Project Details
Projekt
In vivo RNAi screen to identify new inhibitory targets in tumour-specific T lymphocytes during liver cancer development
Applicant
Tetyana Yevsa, Ph.D.
Subject Area
Gastroenterology
Hematology, Oncology
Immunology
Hematology, Oncology
Immunology
Term
from 2015 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 270823663
We have recently found that induction of Th1-polarized adaptive immunity was crucial for suppression of NrasG12V-expressing liver tumours (Kang & Yevsa et al, Nature, 2011). Our data and data obtained from patients with liver- and other malignancies imply a central role of T cells in modulating tumour progression. However, liver tumor microenvironment continuously inhibits T cell immune responses. We hypothesize, that the majority of inhibitory factors (genes) in T cells remains unknown and to identify the main T cell inhibitory genes, we propose to perform an in vivo RNAi screen using a thematically focused shRNA library targeting a list of genes up-regulated in memory T cells during liver cancer development. We will use a combination of mir30-based RNAi- and transposon mediated oncogene delivery platforms, recently established in our studies (Kang & Yevsa, et al, Nature, 2011; Wüstefeld et al, Cell, 2013). Importantly, in the liver cancer model that we are going to use, liver tumours develop similarly to human tumours and are not based on cell transplantation. To our knowledge until now nobody has performed a similar RNAi screen in immune system in mice bearing liver malignancies. The proposed project has a great promise for later preclinical and clinical strategies for T cell-immunotherapy in cancer patients. Blocking of inhibitory molecules in T cells either alone or in combination with additional (immuno-) therapy will significantly inhibit tumour growth and increase the overall survival of patients with hepatic malignancies.
DFG Programme
Research Grants
