Anstee, Joanne E., Feehan, Karen T., Opzoomer, James W., Dean, Isaac, Muller, Henrike P., Bahri, Meriem, Cheung, Tik Shing, Liakath-Ali, Kifayathullah, Liu, Ziyan, Choy, Desmond, Caron, Jonathan, Sosnowska, Dominika, Beatson, Richard, Muliaditan, Tamara, An, Zhengwen, Gillett, Cheryl E., Lan, Guocheng, Zou, Xiangang, Watt, Fiona M., Ng, Tony, Burchell, Joy M., Kordasti, Shahram, Withers, David R., Lawrence, Toby and Arnold, James N. (2023) LYVE-1+ macrophages form a collaborative CCR5-dependent perivascular niche that influences chemotherapy responses in murine breast cancer. Developmental Cell, 58 (17), 1548-1561, [e10]. (doi:10.1016/j.devcel.2023.06.006).
Abstract
Tumor-associated macrophages (TAMs) are a heterogeneous population of cells that facilitate cancer progression. However, our knowledge of the niches of individual TAM subsets and their development and function remain incomplete. Here, we describe a population of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1)-expressing TAMs, which form coordinated multi-cellular "nest" structures that are heterogeneously distributed proximal to vasculature in tumors of a spontaneous murine model of breast cancer. We demonstrate that LYVE-1+ TAMs develop in response to IL-6, which induces their expression of the immune-suppressive enzyme heme oxygenase-1 and promotes a CCR5-dependent signaling axis, which guides their nest formation. Blocking the development of LYVE-1+ TAMs or their nest structures, using gene-targeted mice, results in an increase in CD8+ T cell recruitment to the tumor and enhanced response to chemotherapy. This study highlights an unappreciated collaboration of a TAM subset to form a coordinated niche linked to immune exclusion and resistance to anti-cancer therapy.
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