Antibody-based immunotherapy may be improved by adding an “appetiser” to stimulate the activity of macrophages, according to a new study.
US researchers say they have successfully tested their technique to show it can improve the effectiveness of rituximab in the treatment of lymphoma cell lines in the lab.
Macrophages search the body for cells and debris tagged with the antibody IgG, detected using the Fc receptor (FcR). This ‘eat-me’ signal leads to the clustering of FcR, which activates the process leading to the macrophage eating the cell, called phagocytosis.
But much about the process of macrophage phagocytosis is unclear, particularly the timing and amount of stimulus needed to activate phagocytosis.
Scientists at the University of California, Santa Barbara, developed a technique to artificially stimulate FcR clustering, in order to understand how a macrophage decides whether to eat a cell. The technique uses blue light to activate clustering of a specially engineered Fc receptor, without the presence of IgG antibody.
The research, reported in Developmental Cell, showed that macrophages primed by this technique later consumed an increased number of cells tagged with IgG – as if the ‘appetiser’ makes the macrophages hungrier for their next meal. The team also showed there was an optimal level of priming – too much of the ‘appetiser’ reduced subsequent macrophage activity, as if “they weren't hungry anymore”.
The team then went on to test whether this approach could increase the effectiveness of rituximab – an IgG antibody-based drug which is used to treat lymphomas. Using cancer cell lines in the lab, the team demonstrated that the ‘appetiser’ approach did indeed increase the ability of macrophages to eat cancer cells.
Researchers Annalise Bond and Dr Meghan Morrissey say the findings suggest that immunotherapy may work best in small doses rather than in a single large dose.
The research also sheds light on an unappreciated sophistication of macrophages, suggesting the cells are more complex decision-makers than previously thought.
Dr Morrissey said: “Macrophages need to think about the situation they’re in. Are they in healthy tissue and need to avoid autoimmunity, or are they fighting an infection and need to go out guns blazing?”
Source:
Bond A, Fiaz S, Rollins K, Nario JEQ, Snyder ET, Atkins DJ, Rosen SJ, Granados A, Dey SS, Wilson MZ, Morrissey MA. (2024) “Prior Fc receptor activation primes macrophages for increased sensitivity to IgG via long-term and short-term mechanisms.” Developmental Cell, 12 August 2024, doi: 10.1016/j.devcel.2024.07.017
Link: https://www.sciencedirect.com/science/article/pii/S153458072400457X
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