Perivascular macrophages collaborate to facilitate chemotherapy resistance in cancer

Anstee, J. E.; Opzoomer, J. W.; Dean, I.; Muller, H. P.; Bahri, M.; Liakath-Ali, K.; Liu, Z.; Choy, D.; Caron, J.; Sosnowska, D.; Beatson, R.; Muliaditan, T.; An, Z.; Gillett, C. E.; Lan, G.; Zou, X.; Watt, F. M.; Ng, T.; Burchell, J. M.; Kordasti, S.; Withers, D. R.; Lawrence, T.; Arnold, J. N.

doi:10.1101/2022.02.03.478952

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bioRxiv · 10.1101/2022.02.03.478952

Perivascular macrophages collaborate to facilitate chemotherapy resistance in cancer

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Abstract

A subset of tumor associated macrophages (TAMs) identified by their expression of the lymphatic vessel endothelial hyaluronan receptor-1 (Lyve-1) reside proximal to blood vasculature and contribute to disease progression. Using a spontaneous murine model of mammary adenocarcinoma (MMTV-PyMT), we show that Lyve-1+ TAMs, which co-express heme oxygenase-1, form coordinated multi-cellular nest structures in the perivascular niche. We show that TAM nest formation is dependent on IL-6 and a communication axis involving CCR5 and its cognate ligands CCL3/4. We demonstrate that Lyve-1+ TAM nests are associated with CD8+ T-cell exclusion from the tumor and the resistance to immune-stimulating chemotherapeutics. This study highlights an unappreciated collaboration between TAMs and uncovers a spatially driven therapeutic resistance mechanism of these cells in cancer which can be therapeutically targeted.

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Anstee, J. E., Opzoomer, J. W., Dean, I., Muller, H. P., Bahri, M., Liakath-Ali, K., Liu, Z., Choy, D., Caron, J., Sosnowska, D., Beatson, R., Muliaditan, T., An, Z., Gillett, C. E., Lan, G., Zou, X., Watt, F. M., Ng, T., Burchell, J. M., Kordasti, S., Withers, D. R., Lawrence, T., Arnold, J. N.. 2022-02-04. Perivascular macrophages collaborate to facilitate chemotherapy resistance in cancer. https://doi.org/10.1101/2022.02.03.478952

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