Antigen-specific regression of established tumors induced by active immunization with irradiated IL-12- but not B7-1-transfected tumor cells
Antigen-specific regression of established tumors induced by active immunization with irradiated IL-12- but not B7-1-transfected tumor cells
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DOI：
10.1093/intimm/9.9.1259
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发表时间：
1997-09-01
影响因子：
4.4
通讯作者：
Gajewski, TF
中科院分区：
文献类型：
--
作者：
Fallarino, F;Ashikari, A;Gajewski, TF
转染中等免疫原性肿瘤以表达B7家族共刺激分子导致它们被同基因小鼠排斥，这表明在癌症患者中可能的临床应用。用经辐照的B7-1转染的P1.HTR细胞免疫幼稚小鼠足以诱导特异性细胞溶解性T淋巴细胞（CTL）并保护免受肿瘤攻击，然而，待治疗的患者将具有现有的肿瘤负荷;与预期相反，用辐照的B7-1转染的P1.HTR细胞免疫小鼠对预先建立的对照转染的肿瘤的生长没有影响。携带对照转染的P1.HTR肿瘤的小鼠成功地排斥对侧腹的活B7-1转染子，证明了荷瘤小鼠对B7共刺激的应答能力。由于IL-12是CTL成熟的另一个重要因素，因此构建了表达B7-1和/或IL-12的P1.HTR转染子。值得注意的是，即使没有B7-1的共表达，用照射的IL-12转染子免疫后也实现了预先建立的肿瘤的消退。排斥需要与用于免疫的肿瘤共享抗原，单独使用rIL-12不能再现，依赖于宿主T淋巴细胞，并与高IFN-γ产生的T细胞表型相关。此外，IL-12促进的肿瘤排斥需要与宿主提供的CTLA-4配体合作，并且与宿主抗原呈递细胞上B7-1和B7-2的上调相关。因此，在建立的肿瘤环境中的主动免疫大大受益于IL-12的提供，其可以从宿主募集足够的B7共刺激的参与，从而不需要外源性提供。
Transfection of modestly immunogenic tumors to express B7 family co-stimulator molecules results in their rejection by syngeneic mice, suggesting a possible clinical application in cancer patients, Immunization of naive mice with irradiated B7-1-transfected P1.HTR cells is sufficient to induce specific cytolytic T lymphocytes (CTL) and to protect against tumor challenge, However, patients to be treated will have an existing tumor burden; thus, preclinical models should examine therapeutic efficacy in an established tumor setting, Contrary to expectations, immunization of mice with irradiated B7-1-transfected P1.HTR cells had no impact on the growth of pre-established control-transfected tumors, Mice bearing control-transfected P1.HTR tumors successfully rejected living B7-1 transfectants on the contralateral flank, demonstrating the ability of tumor-bearing mice to respond to B7 co-stimulation. Inasmuch as IL-12 is another important factor for CTL maturation, P1.HTR transfectants expressing B7-1 and/or IL-12 were then constructed, Remarkably, regression of preestablished tumors was achieved following immunization with irradiated IL-12 transfectants, even without co-expression of B7-1, Rejection required a shared antigen with the tumor used for immunization, could not be reproduced with rIL-12 alone, depended on host T lymphocytes and correlated with a high IFN-gamma-producing T cell phenotype. In addition, IL-12-facilitated tumor rejection required co-operation with a CTLA-4 ligand provided by the host, and correlated with up-regulation of B7-1 and B7-2 on host antigen-presenting cells, Thus, active immunization in the established tumor setting is benefitted greatly by the provision of IL-12, which may recruit participation of sufficient B7 co-stimulation from the host that it need not be provided exogenously.