Combinatorial macrophage induced innate immunotherapy against Ewing sarcoma: Turning "Two Keys" simultaneously.

Autor: Luo W; Department of Pediatrics, New York Medical College, 15 Dana Road, Valhalla, NY, 10595, USA. Wen_Luo@nymc.edu.; Department of Pathology, Immunology and Microbiology, New York Medical College, Valhalla, NY, 10595, USA. Wen_Luo@nymc.edu., Hoang H; Department of Pediatrics, New York Medical College, 15 Dana Road, Valhalla, NY, 10595, USA., Miller KE; Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.; Department of Pediatrics, The Ohio State University, Columbus, OH, USA., Zhu H; Department of Pediatrics, New York Medical College, 15 Dana Road, Valhalla, NY, 10595, USA., Xu S; James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA., Mo X; Department of Biomedical Informatics, Center for Biostatistics, The Ohio State University, Columbus, OH, USA., Garfinkle EAR; Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.; Department of Pediatrics, The Ohio State University, Columbus, OH, USA., Costello H; Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., Wijeratne S; Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA., Chemnitz W; Department of Medicine, New York Medical College, Valhalla, NY, USA., Gandhi R; University of Chicago, Chicago, IL, USA., Liao Y; Department of Pediatrics, New York Medical College, 15 Dana Road, Valhalla, NY, 10595, USA., Ayello J; Department of Pediatrics, New York Medical College, 15 Dana Road, Valhalla, NY, 10595, USA., Gardenswartz A; Department of Pediatrics, New York Medical College, 15 Dana Road, Valhalla, NY, 10595, USA., Rosenblum JM; Department of Pediatrics, New York Medical College, 15 Dana Road, Valhalla, NY, 10595, USA., Cassady KA; Center for Childhood Cancer Research, Nationwide Children's Hospital, Columbus, OH, USA., Mardis ER; Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.; Department of Pediatrics, The Ohio State University, Columbus, OH, USA.; Department of Neurosurgery, The Ohio State University, Columbus, OH, USA., Lee DA; Department of Pediatrics, The Ohio State University, Columbus, OH, USA., Cripe TP; Department of Pediatrics, The Ohio State University, Columbus, OH, USA.; Center for Childhood Cancer Research, Nationwide Children's Hospital, Columbus, OH, USA., Cairo MS; Department of Pediatrics, New York Medical College, 15 Dana Road, Valhalla, NY, 10595, USA. Mitchell_Cairo@nymc.edu.; Department of Pathology, Immunology and Microbiology, New York Medical College, Valhalla, NY, 10595, USA. Mitchell_Cairo@nymc.edu.; Department of Medicine, New York Medical College, Valhalla, NY, USA. Mitchell_Cairo@nymc.edu.; Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, USA. Mitchell_Cairo@nymc.edu.
Jazyk: angličtina
Zdroj: Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2024 Jul 11; Vol. 43 (1), pp. 193. Date of Electronic Publication: 2024 Jul 11.
DOI: 10.1186/s13046-024-03093-w
Abstrakt: Background: 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.
Methods: Macrophages were derived from human peripheral blood monocytes by granulocyte-macrophage 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.
Results: We found that MAG significantly increased macrophage phagocytosis of ES cells in vitro (p < 0.01) and had significant effect on reducing tumor burden (p < 0.01) and increasing survival in NSG mouse model (p < 0.001). The csCRT level on ES cells was significantly enhanced by DOX in a dose- and time-dependent manner (p < 0.01). Importantly, DOX combined with MAG significantly enhanced macrophage phagocytosis of ES cells in vitro (p < 0.01) and significantly decreased tumor burden (p < 0.01) and lung metastasis (p < 0.0001) and extended animal survival in vivo in two different mouse models of ES (p < 0.0001). 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.
Conclusions: By turning "two keys" 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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