The role of The Xenopus Nonclassical MHC class I molecule XNC10 in Tumor Immunity

 描述(申请人提供)：使用先天(I)T细胞，如CD1d限制的先天T细胞用于癌症免疫治疗，需要更好地了解它们的促肿瘤和抗肿瘤特性。利用比较的非洲爪蛙蝌蚪癌症模型，我们建议研究非洲爪哇非经典MHC类Ib XNC10限制性it细胞(功能类似于CD1d限制性iNKT细胞)在肿瘤免疫中的作用。将非洲爪哇胸腺淋巴样肿瘤(15/0)移植到自然MHC Ia类阴性的蝌蚪体内，发现XNC10分子和XNC10限制的it细胞在肿瘤进展中起作用。值得注意的是，沉默XNC10基因在15/0肿瘤中的表达会导致其急性免疫排斥反应，导致其被大量的it细胞和巨噬细胞渗透的同基因蝌蚪。我们假设XNC10限制的it细胞，类似于哺乳动物的CD1d限制的it细胞；通过调节巨噬细胞来决定淋巴样肿瘤的排斥或进展。我们将研究XNC10功能丧失在肿瘤水平和机体水平(XNC10-it细胞缺陷)的影响，以及巨噬细胞耗尽和过继转移XNC10-it细胞对肿瘤免疫的影响。此外，为了可视化XNC10限制的it细胞如何通过在肿瘤微环境中招募不同类型的免疫效应细胞来促进或防止肿瘤生长，我们将在非洲爪哇半固体肿瘤胶原蛋白植入模型上应用实时活体显微镜。我们预计，我们的发现将为Ib类限制的it细胞在肿瘤免疫中的机制提供进化证据。

 DESCRIPTION (provided by applicant): The use of innate (i)T cells such as CD1d-restricted innate T cells for cancer immunotherapy requires a better understanding of their pro- and anti-tumoral properties. Using a comparative Xenopus tadpole cancer model we propose to investigate the role of Xenopus nonclassical MHC class Ib XNC10- restricted iT cells (functionally analogous to CD1d-restricted iNKT cells) in tumor immunity. Transplantation of Xenopus thymic lymphoid tumors (15/0) into naturally MHC class Ia-negative tadpoles has revealed that XNC10 molecule and XNC10-restricted iT cells contribute to tumor progression. Notably, silencing XNC10 gene expression in 15/0 tumor results in its acute immune rejection by syngeneic tadpoles with a significant infiltration of iT cells and macrophages. We hypothesize that XNC10-restricted iT cells, which are similar to mammalian CD1d-restricted iT cells; dictate lymphoid tumors rejection or progression by regulating macrophages. We will examine the effects of XNC10 loss-of-function at the tumor level and at the organism level (XNC10-iT cell-deficiency) as well as the effect of macrophage depletion and adoptive transfer of XNC10-iT cell on tumor immunity. Furthermore, to visualize how XNC10-restricted iT cells promote or prevent tumor grow by recruiting different immune effector cell types in tumor microenvironment we will apply real time intravital microscopy on a Xenopus semi-solid tumor collagen-embedded engraftment model. We anticipate that our findings will provide evolutionary evidence of the mechanism of class Ib-restricted iT cells in tumor immunity.