title: Extranodal dissemination of non-Hodgkin lymphoma requires CD47 and is inhibited by anti-CD47 antibody therapy.
abstract: Non-Hodgkin lymphoma (NHL) presents as both localized and disseminated disease with spread to secondary sites carrying a worse prognosis. Although pathways driving NHL dissemination have been identified, there are few therapies capable of inhibiting them. Here, we report a novel role for the immunomodulatory protein CD47 in NHL dissemination, and we demonstrate that therapeutic targeting of CD47 can prevent such spread. We developed 2 in vivo lymphoma metastasis models using Raji cells, a human NHL cell line, and primary cells from a lymphoma patient. CD47 expression was required for Raji cell dissemination to the liver in mouse xenotransplants. Targeting of CD47 with a blocking antibody inhibited Raji cell dissemination to major organs, including the central nervous system, and inhibited hematogenous dissemination of primary lymphoma cells. We hypothesized that anti-CD47 antibody-mediated elimination of circulating tumor cells occurred through phagocytosis, a previously described mechanism for blocking anti-CD47 antibodies. As predicted, inhibition of dissemination by anti-CD47 antibodies was dependent on blockade of phagocyte SIRPα and required macrophage effector cells. These results demonstrate that CD47 is required for NHL dissemination, which can be therapeutically targeted with a blocking anti-CD47 antibody. Ultimately, these findings are potentially applicable to the dissemination and metastasis of other solid tumors.
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford Cancer Center, and Ludwig Center at Stanford, Stanford, CA, USA. mpchao@stanford.edu
authors.forename: Mark P
authors.initials: MP
authors.lastname: Chao
authors.forename: Chad
authors.initials: C
authors.lastname: Tang
authors.forename: Russell K
authors.initials: RK
authors.lastname: Pachynski
authors.forename: Robert
authors.initials: R
authors.lastname: Chin
authors.forename: Ravindra
authors.initials: R
authors.lastname: Majeti
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
mesh_terms: D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D051928:CD47 Antigen / Q000276:immunology* / Q000502:physiology*; D006801:Humans; D007116:Immunization, Passive; D008198:Lymph Nodes; D008207:Lymphatic Metastasis; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000906:Antibodies; D051928:CD47 Antigen