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| Abstract |
Dendritic cell (DC)-based immunotherapy is a potent, active and specific cancer immunotherapy, as DCs are preferable professional APCs (pAPCs) that prime the tumor-associated antigen (TAA)-specific CD...8^+ T-cell response. In DC-based immunotherapy, allogeneic DCs may be an alternative source of DCs for patients in whom it is difficult to obtain a sufficient number of quality-guaranteed, autologous DCs. However, the usefulness of fully allogeneic DCs in DC-based immunotherapy is controversial, and many investigators have failed to demonstrate that fully allogeneic DCs can induce an efficient antitumor effect in various experimental settings. In this study, we found that the injection of Fas-deficient fully allogeneic DCs via an intratumoral injection route exerted efficient antitumor effects, as did syngeneic DCs, but wild-type fully allogeneic DCs did not. Intratumoral injection therapy using Fas-deficient syngeneic DCs does not show superior tumor growth suppression compared to that using wild-type syngeneic DCs, suggesting that the inhibition of functional Fas may be critical for overcoming the unfavorable factor related to allogeneic DCs, especially overcoming the rejection response to alloantigens, in therapy using fully allogeneic DCs. In addition, the intratumoral injection therapy using Fas-deficient fully allogeneic DCs induced the generation of a significant tumor-specific CD8^+ T-cell response, which is restricted by a host-derived major histocompatibility antigen. Therefore, intratumoral injection therapy using fully allogeneic DCs of which functional Fas is inhibited may be an alternative in clinical DC-based immunotherapy, under circumstances that do not allow the use of autologous DCs.
樹状細胞はプロフェッショナル抗原提示細胞で強力な腫瘍関連抗原特異的CD8T細胞応答を惹起するため,それを利用した樹状細胞免疫療法は強力で特異的ながん免疫療法となることが期待できる.樹状細胞免疫療法において,アロの樹状細胞は,質的量的に樹状細胞が採取困難な患者における代価細胞として期待できるが,その有効性は議論の余地があり,実際,種々のプロトコールで良好な結果が得られていない.本研究において,我々は,Fasが正常なアロの樹状細胞の腫瘍内投与は全く抗腫瘍効果を発揮しないが,Fas欠損アロ樹状細胞を腫瘍内投与すると,同系マウスの樹状細胞に匹敵する抗腫瘍効果を発揮することを初めて報告する.この時,Fasが欠損している同系のマウスから得られた樹状細胞は同系の樹状細胞より強い効果を発揮することはなかったことから,Fasの欠損はアロ樹状細胞にのみにおこる不利な応答を克服するのに必要な分子であることが示唆された.更に,このFas欠損アロ樹状細胞を用いた腫瘍内樹状細胞療法は,宿主の主要組織適合抗原に拘束される腫瘍関連抗原特異的CD8T細胞応答を惹起した.よって,Fas分子の機能抑制を施したアロ樹状細胞は,自己樹状細胞が採取困難な患者の代価樹状細胞として有用である可能性が示唆された.show more
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