Periodic Reporting for period 4 - HepatoMetaboPath (Cellular and molecular mechanisms of metabolic immune activation triggering non-alcoholic steatohepatitis (NASH) and HCC)
Période du rapport: 2020-07-01 au 2021-06-30
Chronic hepatitis in the liver is the main driver of liver cancer, the second most common cause for cancer related death in humans. Several different etiologies have been demonstrated to cause chronic liver disease with prominent inflammation including chronic viral infections with Hepatitis B or C (HBV, HCV) but also chronic alcohol consumption or chronic high caloric diet in combination with a sedentary life style.
Due to the consumption of high caloric food combined with increased sedentary lifestyle, overweight and obesity incidence has grown rapidly in Western countries (e.g. USA, Europe) but notably also in developing countries (e.g. India, China), affecting both adults and children. Although chronic viral infections are still the leading cause for hepatocellular carcinoma (HCC), alcoholic steatohepatitis (ASH), non-alcoholic fatty liver (NAFL) and subsequent non-alcoholic steatohepatitis (NASH) have become important etiologies for HCC. We and others have generated and characterized several pre-clinical mouse models that enable studying the mechanisms of inflammation induced liver cancer (e.g. NASH development and NASH to HCC transition in the context of a metabolic syndrome). Remarkably, these models recapitulated several human pathophysiological hallmarks of inflammation induced HCC. It has become apparent that adaptive immune cells but also innate immune cells play an important role in driving HCC - but at the same time actively participate in tumor surveillance.
Of particular interest and as an overall objective in this context is to understand the key role of immune cells (e.g. adaptive immune cells; platelets) in regulating intrahepatic inflammation and metabolic reprogramming.
In the context of this ERC consolidator grant we aim to understand and identify the different kinds of innate and adaptive immune cells, their metabolism and their effect on the epigenetic and genetic rearrangement of liver cancer initiation and progression. We will elucidate the processes that can drive primary liver cancer like NASH induced HCC or intrahepatic cholangiocarcinoma (iCC) and have already identified novel targets to treat inflammation induced liver cancer (e.g. in the context of NASH).
We aim to establish novel models and technologies to bring liver cancer research and prelcinical models to a next level.
Moreover, we aim to change the patient stratification to identify the patients who profit the most from immunotherapy.
Due to the consumption of high caloric food combined with increased sedentary lifestyle, overweight and obesity incidence has grown rapidly in Western countries (e.g. USA, Europe) but notably also in developing countries (e.g. India, China), affecting both adults and children. Although chronic viral infections are still the leading cause for hepatocellular carcinoma (HCC), alcoholic steatohepatitis (ASH), non-alcoholic fatty liver (NAFL) and subsequent non-alcoholic steatohepatitis (NASH) have become important etiologies for HCC. We and others have generated and characterized several pre-clinical mouse models that enable studying the mechanisms of inflammation induced liver cancer (e.g. NASH development and NASH to HCC transition in the context of a metabolic syndrome). Remarkably, these models recapitulated several human pathophysiological hallmarks of inflammation induced HCC. It has become apparent that adaptive immune cells but also innate immune cells play an important role in driving HCC - but at the same time actively participate in tumor surveillance.
Of particular interest and as an overall objective in this context is to understand the key role of immune cells (e.g. adaptive immune cells; platelets) in regulating intrahepatic inflammation and metabolic reprogramming.
In the context of this ERC consolidator grant we aim to understand and identify the different kinds of innate and adaptive immune cells, their metabolism and their effect on the epigenetic and genetic rearrangement of liver cancer initiation and progression. We will elucidate the processes that can drive primary liver cancer like NASH induced HCC or intrahepatic cholangiocarcinoma (iCC) and have already identified novel targets to treat inflammation induced liver cancer (e.g. in the context of NASH).
We aim to establish novel models and technologies to bring liver cancer research and prelcinical models to a next level.
Moreover, we aim to change the patient stratification to identify the patients who profit the most from immunotherapy.
From the beginning of the project we have focused on the characterization of immune cells involved in the development of fatty liver disease and liver cancer. This resulted in the definition of so far unrecognized cells involved in liver cancer as well as molecules driving liver inflammation, metabolic reprogramming and pathology. As the most important result we have identified a novel target in the treatment of fatty liver disease and fatty liver disease to liver cancer – GpIba – and could show in a pilot clinical trial that platelet deactivation is an important driver of liver pathology (Malehmir et al., Nature Medicine 2019).
