Adjuvant effects of formalin-inactivated HSV through activation of dendritic cells and inactivation of myeloid-derived suppressor cells in cancer immunotherapy.
Use of adequate adjuvant is necessary for induction of effective antitumor immune responses. To develop an effective adjuvant for cancer immunotherapy, we selected formalin-inactivated (f)-HSV as an adjuvant component, and analyzed the mechanisms underlying its adjuvant effects. First, we found that f-HSV can induce the tumor antigen-specific CTLs by enhancing antigen cross-presentation by dendritic cells (DCs), mainly through TLR2, but not TLR9. Next, f-HSV was also found to prevent the accumulation of myeloid-derived suppressor cells (MDSCs). We demonstrated that the expansion of MDSCs in the blood and spleen during tumor progression required B cells producing the inflammatory angiogenesis factors, vascular endothelial growth factor (VEGF)-A and neuropilin-1 (NRP-1), a co-receptor for VEGF receptor-2 (VEGFR-2). Interestingly, the transmembrane-type NRP-1 on B cells changed to soluble-type NRP-1 (sNRP-1) by f-HSV treatment. We further showed that the sNRP-1 and VEGF-A secreted from B cells by f-HSV treatment could abrogate the immunosuppressive ability of MDSCs. These results suggest that f-HSV can enhance antitumor immune responses as an adjuvant, not only through activation of DCs, but also inactivation of MDSCs via B cells.
Ohkusu-Tsukada
Kozo
K
Neuroimmunology Research Group, Keio University School of Medicine, Tokyo, Japan.
Ohta
Shigeki
S
Kawakami
Yutaka
Y
Toda
Masahiro
M
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D045142:Cross-Priming / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005557:Formaldehyde; D007114:Immunization / Q000379:methods; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D018139:Simplexvirus / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000276:immunology / Q000378:metabolism; D014709:Vero Cells
D000276:Adjuvants, Immunologic; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D015164:Vaccines, Inactivated; D042461:Vascular Endothelial Growth Factor A; D005557:Formaldehyde; D040301:Vascular Endothelial Growth Factor Receptor-2