Tumor immunotherapy using bone marrow-derived dendritic cells overexpressing Toll-like receptor adaptors.
Myeloid dendritic cells (mDCs) play an important role in the initiation of immune responses to cancer and infectious diseases. Toll-like receptors (TLRs) expressed on mDCs recognize microbial products to elicit signals for mDC maturation, including cytokine production, antigen-presentation and induction of effector cells. TLR agonists work as adjuvants to modulate the function of mDCs. In TLR signaling, MyD88 and TRIF/TICAM-1 are major TLR adaptor molecules, which when overexpressed are able to transduce downstream signals without TLR stimuli. We successfully introduced the adaptors into mouse bone marrow-derived mDCs using lentiviral vectors. Introduction of MyD88 into mDCs in vitro led to the production of IL-6 and IL-12p40 while introduction of TICAM-1 stimulated interferon (IFN)-alpha production. Expression of TICAM-1, but not MyD88, in mDCs slightly induced the co-stimulatory molecule CD86, while significant upregulation of CD86 was observed in response to other TLR stimuli. Both MyD88 and TICAM-1 augmented allogeneic mixed lymphocyte reaction (MLR). Ex vivo mouse spleen cells pre-exposed to tumor antigen exhibited antitumor cytotoxicity when incubated with MyD88- or TICAM-1-expressing mDCs. Using mDC adoptive transfer and a syngeneic mouse tumor implant model, we established an antitumor immunotherapy whereby tumor growth is retarded by adaptor-manipulated mDCs.
Akazawa
Takashi
T
Department of Immunology, Osaka Medical Center for Cancer, Nakamichi 1-3-2, Higashinari-ku, Osaka 537-8511, Japan.
Shingai
Masashi
M
Sasai
Miwa
M
Ebihara
Takashi
T
Inoue
Norimitsu
N
Matsumoto
Misako
M
Seya
Tsukasa
T
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D002460:Cell Line; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007167:Immunotherapy; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*
D033942:Adaptor Proteins, Vesicular Transport; C476286:Ticam1 protein, mouse