Okano Shinji, Kondoh Haruhiko, Toshima Takeo, Nakagawara Hidekazu, Yoshizumi Tomoharu, Soejima Yuji, Shirabe Ken, Harada Mamoru, Yoshikai Yasunobu, Maehara Yoshihiko
Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Fukuoka Igaku Zasshi. 2013 Jan;104(1):15-26.
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.
基于树突状细胞（DC）的免疫疗法是一种强大、主动且特异性的癌症免疫疗法，因为DC是引发肿瘤相关抗原（TAA）特异性CD8 + T细胞反应的理想专职抗原呈递细胞（pAPC）。在基于DC的免疫疗法中，对于难以获得足够数量且质量有保证的自体DC的患者，同种异体DC可能是DC的替代来源。然而，完全同种异体DC在基于DC的免疫疗法中的有效性存在争议，许多研究人员未能证明完全同种异体DC在各种实验环境中能诱导有效的抗肿瘤作用。在本研究中，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可发挥有效的抗肿瘤作用，同基因DC也是如此，但野生型完全同种异体DC则不然。与使用野生型同基因DC相比，使用Fas缺陷的同基因DC进行瘤内注射治疗并未显示出更优的肿瘤生长抑制效果，这表明在使用完全同种异体DC的治疗中，抑制功能性Fas可能对于克服与同种异体DC相关的不利因素至关重要，尤其是克服对同种异体抗原的排斥反应。此外，使用Fas缺陷的完全同种异体DC进行瘤内注射治疗可诱导产生显著的肿瘤特异性CD8 + T细胞反应，该反应受宿主来源的主要组织相容性抗原限制。因此，在不允许使用自体DC的情况下，使用功能性Fas被抑制的完全同种异体DC进行瘤内注射治疗可能是基于DC的临床免疫疗法的一种替代方法。
