CD16 is indispensable for antibody-dependent cellular cytotoxicity by human monocytes

Abstract

Antibody-dependent cellular cytotoxicity (ADCC) is exerted by immune cells expressing surface Fcγ receptors (FcγRs) against cells coated with antibody, such as virus-infected or transformed cells. CD16, the FcγRIIIA, is essential for ADCC by NK cells, and is also expressed by a subset of human blood monocytes. We found that human CD16− expressing monocytes have a broad spectrum of ADCC capacities and can kill cancer cell lines, primary leukemic cells and hepatitis B virus-infected cells in the presence of specific antibodies. Engagement of CD16 on monocytes by antibody bound to target cells activated β2-integrins and induced TNFα secretion. In turn, this induced TNFR expression on the target cells, making them susceptible to TNFα-mediated cell death. Treatment with TLR agonists, DAMPs or cytokines, such as IFNγ, further enhanced ADCC. Monocytes lacking CD16 did not exert ADCC but acquired this property after CD16 expression was induced by either cytokine stimulation or transient transfection. Notably, CD16+ monocytes from patients with leukemia also exerted potent ADCC. Hence, CD16+ monocytes are important effectors of ADCC, suggesting further developments of this property in the context of cellular therapies for cancer and infectious diseases.

Monocyte heterogeneity and functions in cancer

“…However, many cancer cells are resistant to TRAIL‐mediated apoptosis and TRAIL can instead stimulate secretion of protumoral cytokines such as CCL2 and IL‐8 . Monocytes can also induce cancer cell death through Ab‐dependent cellular cytotoxicity, which both CD14 + and CD16 + monocyte subsets have the capacity for . CD16 + monocytes require contact with tumor cells and TNF‐α signaling for induction of tumor cell cytolysis .…”

“…58 Monocytes can also induce cancer cell death through Ab-dependent cellular cytotoxicity, which both CD14 + and CD16 + monocyte subsets have the capacity for. 59,60 CD16 + monocytes require contact with tumor cells and TNF-signaling for induction of tumor cell cytolysis. 60 Monocytes collected from peripheral blood or ascites fluid of human ovarian cancer patients display reduced capacity for Ab-dependent cytolysis and phagocytosis of tumor cells upon activation in vitro.…”

Concise Review: Human Pluripotent Stem Cells to Produce Cell-Based Cancer Immunotherapy

“…NK cytolytic function also requires engagement of strong activating signals. These activating receptors include natural cytotoxicity receptors, NKG2D and CD16, the receptor that mediates antibody‐dependent cellular cytotoxicity (ADCC) to direct NK cells' activity to target cells .…”

“…Generally, NK cell‐mediated killing is determined by a summation of positive and negative intracellular signaling . One key activating receptor is the Fc receptor CD16a which activates NK cell killing by binding the Fc portion of IgG molecules resulting in ADCC . This potent anti‐tumor response is already of routine clinical relevance, as there are a number of cancers already being treated by therapeutic antibodies .…”

Alga‐Made Anti‐Hepatitis B Antibody Binds to Human Fcγ Receptors

“…Cellular binding assays and surface plasmon resonance (SPR) was used to assess the binding kinetics of the alga‐made antibodies to human FcγRs. Two representative receptors were selected for this study, FcγRI, that is well known to capture monomeric IgG1 effectively with high affinity and is involved in mediating phagocytosis, and a lower affinity FcγRIIIa that plays a major role in inducing ADCC . To the best of our knowledge, this is the first demonstration that a recombinant mAb produced in microalgae is able to bind human FcγRs.…”