Fas-deficient fully allogeneic dendritic cells administered via an intratumoral injection route show efficient antitumor effects in murine models.
Fas-deficient fully allogeneic dendritic cells administered via an intratumoral injection route show efficient antitumor effects in murine models.
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发表时间：
2013
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通讯作者：
S. Okano;H. Kondoh;T. Toshima;H. Nakagawara;T. Yoshizumi;Y. Soejima;K. Shirabe;M. Harada;Y. Yoshikai;Y. Maehara
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作者：
S. Okano;H. Kondoh;T. Toshima;H. Nakagawara;T. Yoshizumi;Y. Soejima;K. Shirabe;M. Harada;Y. Yoshikai;Y. Maehara
基于树突状细胞（DC）的免疫疗法是有效的、主动的和特异性的癌症免疫疗法，因为DC是优选的专业APC（pAPC），其引发肿瘤相关抗原（TAA）特异性CD8+ T细胞应答。在基于DC的免疫治疗中，同种异体DC可能是难以获得足够数量的有质量保证的自体DC的患者的DC的替代来源。然而，完全同种异体DC在基于DC的免疫治疗中的有用性是有争议的，并且许多研究者未能证明完全同种异体DC可以在各种实验环境中诱导有效的抗肿瘤作用。在这项研究中，我们发现，通过瘤内注射途径注射Fas缺陷的完全同种异体DC产生了有效的抗肿瘤作用，同基因DC，但野生型完全同种异体DC没有。与使用野生型同基因DC相比，使用Fas缺陷的同基因DC的瘤内注射治疗没有显示出上级肿瘤生长抑制，这表明在使用完全同种异体DC的治疗中，功能性Fas的抑制对于克服与同种异体DC相关的不利因素，特别是克服对同种抗原的排斥反应可能是至关重要的。此外，使用Fas缺陷型完全同种异体DC的瘤内注射疗法诱导产生显著的肿瘤特异性CD8+ T细胞应答，这受到宿主来源的主要组织相容性抗原的限制。因此，在不允许使用自体DC的情况下，使用其功能性Fas被抑制的完全同种异体DC的肿瘤内注射疗法可能是基于临床DC的免疫疗法的替代方案。
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 CD8+ 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.