Suppression of an already established tumor growing through activated mucosal CTLs induced by oral administration of tumor antigen with cholera toxin
Suppression of an already established tumor growing through activated mucosal CTLs induced by oral administration of tumor antigen with cholera toxin
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DOI：
10.4049/jimmunol.180.6.4000
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发表时间：
2008-03-15
影响因子：
4.4
通讯作者：
Takahashi, Hidemi
中科院分区：
文献类型：
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作者：
Wakabayashi, Ayako;Nakagawa, Yohko;Takahashi, Hidemi
在各种肿瘤起源的粘膜部位启动CTL似乎对控制肿瘤至关重要。本研究探讨了口服卵清蛋白(OVA)和佐剂霍乱毒素(CT)对小鼠胃粘膜抗原特异性CTL的诱导作用及其对肿瘤消退的影响。虽然口服CT后，OVA四聚体可在新鲜分离的上皮内淋巴细胞和脾细胞中检测到表达需要体外再刺激以获得特异性细胞毒作用的淋巴细胞的OVA特异性TCR，但那些直接具有细胞毒活性而不需要体外再刺激的TCR主要在上皮内淋巴细胞中观察到。第二次口服完整CT的OVA后，粘膜部位的这种直接细胞毒作用显著增强，但不包括其亚单位A亚单位(CTA)或B亚单位(CTB)。在C57BL/6小鼠体内，无论是胃组织还是真皮，OVA+CT均能明显抑制肿瘤生长，而S.C.或者IP。注射OVA加CT未见明显抑制作用。这些具有直接细胞毒性的粘膜OVA特异性CTL表达CD8αβ，但不表达CD8α，表明它们来自胸腺教育细胞。此外，在被抑制的肿瘤组织中观察到这种OVA特异性CD8(+)CTL的渗透。这些结果表明，通过口服肿瘤抗原和适当的粘膜佐剂，激活的具有肿瘤特异性细胞毒作用的CD8αβCTL可以抑制正在进行的肿瘤细胞的生长。
Priming of CTLs at mucosal sites, where various tumors are originated, seems critical for controlling tumors. In the present study, the effect of the oral administration of OVA plus adjuvant cholera toxin (CT) on the induction of Ag-specific mucosal CTLs as well as their effect on tumor regression was investigated. Although OVA-specific TCRs expressing lymphocytes requiring in vitro restimulation to gain specific cytotoxicity could be detected by OVA peptide-bearing tetramers in both freshly isolated intraepithelial lymphocytes and spleen cells when OVA was orally administered CT, those showing direct cytotoxic activity without requiring in vitro restimulation were dominantly observed in intraepithelial lymphocytes. The magnitude of such direct cytotoxicity at mucosal sites was drastically enhanced after the second oral administration of OVA with intact whole CT but not with its subcomponent, an A subunit (CTA) or a B subunit (CTB). When OVA plus CT were orally administrated to C57BL/6 mice bearing OVA-expressing syngeneic tumor cells, E.G7-OVA, in either gastric tissue or the dermis, tumor growth was significantly suppressed after the second oral treatment; however, s.c. or i.p. injection of OVA plus CT did not show any remarkable suppression. Those mucosal OVA-specific CTLs having direct cytotoxicity expressed CD8 alpha beta but not CD8 alpha alpha, suggesting that they originated from thymus-educated cells. Moreover, the infiltration of such OVA-specific CD8(+) CTLs was observed in suppressed tumor tissues. These results indicate that the growth of ongoing tumor cells can be suppressed by activated CD8 alpha beta CTLs with tumor-specific cytotoxicity via an orally administered tumor Ag with a suitable mucosal adjuvant.