LYVE-1+ macrophages form a collaborative CCR5-dependent perivascular niche that influences chemotherapy responses in murine breast cancer.
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; Arnold, James N
(2023) Developmental Cell, volume 58, issue 17, pp. 1548 - 1561.e10
(Article)
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
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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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Keywords: CCR5, IL-6, LYVE-1, TAM subset development, chemotherapy resistance, immune exclusion, macrophage, perivascular niche, spatial, tumor, General Biochemistry,Genetics and Molecular Biology, Molecular Biology, Cell Biology, Developmental Biology
ISSN: 1534-5807
Publisher: Cell Press
Note: Funding Information: The authors thank Dr. Yasmin Haque (KCL) and the NIHR BRC flow cytometry platform at Guy’s and St Thomas’ Biomedical Research Centre for cell sorting and flow cytometry assistance and Dr. James Levitt and the Nikon Imaging Centre (KCL) for the use of their facilities and assistance with confocal microscopy analyses. The authors would like to thank Drs. Paul Lavender, Tracey Mitchell, Gilbert Fruhwirth (KCL), and Professor Awen Gallimore (University of Cardiff) for useful discussion/advice/support; Miss Rosamond Nuamah (KCL) for running the microarray; and Mr. Stuart Newman (KCL) for help with the rederivation of the HO-1 Luc/ E GFP reporter mouse. The authors thank Professor George Kollias (University of Athens) for the use of the Hmox1 fl/fl allele mice. The authors would like to thank Miss Jiaying Yao for the initial optimization of the focal-point macrophage migration assay. This work was funded by the following grants: Cancer Research UK grant DCRPGF\100009 (J.N.A.), European Research Council grant 335326 (J.N.A.), Cancer Research Institute/Wade F.B. Thompson CLIP grant ( CRI3645 ) (J.N.A.), Medical Research Council grant MR/N013700/1 (J.E.A.), Medical Research Council grant MR/PO18823/1 (F.M.W.), Wellcome Trust grant 206439/Z/17/Z (F.M.W.), and Cancer Research UK grant C54019/A27535 (D.R.W.). The research was supported by the Cancer Research UK King’s Health Partners Centre and Experimental Cancer Medicine Centre at King’s College London and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London . The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. Funding Information: The authors thank Dr. Yasmin Haque (KCL) and the NIHR BRC flow cytometry platform at Guy's and St Thomas’ Biomedical Research Centre for cell sorting and flow cytometry assistance and Dr. James Levitt and the Nikon Imaging Centre (KCL) for the use of their facilities and assistance with confocal microscopy analyses. The authors would like to thank Drs. Paul Lavender, Tracey Mitchell, Gilbert Fruhwirth (KCL), and Professor Awen Gallimore (University of Cardiff) for useful discussion/advice/support; Miss Rosamond Nuamah (KCL) for running the microarray; and Mr. Stuart Newman (KCL) for help with the rederivation of the HO-1Luc/EGFP reporter mouse. The authors thank Professor George Kollias (University of Athens) for the use of the Hmox1fl/fl allele mice. The authors would like to thank Miss Jiaying Yao for the initial optimization of the focal-point macrophage migration assay. This work was funded by the following grants: Cancer Research UK grant DCRPGF\100009 (J.N.A.), European Research Council grant 335326 (J.N.A.), Cancer Research Institute/Wade F.B. Thompson CLIP grant (CRI3645) (J.N.A.), Medical Research Council grant MR/N013700/1 (J.E.A.), Medical Research Council grant MR/PO18823/1 (F.M.W.), Wellcome Trust grant 206439/Z/17/Z (F.M.W.), and Cancer Research UK grant C54019/A27535 (D.R.W.). The research was supported by the Cancer Research UK King's Health Partners Centre and Experimental Cancer Medicine Centre at King's College London and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas’ NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. J.E.A. and J.N.A. conceived the project, designed the approach, performed the experiments, interpreted the data, and wrote the manuscript. K.T.F. J.W.O. I.D. H.P.M. M.B. T.S.C. K.L.-A. Z.L. D.C. J.C. D.S. R.B. T.M. Z.A. and G.L. designed the approach, performed the experiments, and interpreted the data. C.E.G. X.Z. F.M.W. T.N. J.M.B. S.K. D.R.W. and T.L. designed the experiments, interpreted the data, and provided key expertise. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. Publisher Copyright: © 2023 The Author(s)
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