title: Exosome-SIRPα, a CD47 blockade increases cancer cell phagocytosis.
abstract: CD47, a "don't eat me" signal, is over-expressed on the surface of most tumors that interacts with signal regulatory protein α (SIRPα) on phagocytic cells. By engaging SIRPα, CD47 limits the ability of macrophages to engulf tumor cells, which acts as a major phagocytic barrier. In this study, we developed an exosome-based immune checkpoint blockade that antagonizes the interaction between CD47 and SIRPα. These exosomes harboring SIRPα variants (SIRPα-exosomes) were sufficient to induce remarkably augmented tumor phagocytosis, lead to prime effective anti-tumor T cell response. Given that clustering of native CD47 provides a high binding avidity to ligate dimerized SIRPα on macrophage, nature-derived exosomes could be appreciable platform to antagonize CD47. Disruption of CD47-SIRPα interaction by SIRPα-exosomes leads to an increase in cells being engulfed by macrophages and a concomitant inhibition of tumor growth in tumor-bearing mice. Moreover, SIRPα-exosomes therapy promotes an intensive T cell infiltration in syngeneic mouse models of cancer, raising the possibility of CD47-targeted therapies to unleash both an innate and adaptive anti-tumor response. Note that very small amount of exosomal SIRPα proteins could effectively lead to phagocytic elimination of tumor cells both in vitro and in vivo. Our results suggest that superlative exosome-based platform has broad potential to maximize the therapeutic efficacy of membrane-associated protein therapeutics.
authors.affiliation: Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Eunee
authors.initials: E
authors.lastname: Koh
authors.affiliation: Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Gi-Hoon
authors.initials: GH
authors.lastname: Nam
authors.affiliation: Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Yeonsun
authors.initials: Y
authors.lastname: Hong
authors.affiliation: Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Eunji
authors.initials: E
authors.lastname: Cho
authors.affiliation: Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea. Electronic address: ysyang@kist.re.kr.
authors.forename: Yoosoo
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea. Electronic address: iskim14@kist.re.kr.
authors.forename: In-San
authors.initials: IS
authors.lastname: Kim
mesh_terms: D000943:Antigens, Differentiation / Q000378:metabolism*; D051928:CD47 Antigen / Q000378:metabolism*; D057899:Cytophagocytosis; D055354:Exosomes / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D009374:Neoplasms, Experimental / Q000473:pathology* / Q000503:physiopathology*; D011971:Receptors, Immunologic / Q000378:metabolism*
chemical_list: D000943:Antigens, Differentiation; D051928:CD47 Antigen; C497894:CD47 protein, human; D011971:Receptors, Immunologic; C501920:SIRPA protein, human
keywords: CD47; Cancer immunotherapy; Exosome; Phagocytosis; Signal regulatory protein α