Journal
BLOOD
Volume 136, Issue 18, Pages 2065-2079Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2020005571
Keywords
-
Categories
Funding
- National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases [AI-114554]
- NIH National Institute of Diabetes and Digestive and Kidney Diseases [DK-119285]
- University of Rochester Wilmot Cancer Institute
- Acerta Pharma, LLC grant [005656]
- University of Rochester Research Award
- Wilmot Cancer Institute
- Acerta Pharma, LLC
- University of Rochester Immunology Training T32 Grant from the NIH National Institute of Allergy and Infectious Diseases [AI-007285]
Ask authors/readers for more resources
Macrophage antibody (Ab)-dependent cellular phagocytosis (ADCP) is a major cytotoxic mechanism for both therapeutic unconjugated monoclonal Abs (mAbs) such as rituximab and Ab-induced hemolytic anemia and immune thrombocytopenia. Here, we studied the mechanisms controlling the rate and capacity of macrophages to carry out ADCP in settings of high target/effector cell ratios, such as those seen in patients with circulating tumor burden in leukemic phase disease. Using quantitative live-cell imaging of primary human and mouse macrophages, we found that, upon initial challenge with mAb-opsonized lymphocytes, macrophages underwent a brief burst (<1 hour) of rapid phagocytosis, which was then invariably followed by a sharp reduction in phagocytic activity that could persist for days. This previously unknown refractory period of ADCP, or hypophagia, was observed in all macrophage, mAb, and target cell conditions tested in vitro and was also seen in vivo in Kupffer cells from mice induced to undergo successive rounds of alpha CD20 mAb-dependent clearance of circulating B cells. Importantly, hypophagia had no effect on Ab-independent phagocytosis and did not alter macrophage viability. In mechanistic studies, we found that the rapid loss of activating Fc receptors from the surface and their subsequent proteolytic degradation were the primary mechanisms responsible for the loss of ADCP activity in hypophagia. These data suggest hypophagia is a critical limiting step in macrophage-mediated clearance of cells via ADCP, and understanding such limitations to innate immune system cytotoxic capacity will aid in the development of mAb regimens that could optimize ADCP and improve patient outcome.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available