January 21, 2022 /Bio Valley BIOON/---Blocking the inhibitory checkpoint SIRPα-CD47 can promote the phagocytosis of cancer cells by macrophages, which is a promising approach in anticancer therapy. Efficient phagocytosis is strictly dependent on the co-engagement of prophagocytic receptors—Fc receptors (FcR), integrin CD11b or SLAMF7—with ligands on the surface of cancer cells.
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In a new study, researchers from Canada's Université de Montréal and the Montreal Institute for Clinical Research used two molecules on the surface of macrophages -- CD11a and CD11c -- to awaken the immune system's instinct to destroy cancer , which is a promising avenue for cancer treatment. The results of the study were recently published in the journal Cell Reports under the title "Inflammatory macrophages exploit unconventional pro-phagocytic integrins for phagocytosis and anti-tumor immunity".
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For several years, immunology and personalized medicine have given doctors and patients new hope in the fight against cancer. The new research uncovers an innovative way to treat cancer, in line with the burgeoning field of precision medicine. These authors investigated whether more prophagocytic receptors could be used to expand the scope of phagocytosis. Inflammatory stimuli, including multiple cytokines and TLR (Toll-like receptor) ligands, enhanced phagocytosis efficiency and completely alleviated the requirement of FcR, CD11b and SLAMF7 for phagocytosis. These effects are mediated by the atypical prophagocytic integrins CD11a and CD11c, which act in conjunction with CD18 to initiate actin polarization leading to phagocytosis. Some inflammatory stimuli enable phagocytosis even in the absence of SIRPα-CD47 blockade. In clinical studies, higher CD11c expression in macrophage-rich tumors was associated with improved survival. Thus, inflammatory macrophages utilize atypical phagocytosing integrins to enhance phagocytic capacity and antitumor immunity.

Image from Cell Reports, 2021, doi:10.1016/j.celrep.2021.110111.

These advanced therapies primarily target immune cells in the immune system called T cells, which work both to protect the body from foreign agents such as harmful viruses, bacteria and parasites, and to fight cancer cells .
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Among the "body guards" are also immune cells called macrophages, whose main role is to destroy harmful substances by ingesting them. Scientists and pharmaceutical companies are increasingly interested in targeting macrophages for therapeutic purposes.
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In the new study, co-corresponding author Dr. André Veillette of the University of Montreal and his team found that macrophages are particularly good at destroying certain types of cancer cells. What's more, they were able to greatly stimulate the appetite of macrophages. In particular, they identified two molecules on the surface of macrophages (CD11a and CD11c) that, when activated, increase the macrophage's instinct to destroy tumor cells. In animal models and human cell cultures in the laboratory, stimulated macrophages became super-phagocytic cells of cancer cells.
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"The ability to unleash the destructive power of macrophages is an important discovery that paves the way for some truly exciting new possibilities in personalized medicine," said Zhenghai Tang, co-first author of the paper. "We help the body better protect itself," added author Dominique Davidson.
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This new way of using CD11a and CD11c to help the body better fight cancer is the product of ongoing research work by Veillette's team. Veillette's team has spent the past 30 years studying the mechanisms that regulate the functioning of the immune system. In a 2017 study published in the journal Nature, the team elucidated the SLAMF7 molecule, which also plays a role in the destructive power of macrophages (Nature, 2017, doi:10.1038/nature22076).
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"The more we learn about how the immune system works, the better we can find effective, less toxic treatments to fight disease," Veillette said. "Immune cells like macrophages are not only available in current immunology research. There is tremendous concern, but also in the pharmaceutical industry, because this is truly the future of treatment for many deadly diseases."
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He added, "For us, the next step will be to determine the extent to which the CD11a and CD11c molecules can act as biomarkers to identify patients most likely to respond to this type of treatment." (Bioon. com)