In the final funding period of this ERC-Consolidator grant we have been able to finalize all projected and prospected aims and milestones - and already have published most of them or currently prepare as a publication (see below). The last part of this funding period enabled us to publish our findings over the last years in high ranking journals, including: Nature, Nature Medicine, Nature Methods, Gastroenterology and also in the highest review journals of our field: Nature Reviews Cancer, Nature Reviews clinical oncology, Cancer Cell. Importantly, we also have achieved an active outreach of our research project in the public Media (e.g. interview in RTL-Aktuell) with several million people watching, as well as numerous newspapers with strong outreach in Germany (e.g. “Die Woche”; “Welt am Sonntag”). In the frame of aim 1, “Identify the priming cell types in metabolic CD8+ T-, NKT-cell activation and the molecular mechanisms of immune cell-hepatocyte crosstalk” (milestone 1) - we could describe novel immune-cell mechanisms that drive NASH and NASH-HCC transition as well as for the first time were able to stratify human liver cancer patients for their efficient response to anti-cancer immunotherapy (Pfister et al., Nature, 2021). This paper was cited 70 times in the first 7 months post publication and was clicked > 60.000. In milestone 2 of aim 1 we could identify and better characterize the immune cells that contribute to the metabolic reprogramming. For this we also have generated a novel technology that involves spatial metabolomics (SPACEM) (Rappez et al., Nature Methods, 2021). In aim 2, “Determine the role of antigen recognition and danger- or pathogen- associated molecular patterns in NASH/HCC”. milestones 1/2/3 show that NASH is an auto-aggressive disease (Dudek et al., Nature, 2021; Li et al., Nature Reviews Cancer 2021). We could further identify the mechanisms of auto-aggression of T cells in NASH, which appeared to be antigen independent. WE could also show in this publication that acetate and activation of purinergic receptors is driving this disease. Further, we could show that dendritic cells help activating T cells (Deczkowska et al., Nature Medicine, 2021). In the frame of aim 3 “Identify the environmental and genetic determinants of NASH to HCC transition” milestones 1/2 we have identified novel markers that could predict NASH and NAS-HCC transition. This project is currently in preparation for a publication.
In the final funding period of this ERC-Consolidator grant we have been able to finalize all projected and prospected aims and milestones - and already have published most of them or currently prepare as a publication (see below). The last part of this funding period enabled us to publish our findings over the last years in high ranking journals, including: Nature, Nature Medicine, Nature Methods, Gastroenterology and also in the highest review journals of our field: Nature Reviews Cancer, Nature Reviews clinical oncology, Cancer Cell. Importantly, we also have achieved an active outreach of our research project in the public Media (e.g. interview in RTL-Aktuell) with several million people watching, as well as numerous newspapers with strong outreach in Germany (e.g. “Die Woche”; “Welt am Sonntag”). In the frame of aim 1, “Identify the priming cell types in metabolic CD8+ T-, NKT-cell activation and the molecular mechanisms of immune cell-hepatocyte crosstalk” (milestone 1) - we could describe novel immune-cell mechanisms that drive NASH and NASH-HCC transition as well as for the first time were able to stratify human liver cancer patients for their efficient response to anti-cancer immunotherapy (Pfister et al., Nature, 2021). This paper was cited 70 times in the first 7 months post publication and was clicked > 60.000. In milestone 2 of aim 1 we could identify and better characterize the immune cells that contribute to the metabolic reprogramming. For this we also have generated a novel technology that involves spatial metabolomics (SPACEM) (Rappez et al., Nature Methods, 2021). In aim 2, “Determine the role of antigen recognition and danger- or pathogen- associated molecular patterns in NASH/HCC”. milestones 1/2/3 show that NASH is an auto-aggressive disease (Dudek et al., Nature, 2021; Li et al., Nature Reviews Cancer 2021). We could further identify the mechanisms of auto-aggression of T cells in NASH, which appeared to be antigen independent. WE could also show in this publication that acetate and activation of purinergic receptors is driving this disease. Further, we could show that dendritic cells help activating T cells (Deczkowska et al., Nature Medicine, 2021). In the frame of aim 3 “Identify the environmental and genetic determinants of NASH to HCC transition” milestones 1/2 we have identified novel markers that could predict NASH and NAS-HCC transition. This project is currently in preparation for a publication.
Our results open up novel therapeutic tools and targets to treat NASH and NASH to HCC transition. Moreover, we have identified a novel technology to investigate the metabolic reprogramming of hepatocytes and immune cells on single cell level in situ.
Finally, we have revealed a novel stratification method to identify liver cancer patients who profit best from immunotherapy.
Finally, we have revealed a novel stratification method to identify liver cancer patients who profit best from immunotherapy.