title: Macrophage inflammatory protein derivative ECI301 enhances the alarmin-associated abscopal benefits of tumor radiotherapy.
abstract: Radiotherapy can produce antitumor benefits beyond the local site of irradiation, an immune-based phenomenon known as the abscopal effect, but the mechanisms underlying these benefits are poorly understood. Preclinical studies of ECI301, a mutant derivative of macrophage inhibitory protein-1α, have shown that its administration can improve the antitumor effects of radiotherapy in a manner associated with a tumor-independent abscopal effect. In this article, we report that i.v. administration of ECI301 after intratumoral injection of tumor cell lysates can inhibit tumor growth, not only at the site of injection but also at nontreated sites. Effects of the tumor lysate were further recapitulated by intratumoral injection [corrected] of the alarmins HSP70 or HMGB1, but not HSP60, and i.v. administration [corrected] of ECI301 + HSP70 were sufficient to inhibit tumor growth. Although i.v. administration [corrected] of ECI301 + HMGB1 did not inhibit tumor growth, we found that administration of a neutralizing HMGB1 antibody neutralized the cooperative effects of ECI301 on tumor irradiation. Moreover, mice genetically deficient in TLR4, an immune pattern receptor that binds alarmins, including HMGB1 and HSP70, did not exhibit antitumor responses to irradiation with ECI301 administration. Although ECI301 was cleared rapidly from peripheral blood, it was found to bind avidly to HSP70 and HMGB1 in vitro. Our results suggest a model in which sequential release of the alarmins HSP70 and HMGB1 from a tumor by irradiation may trap circulating ECI301, thereby licensing or restoring tumor immunosurveillance capabilities of natural killer cells or CD4(+) and CD8(+) T cells against tumor cells that may evade irradiation. Cancer Res; 74(18); 5070-8. ©2014 AACR.
authors.affiliation: Central Laboratory, Effector Cell Institute (ECI) Inc., Meguro-ku, Tokyo, Japan. YU-ECI Research Center for Medical Science, Yeungnam University, Gyeongsan, Gyongbuk, Republic of Korea.
authors.forename: Shiro
authors.initials: S
authors.lastname: Kanegasaki
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, the University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
authors.affiliation: Department of Radiology, University Hospital, the University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Kenshiro
authors.initials: K
authors.lastname: Shiraishi
authors.affiliation: Department of Radiology, University Hospital, the University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Nakagawa
authors.affiliation: Central Laboratory, Effector Cell Institute (ECI) Inc., Meguro-ku, Tokyo, Japan. YU-ECI Research Center for Medical Science, Yeungnam University, Gyeongsan, Gyongbuk, Republic of Korea. ttsuchiy-tky@umin.ac.jp.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tsuchiya
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002417:Cattle; D045744:Cell Line, Tumor; D054405:Chemokine CCL3 / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D004357:Drug Synergism; D005260:Female; D024243:HMGB1 Protein / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins / Q000494:pharmacology; D006801:Humans; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000532:radiotherapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D015398:Signal Transduction
chemical_list: D054405:Chemokine CCL3; D024243:HMGB1 Protein; D018840:HSP70 Heat-Shock Proteins