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.

Public Health Relevance

The goal of this project is to develop the Xenopus laevis tadpole as a biomedical model alternative to mouse for better understanding the role of so called innate T cells in tumor immunity. We will take advantage of transparent tadpoles bearing tumors for real-time intravital microscopy and the use of reverse genetic to assess gene function and trace immune cells by fluorescence in transgenic tadpoles. These studies will provide a framework for designing novel immune therapies that can take advantage of overcoming immune suppression by stimulating innate T cells using nonclassical MHC molecules.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31CA192664-02
Application #
9126961
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mcneil, Nicole E
Project Start
2015-08-01
Project End
2019-06-30
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Rochester
Department
Microbiology/Immun/Virology
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Banach, Maureen; Edholm, Eva-Stina; Robert, Jacques (2017) Exploring the functions of nonclassical MHC class Ib genes in Xenopus laevis by the CRISPR/Cas9 system. Dev Biol 426:261-269
Banach, Maureen; Robert, Jacques (2017) Tumor immunology viewed from alternative animal models-the Xenopus story. Curr Pathobiol Rep 5:49-56
Edholm, Eva-Stina; Banach, Maureen; Robert, Jacques (2016) Evolution of innate-like T cells and their selection by MHC class I-like molecules. Immunogenetics 68:525-36
Haynes-Gimore, Nikesha; Banach, Maureen; Brown, Edward et al. (2015) Semi-solid tumor model in Xenopus laevis/gilli cloned tadpoles for intravital study of neovascularization, immune cells and melanophore infiltration. Dev Biol 408:205-12
Haynes-Gilmore, Nikesha; Banach, Maureen; Edholm, Eva-Stina et al. (2014) A critical role of non-classical MHC in tumor immune evasion in the amphibian Xenopus model. Carcinogenesis 35:1807-13