SCS macrophages suppress melanoma by restricting tumor-derived vesicle–B cell interactions

Macrophages block tumors' spread Tumors constantly communicate with their surrounding tissue and the immune system. One way tumors likely do this is by secreting extracellular vesicles (tEVs), which can carry bits of the tumor to distant sites in the body. Pucci et al. tracked tEVs in tumor-bearing mice and people and studied how they affect cancer progression. They found that tEVs disseminate through lymph to nearby lymph nodes, where a specialized population of macrophages largely block any further travel. This barrier breaks down, however, as cancer progresses and also in the face of certain therapies. The tEVs can then penetrate lymph nodes, where they interact with B cells that promote further tumor growth. Science, this issue p. 242 Lymph node macrophages provide a physical barrier against tumor spread. Tumor-derived extracellular vesicles (tEVs) are important signals in tumor–host cell communication, yet it remains unclear how endogenously produced tEVs affect the host in different areas of the body. We combined imaging and genetic analysis to track melanoma-derived vesicles at organismal, cellular, and molecular scales to show that endogenous tEVs efficiently disseminate via lymphatics and preferentially bind subcapsular sinus (SCS) CD169+ macrophages in tumor-draining lymph nodes (tdLNs) in mice and humans. The CD169+ macrophage layer physically blocks tEV dissemination but is undermined during tumor progression and by therapeutic agents. A disrupted SCS macrophage barrier enables tEVs to enter the lymph node cortex, interact with B cells, and foster tumor-promoting humoral immunity. Thus, CD169+ macrophages may act as tumor suppressors by containing tEV spread and ensuing cancer-enhancing immunity.