CD47 as a Cancer Target May Rely on Dendritic Cells Rather than Macrophages

CD47 is a marker for cancer cells in a broad range of cancers, and thus targeting it offers the prospect of a cancer treatment that can be applied to many more patients than is usually the case. A number of research groups are working on refining this basic idea into practical treatments, or improving first attempts, as is the case here:

By changing the mouse model they use to study how the immune system responds to cancer, a team of researchers hopes to shift the focus for one emerging form of cancer immunotherapy back to the standard approach - relying on antigen-presenting dendritic cells - and away from the current upstart, macrophages. Although macrophages, like dendritic cells, also take up antigens, they are more likely to degrade them than present them to T cells. The recent emphasis on macrophages stems, in part, from promising, but problematic, efforts to develop an effective macrophage-driven T cell-mediated immunotherapy.

Researchers report that using a monoclonal antibody called anti-CD47, which blocks the "don't-eat-me" signal on malignant cells, to treat mice with an intact immune system provides a much more lifelike way to study and develop an immune-based cancer therapy. "Tumor rejection requires both innate and adaptive immune responses against tumor cells. We think our approach, along with further investigation of scheduling and dosing, could improve survival and quality of life for patients battling advanced cancer."

The shift of focus from one set of scavengers, dendritic cells, to another, macrophages, was initiated by ground-breaking studies demonstrating that many aging cells, and most cancer cells, display a protein called CD47 on the cell surface. The presence of CD47 protects these cells; it instructs circulating macrophages not to devour them. But as cells age or evolve, many slowly lose their protective CD47 and the macrophage system can confront them. The investigators found that when they used antibodies against CD47 to negate this "don't-eat-me" signal, macrophages were able to chew up many of these cancer cells.

Researchers now point out that these initial studies relied on human tumors transplanted into mice. The mice also had significant immune defects. They argue that a more appropriate model, transplanting tumors from mice into genetically identical hosts with fully intact immune systems, would be more informative and clinically relevant. When they used such mice to test their approach, they found that the bulk of therapeutic effect from CD47 blockade relied not on macrophages but on dendritic cells. These triggered the secretion of interferons, an immune system activator, and the priming of CD8+ T cells. They note that anti-CD47-mediated tumor rejection "requires both innate and adaptive immune responses."

Link: http://www.sciencedaily.com/releases/2015/08/150831120316.htm

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