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

非洲爪蟾非经典MHC I类分子XNC10在肿瘤免疫中的作用

• 批准号: 9531876
• 负责人: Maureen Ludmila Banach
• 金额: $ 2.22万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9531876
• 关键词: Acute; Address; Adoptive Transfer; Amphibia; Antitumor Response; Binding; Biological Metamorphosis; Biological Models; Cancer Model; Cells; Clinical Trials; Collagen; Confocal Microscopy; Development; Distant; Effector Cell; Engraftment; Flow Cytometry; Fluorescence; Gene Expression; Gene Silencing; Gene Transfer Techniques; Goals; Histocompatibility Antigens Class I; Human; Immune; Immunity; Immunosuppression; Immunotherapy; Infiltration; Kinetics; Label; Ligands; Malignant Neoplasms; Mediating; Microscopy; Modeling; Mus; Myeloid Cells; Nature; Organism; Outcome; Property; RNA Interference; Regulation; Resistance; Role; Signal Transduction; Solid; Solid Neoplasm; Surface; System; T-Lymphocyte; Tadpoles; Techniques; Testing; Thymus Gland; Time; Transgenic Organisms; Transplantation; Tumor Cell Line; Tumor Escape; Tumor Immunity; Xenopus; Xenopus laevis; base; cancer immunotherapy; cell type; comparative; design; gene function; immune function; interest; intravital microscopy; loss of function; lymphoid neoplasm; macrophage; mouse model; neoplastic cell; novel; prevent; public health relevance; recruit; reverse genetics; success; tool; tumor; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic

 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.

 描述（由申请人提供）：使用先天（i）T细胞（如CD 1d限制性先天T细胞）进行癌症免疫治疗需要更好地了解其促肿瘤和抗肿瘤特性。使用比较非洲爪蟾蝌蚪癌模型，我们建议调查非洲爪蟾非经典的MHC Ib类XNC 10限制的iT细胞（功能类似于CD 1d限制的iNKT细胞）在肿瘤免疫中的作用。将非洲爪蟾胸腺淋巴瘤（15/0）移植到天然MHC Ia类阴性蝌蚪中，揭示了XNC 10分子和XNC 10限制性iT细胞有助于肿瘤进展。值得注意的是，沉默15/0肿瘤中的XNC 10基因表达导致其被同基因蝌蚪的急性免疫排斥，伴随iT细胞和巨噬细胞的显著浸润。我们假设，XNC 10限制性iT细胞，这是类似于哺乳动物的CD 1d限制性iT细胞，通过调节巨噬细胞决定淋巴肿瘤的排斥或进展。我们将检查XNC 10功能丧失在肿瘤水平和生物体水平（XNC 10-iT细胞缺陷）的影响，以及巨噬细胞耗竭和XNC 10-iT细胞过继转移对肿瘤免疫的影响。此外，为了可视化XNC 10限制性iT细胞如何通过在肿瘤微环境中募集不同的免疫效应细胞类型来促进或阻止肿瘤生长，我们将在爪蟾半实体瘤胶原包埋的移植模型上应用真实的时间活体显微镜。我们预计，我们的研究结果将提供Ib类限制性iT细胞在肿瘤免疫中的机制的进化证据。