[Anticancer immunotherapy using inactivated Sendai virus particles].
Ultraviolet-inactivated, replication-defective Sendai virus particles (Hemagglutinating virus of Japan envelope, HVJ-E) injected into murine colon carcinoma (CT26) tumors growing in syngeneic Balb/c mice eradicated 60-80% of the tumors and obviously inhibited the growth of the remainder. Induced adaptive anti-tumor immune responses were dominant in the tumor eradication process because the effect was abrogated in severe combined immunodeficient (SCID) mice. Murine and human dendritic cells (DCs) underwent dose-dependent maturation by HVJ-E in vitro. Profiles of cytokines secreted by DCs after HVJ-E stimulation showed that the amount of IL-6 released was comparable to that elicited by live HVJ. Real-time RT-PCR and immunohistochemistry revealed that HVJ-E induced a remarkable infiltration of DCs, CD4+ and CD8+ T cells into tumors and CT26 specific cytotoxic T lymphocytes (CTL) were induced. On the other hand, conditioned medium from DCs stimulated by HVJ-E (H-DCCM) rescued CD4+CD25- effector T cell proliferation from Foxp3+CD4+CD25+ regulatory T cell (Treg) mediated suppression and IL-6 was presumably dominant for this phenomenon. We also confirmed such rescue in mice treated with HVJ-E in vivo. Moreover, anti-tumor effect of HVJ-E was significantly reduced by an in vivo blockade of IL-6 signaling. Depending on cancer cell types, it is also expected that HVJ-E eradicates tumor by its direct cytotoxity against cancer cells or activating NK cells. Because it can enhance anti-tumor immunity and simultaneously remove Treg mediated suppression, HVJ-E shows promise as a novel therapeutic for cancer immunotherapy.
kurooka@gts.med.osaka-u.ac.jp
Masayuki
M
Kurooka
Yasufumi
Y
Kaneda
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002277:Carcinoma / Q000276:immunology* / Q000628:therapy*; D003110:Colonic Neoplasms / Q000276:immunology* / Q000628:therapy*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D015850:Interleukin-6 / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D029082:Sendai virus; D014771:Virion; D038301:Virus Inactivation
D015850:Interleukin-6