Melanoma Study in Mice Finds a Macrophage Group with Unusual Ability to Protect Against Cancer Progression

Melanoma Study in Mice Finds a Macrophage Group with Unusual Ability to Protect Against Cancer Progression

Massachusetts General Hospital researchers working in a mouse model of melanoma found that a specific type of immune cell — called subcapsular sinus (SCS) macrophages — forms a protective coat around lymph nodes to prevent cancer tissue invasion and to protect against tumor progression. But the coating is temporary, breaking down as tumors develop and under certain chemotherapy and immune therapy drugs.

The study, “SCS macrophages suppress melanoma by restricting tumor-derived vesicle–B cell interactions,” published in Science, raises important questions for treatments being developed to promote the depletion of tumor-promoting macrophages.

Tumors constantly communicate with their surroundings and the immune system, although through mechanisms that are not entirely known. A possible mechanism at play, by which tumors send molecular signals to host cells, is through tumor-derived extracellular vesicles (tEVs), small membrane-bound compartments that carry bits of tumor to distant sites in the body, and are known to bind to and activate different types of cells. Measuring tVEs levels is a predictor of treatment and survival outcomes, yet the impact of tVEs in living animals and in different regions of the body remains unclear.

Researchers used genetically modified mice to track the behavior of tVEs. They observed that these vesicles exit tumors, travel through the body, and become more concentrated around lymph nodes. To evaluate if this effect was relevant in humans, the team examined lymph nodes closest to tumors from 13 melanoma patients. It found melanoma-derived material in SCS macrophages surrounding nodes in 90 percent of the patients, although the lymph nodes themselves were cancer-free.

Further experiments revealed that SCS macrophages suppressed tumors in two mouse models of melanoma and in a lung cancer model, a stark difference from macrophages found within tumors, which are known to promote cancer progression. Importantly, as the tumors grew the density of SCS macrophages around lymph nodes was seen to begin to decrease, a behavior also observed after treatment with some chemotherapy and immune therapy drugs.

“Since there currently is interest in developing therapies that deplete tumor-promoting macrophages within tumors, it could be useful to determine whether these treatments also affect protective SCS macrophages,” Dr. Mikael Pittet, a study leader, said in a news release. “The best outcome would probably be getting rid of the tumor-promoting activities of macrophages within tumors, while preserving the tumor-suppressing activities of SCS macrophages. It also would be useful to determine whether SCS macrophages can be strengthened to prevent delivery of tEVs into the lymph nodes, and to better understand how tEV-activated B cells promote cancer growth.”

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