responsible for their therapeutic activity is of major importance. While Fcγ receptors (FcγR) have well-appreciated roles as effectors of cytotoxic IgG activity, it has only recently become clear that the functionality of immunomodulatory and neutralizing IgG preparations also depends on cellular FcγRs. Here, we review current models of IgG activity in infectious and inflammatory settings, and examine the importance of cell type-specific expression of FcγRs in determining functional outcome. We discuss how this knowledge may be used to improve the activity of therapeutic antibody preparations and outline important areas of focus for future research.