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Adjuvant effects of formalin‐inactivated HSV through activation of dendritic cells and inactivation of myeloid‐derived suppressor cells in cancer immunotherapy
Author(s) -
OhkusuTsukada Kozo,
Ohta Shigeki,
Kawakami Yutaka,
Toda Masahiro
Publication year - 2010
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.25319
Subject(s) - adjuvant , tlr9 , myeloid derived suppressor cell , cancer research , immune system , immunology , immunotherapy , cross presentation , cancer immunotherapy , dendritic cell , antigen , tlr2 , angiogenesis , medicine , cancer , antigen presentation , t cell , biology , innate immune system , suppressor , biochemistry , gene expression , dna methylation , gene
Abstract 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.