Integrated Stress Responses and Liver Cancer Immunotherapy
“Cancer cells learn how to face a hostile environment to sustain high proliferation and escape the immune pressure. We try to understand the way they do it and aim to fight it.”
DR. JOSEPMARÍA ARGEMÍ RESEARCHER. INTEGRATED STRESS RESPONSES AND LIVER CANCER IMMUNOTHERAPY RESEARCH GROUP
Our group studies the strategies of cancer cells to generate an immunosuppressive environment aiming at developing therapeutic tools to block them. The focus of our projects is the Integrated Stress Response, a translational switch the cancer cell promotes when challenged with internal or external conditions such as energy or nutrient deficiency.
We study the relevance of this phenomenon using clinically meaningful cultured cells and in vivo mouse models and advanced omic technologies and base our premises on deep in silico analysis of human data and biomarker studies. With the intention of unveiling the role of stress responses in the cancer-immune cell synapse, we use cutting edge technologies to study the immune microenvironment. Our group is highly translational and multidisciplinary.
Led by a Physician Scientist who across the street treats patients with liver cancer in the Liver Unit of the Cancer Center Clinica Universidad de Navarra, our team has a purposedly clear focus on the translation of the findings to the bedside. We work in national and international collaborative networks under competitive grants and industry programs.
GROUP LEADERS
| Dr. Josepmaria Argemi | |
| +34 948 194 700 | Ext. 81 4019 | |
| jargemi@unav.es | |
| Research profile | |
Oncology research integrated in the
Cancer Center Clinica Universidad de Navarra
Ours is an emergent group with only a few years of age. With grants from the Ministry of Health, the Spanish Association Against Cancer, and Fundacion Echebano and collaborative grants from strategic funding from Navarras government and laCaixa foundation, we have built strong evidence that confirms the solid base of our current work. We have published a bioinformatic tool leading to the understanding of the metabolic vulnerabilities of human HCC (Barace, Biomolecules, 2024) and the application of low-pass Whole Genome Sequencing to cell-free DNA (Sogbe, CMH 2024).
Both works have settled the ground for the profound bioinformatic studies that can now be carried out in the lab using proprietary and public massive HCC data. Our work includes intense collaboration with clinical and immunology teams to study the combined effect of radiation and immunotherapy on the antigen-specific immune response in patients with HCC, and on the generation of neoantigen-based cancer vaccines.
Together with a multicentric national endeavor we are uncovering the relationship between the microbiome and the integrated stress responses in liver cancer (“RETO-AECC” grant) and searching for non-invasive tools to stratify patients with advanced HCC according to the predicted response to immune checkpoint inhibition (“Immune4all-CIBER” grant).
Our team actively participates in regional collaborative grants such as BLANCA/ALBA (PI: Puri Fortes) searching for immunogenic peptides from non-coding transcripts for cancer vaccines; PITAGORAS (PI: Sandra Hervas) finding and promoting antigen-specific T cell clones to boost immune antitumor responses; MICROBIOMICS (PI: Antonio Pineda) aiming at deciphering intestinal microbiome communities in chronic diseases.
We also receive la Caixa Health funding to develop novel therapies to treat HCC based on functional RNAs aiming at improving radio-, chemo- and immunotherapy (PI: Puri Fortes).
Objectives of the Integrated Stress Responses and Liver Cancer Immunotherapy
Mechanisms of immune evasion
Study the mechanisms of stress-related immune evasion in human liver cancer. Cancer cells develop strategies to cope with proliferation-related stress and these adaptations allow them to escape the immune pressure. We try to identify these mechanisms and develop ways to block them.
Creation of mouse models
Creation of clinically relevant mouse models of hepatocellular carcinoma. The best way to translate our findings to the clinic is to improve our preclinical models to best reproduce the cancer-immunity cycle that occurs in our patients. To do this, we create and adopt the best preclinical models, including mouse models, organoids and patient-derived cells.
