Research Profile

In order to understand the physiology and pathophysiology of T-lymphocyte biology, it is necessary to decode the biochemical processes that integrate key signals received from antigen, cytokine and integrin-receptors as well as inhibitory receptors. The underlying goal of our work is to understand the selective functions of defined signal transduction pathways in CD4+ and CD8+ T-lymphocytes and to use this information to develop strategies for manipulating the immune response, either in order to promote immunosuppression in the context of autoimmune diseases and graft rejection or for augmentation as part of an innovative cancer immunotherapy-based approach.

In the exploration of distinct members of the AGC family of protein serine/threonine kinases and their effector substrates, our recent data strongly suggest that T cell-based immunotherapies could benefit greatly from the modulation of key signalling pathways that govern T cell dysfunctions, i.e. in cancer-mediated immune evasion. Remarkably, the strategy of intracellular NR2F6 and/or Cbl-b checkpoint-targeting therefore appears to be particularly capable of improving efficacy and broadening the applicability of cancer immunotherapy regimes and it consequently has the potential to lead to prolonged patient survival in the future.

The cell genetics team has expertise in mouse genetics and in signal transduction analyses of effector/memory T cell differentiation and the ability of these cells to alter adaptive immune response outcomes. In particular, we have acquired experience in the investigation of molecular signalling processes through the use of hypothesis-driven mechanistic studies and by using unbiased CRISPR/Cas9-based genetics screens and RNA sequencing to characterise key protein-protein and protein-DNA interactions.

 

Our late-braking research topic:

Mechanistic Understanding of T-Cell Persistence in Host-Protective Tumour Immunity
The Cell Genetics team was the first to reveal the T-lymphocyte-intrinsic PKCtheta/NR2F6/Cbl-b axis as an essential signalling node governing the complex host-tumour interactions at the intersection between inflammation and cancer. Modulation of this signalling pathway renders effector T cells capable of rejecting otherwise lethal tumour burdens and their metastases in preclinical cancer model systems. Our research aims to elucidate the inter and intra-cellular mechanisms that reshape the immune contexture to allow superior tumour rejection (Fig. 1).

Fig. 1: Leverage of CD8+ T cell persistence to extend Chimeric Antigen T cell -engineered (CAR-T) therapy to solid cancer.



Fig. 1 © MUI

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