{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:20:57Z","timestamp":1790785257400,"version":"4.1.0"},"reference-count":55,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T00:00:00Z","timestamp":1720656000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T00:00:00Z","timestamp":1720656000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Exp Clin Cancer Res"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Macrophages play important roles in phagocytosing tumor cells. However, tumors escape macrophage phagocytosis in part through the expression of anti-phagocytic signals, most commonly CD47. In Ewing sarcoma (ES), we found that tumor cells utilize dual mechanisms to evade macrophage clearance by simultaneously over-expressing CD47 and down-regulating cell surface calreticulin (csCRT), the pro-phagocytic signal. Here, we investigate the combination of a CD47 blockade (magrolimab, MAG) to inhibit the anti-phagocytic signal and a chemotherapy regimen (doxorubicin, DOX) to enhance the pro-phagocytic signal to induce macrophage phagocytosis of ES cells in vitro and inhibit tumor growth and metastasis in vivo.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Macrophages were derived from human peripheral blood monocytes by granulocyte\u2013macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF). Flow cytometry- and microscopy-based in-vitro phagocytosis assays were performed to evaluate macrophage phagocytosis of ES cells. Annexin-V assay was performed to evaluate apoptosis. CD47 was knocked out by CRISPR\/Cas9 approach. ES cell-based and patient-derived-xenograft (PDX)-based mouse models were utilized to assess the effects of MAG and\/or DOX on ES tumor development and animal survival. RNA-Seq combined with CIBERSORTx analysis was utilized to identify changes in tumor cell transcriptome and tumor infiltrating immune cell profiling in MAG and\/or DOX treated xenograft tumors.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We found that MAG significantly increased macrophage phagocytosis of ES cells in vitro (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01) and had significant effect on reducing tumor burden (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01) and increasing survival in NSG mouse model (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). The csCRT level on ES cells was significantly enhanced by DOX in a dose- and time-dependent manner (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01). Importantly, DOX combined with MAG significantly enhanced macrophage phagocytosis of ES cells in vitro (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01) and significantly decreased tumor burden (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01) and lung metastasis (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001) and extended animal survival in vivo in two different mouse models of ES (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). Furthermore, we identified CD38, CD209, CD163 and CD206 as potential markers for ES-phagocytic macrophages. Moreover, we found increased M2 macrophage infiltration and decreased expression of Cd209 in the tumor microenvironment of MAG and DOX combinatorial therapy treated tumors.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>By turning \u201ctwo keys\u201d simultaneously to reactivate macrophage phagocytic activity, our data demonstrated an effective and highly translatable alternative therapeutic approach utilizing innate (tumor associated macrophages) immunotherapy against high-risk metastatic ES.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13046-024-03093-w","type":"journal-article","created":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T07:02:05Z","timestamp":1720681325000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Combinatorial macrophage induced innate immunotherapy against Ewing sarcoma: Turning \u201cTwo Keys\u201d simultaneously"],"prefix":"10.1186","volume":"43","author":[{"given":"Wen","family":"Luo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai","family":"Hoang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine E.","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwen","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaokui","family":"Mo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A. 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DAL reports personal fees and other from Kiadis Pharma, CytoSen Therapeutics, Courier Therapeutics, and Caribou Biosciences outside the submitted work. In addition, DAL has a patent broadly related to NK cell therapy of cancer with royalties paid to Kiadis Pharma. TPC recently served as a one-time consultant to Blueprint, Incyte, Oncopeptides, DSMB chair for SpringWorks and is a cofounder of Vironexis Biotherapeutics, Inc. Other co-authors declare they have no conflict of interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"193"}}