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Many hematologic and solid tumors are resistant to therapeutic antibodies in the bone marrow (BM), but not in the periphery (e.g., spleen). We previously showed that cyclophosphamide (CTX) sensitizes the BM niche to antibody therapeutics. Here, we show that (i) BM resistance was induced not only by the tumor but also by the intrinsic BM microenvironment; (ii) CTX treatment overcame both intrinsic and extrinsic resistance mechanisms by augmenting macrophage activation and phagocytosis, including significant upregulation of activating Fc\u03b3 receptors (Fc\u03b3RIII and Fc\u03b3RIV) and downregulation of the inhibitory receptor, Fc\u03b3RIIB; and (iii) CTX synergized with cetuximab (anti-EGFR) and trastuzumab (anti-Her2) in eliminating metastatic breast cancer in the BM of humanized mice. These findings provide insights into the mechanisms by which CTX synergizes with antibody therapeutics in resistant niche-specific organs and its applicability in treating BM-resident tumors.<\/jats:p>","DOI":"10.1158\/2326-6066.cir-18-0835","type":"journal-article","created":{"date-parts":[[2019,8,26]],"date-time":"2019-08-26T14:45:10Z","timestamp":1566830710000},"page":"1876-1890","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Cyclophosphamide Enhances Cancer Antibody Immunotherapy in the Resistant Bone Marrow Niche by Modulating Macrophage Fc\u03b3R Expression"],"prefix":"10.1158","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1316-4218","authenticated-orcid":false,"given":"Ali","family":"Roghanian","sequence":"first","affiliation":[{"name":"1Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts."},{"name":"2Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom."},{"name":"3Cancer Research UK Centre, University of Southampton, Southampton, United Kindgom."}]},{"given":"Guangan","family":"Hu","sequence":"additional","affiliation":[{"name":"1Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts."}]},{"given":"Christopher","family":"Fraser","sequence":"additional","affiliation":[{"name":"1Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts."}]},{"given":"Maneesh","family":"Singh","sequence":"additional","affiliation":[{"name":"1Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts."}]},{"given":"Russell 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Medicine, University of Southampton, Southampton, United Kingdom."},{"name":"3Cancer Research UK Centre, University of Southampton, Southampton, United Kindgom."}]},{"given":"Stephen A.","family":"Beers","sequence":"additional","affiliation":[{"name":"2Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom."},{"name":"3Cancer Research UK Centre, University of Southampton, Southampton, United Kindgom."}]},{"given":"Sean H.","family":"Lim","sequence":"additional","affiliation":[{"name":"2Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom."},{"name":"3Cancer Research UK Centre, University of Southampton, Southampton, United Kindgom."}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7451-363X","authenticated-orcid":false,"given":"Margaret","family":"Ashton-Key","sequence":"additional","affiliation":[{"name":"2Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom."},{"name":"3Cancer Research UK Centre, University of Southampton, Southampton, United Kindgom."}]},{"given":"Stephen M.","family":"Thirdborough","sequence":"additional","affiliation":[{"name":"3Cancer Research UK Centre, University of Southampton, Southampton, United Kindgom."}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2077-089X","authenticated-orcid":false,"given":"Mark S.","family":"Cragg","sequence":"additional","affiliation":[{"name":"2Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom."},{"name":"3Cancer Research UK Centre, University of 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