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Deciphering TCR signaling in metabolically activated T-cells in NASH and liver cancer development

Pfister, Dominik

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Abstract

Due to the consumption of high caloric food combined with an increased sedentary lifestyle, the incidence of overweight and obesity is growing rapidly in western cultures, like the USA, Europe and notably also in developing countries (e.g. India, China) - as a consequence of adaptation to the western lifestyle. Thus, obesity-related pathologies like metabolic syndrome have become a major issue in modern medicine, and thus far therapeutic options are limited. The liver - the major metabolic organ of the body - is particularly affected by constant high caloric food intake. Consequently, the liver undergoes dramatic changes, including the development of fatty liver disease, termed non-alcoholic fatty liver disease (NAFLD). In 25% of all NAFLD cases, progression to a more severe pathology termed non-alcoholic steatohepatitis (NASH) can be observed. Immune cell activation in NASH leads to liver fibrosis and subsequently to hepatocellular carcinoma (HCC). Today, more than 90 million people in the USA and 30 million people in Europe are affected by NAFLD. Although chronic viral infections with Hepatitis B or C are the leading etiology causing HCC, it has become clear that NASH is an increasingly important factor for HCC development, a notion supported by the fact that HCC is currently the fastest rising cancer in the USA, with a similar trend in Europe. At the same time, knowledge about the key mechanisms causing NASH and NASH-triggered HCC are scarce and therefore efficient therapies to treat this diseases are lacking. The group of Professor Heikenwälder generated a mouse model of NASH and NASH-driven HCC in the context of a chronic metabolic syndrome6. Mice fed a long-term choline-deficient high fat diet (CD-HFD) develop obesity, steatosis, fibrosis, NASH and NASH-triggered HCC, recapitulating most of the key features found in human patients. In this model, activated CD8+ and NKT-cells drive NASH and HCC through cytokine-mediated crosstalk with hepatocytes. Remarkably, a similar T-cell activation, cytokine and immune cell pattern was found in NASH patients - establishing the clinical relevance of the CD-HFD mouse model.

Aim 1: Deciphering TCR signaling in metabolically activated T-cells in NASH and liver cancer development In this scientific context, I investigated the role of T-cells in greater detail and T-cell receptor (TCR) dependent signaling in NASH development and NASH-induced HCC. By utilizing different dietary (high fat diet (HFD), CD-HFD and western-style diet with trans-fat (WD-HTF), genetic mouse models (C57Bl6, TCRβδ-/-, OT-1, Prf1-/-, Jα18-/-, CD1d-/-) and interventional antibody (α-CD8, α-PD-1, α-NK1.1) -based strategies in dietary mouse models, I shed new light on the key mechanisms of NASH pathology and its progression towards HCC. The data of this PhD thesis indicates that from early time points onwards, activation of subsets of CD8+ T-cells correlate with NASH pathology of different severity. Further, with progression of NASH towards advanced stages, CD8+ T-cells of animals fed NASH-inducing diets (CD-HFD or WD-HTF) expressed increasing amounts of early activation marker CD69 and activation/exhaustion marker PD-1. Also, PD-1+ CD8+ T-cells expressed different TCR variable β chains (TCR vβ), indicating that distinct exhausted repertoires develop over the course of NASH. Next, I showed that NASH pathology is dependent on a functional TCRαβ repertoire with intact TCRαβ effector function, but less on natural killer T-cell (NKT) cell-dependent mechanisms. Consistent with TCRαβ dependency in NASH development, I demonstrated a differential role of CD8+ T-cells depending on the progression state of NASH pathology, with a protective function of CD8+ T-cells in early states of NASH. However, in advanced NASH CD8+ T-cells drive hepatic immune-related adverse effects (irAEs), resulting in liver damage and tumor formation potentially involving a TNF-a-mediated mechanism.

Aim 2: Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer After deciphering the role of T-cells in NASH and NASH-induced hepatocarcinogenesis, I investigated alternative ways to target hepatic inflammation in NASH without targeting potentially inflammation-driving immune cell populations directly. Thus, I investigated the key mechanisms of cell-immune cell interactions driving early NASH pathogenesis and identified platelets and platelet activation as major contributors to NASH pathology and subsequent HCC development. Further, I deciphered that platelets could be targeted by antiplatelet therapy (therapeutic Ticagrelor), thereby ameliorating NASH pathology and potentially subsequent hepatocarcinogenesis. I could show that platelet interaction with Kupffer cells and CD44-hyaluronan are key mechanisms of NASH progression and that GPIbα is an interventional target for NASH therapy. I published these results as a co-first author in Nature Medicine in April 2019 (https://doi.org/10.1038/s41591-019-0379-5).

Item Type: Dissertation
Supervisor: Bartenschlager, Prof. Dr. Ralf
Date of thesis defense: 4 June 2019
Date Deposited: 12 Jun 2019 06:19
Date: 2020
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences
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