Liver cancer immunogenicity
Developing new tools to boost liver cancer immunogenicity. We are a translational laboratory. We are committed to bringing new ideas to the field of innovation and development. With an excellent network of national and international partners, we aim to bring our new tools and molecules to phase I-II clinical trials.
Main lines of research
Description: We leverage knowledge from the study of immunotherapy in human liver cancer to improve rodent models, enabling the investigation of which stress response pathways promote evasion of antitumor immunosurveillance.
Objectives: (1) To understand the intersection between stress, metabolism, and antigenicity in liver cancer; (2) To develop reporter tools that facilitate the discovery and reformulation of new drugs; and (3) To design novel therapeutic strategies capable of targeting regulators of the stress response.
Description: We use cutting-edge multi-omics technology to analyze blood and tissue samples from liver cancer patients participating in our studies, with the goal of early detection of those who will respond to immunotherapy and distinguishing them from those who will require additional therapy beyond immunotherapy.
Objectives: (1) To establish a pipeline from sample collection to omics analysis that enables the clinical translation of results; (2) To utilize multiparametric technology that allows integration with clinical data; and (3) To perform stratification that enhances the treatment of liver cancer patients.
Queremos que nuestros resultados repercutan en la vida real de nuestros pacientes.
Our group is particularly interested in the intersection of cancer metabolism and coping to the translational stress, and how this molecular network impacts in cancer immune evasion.
We want our results to impact the real life of our patients. So, we use every possibility to make advance our discoveries towards new patentable assets.
Our work involves the study of the function of a type of protein called “transcription factors” in human liver diseases and cancer. For example, here we studied the function of HNF4A in alcohol-related acute hepatitis leading to liver failure and described a strong epigenetic conditioning in part caused by a fetal HNF4A isoform abnormally expressed in the hepatocytes of these patients.
Recently we have described a new bioinformatic tool for adapting public metabolic gene sets to the biological context of liver cancer. Although we aimed at better characterizing the footprints of transcription factors, we end up uncovering how the metabolism of mevalonate and the pathway of n-glycan biosynthesis are key for liver cancer proliferation and that targeting specific enzymes could be a good strategy for treating patients with liver cancer.
In another project, related to the search for new biomarkers, we have been able to sequence the whole genome of circulating tumor DNA, at ultra-low depth. This is a novel technology that help us obtain biologic and prognostic data of liver cancer by looking to the blood (liquid biopsy). Our work was featured with a beautiful cover in the Clinical and Molecular Hepatology Journal.
Meet the research team
3rd LEADING CAUSE OF CANCER IN THE WORLD
Liver cancer is the third leading cause of cancer-related deaths worldwide. Highly influenced by chronic viral infections, diet and alcohol, this tumor usually arises in persons with chronic liver disease. The incidence is expected to grow in parallel with that of metabolic and alcohol-related chronic liver disease. The most prominent form of liver cancer is hepatocellular carcinoma (HCC).
HCC is commonly diagnosed in advanced stages, and only one third of these patients have objective responses to the current standard treatment, the combination between an immune check point inhibitor (ICI) with anti VEGF or a double immune checkpoint blockade. One of the causes of this low efficacy is the medium-low level of immunogenic neoantigens and the presence of an immune-excluded or immune suppressive tumor microenvironment. The finding of mechanisms which may enhance and broaden the efficacy of ICI ideally by acting synergistically is a highly unmet need.
Scientific activity of the Integrated Stress Responses and Liver Cancer Immunotherapy Research Group
Latest scientific publications
- Prognostic value of circulating tumor DNA in different cancer types detected by ultra-low-pass whole-genome sequencing. A systematic review and patient-level survival data meta-analysis Nov 16, 2024 | Magazine: Carcinogenesis
- Tracing the fate of AAV vectors in the body [SP] Aug 5, 2024 | Magazine: Nature Biotechnology
- Application of Graph Models to the Identification of Transcriptomic Oncometabolic Pathways in Human Hepatocellular Carcinoma Jun 3, 2024 | Magazine: Biomolecules
- Efficient and Safe Therapeutic Use of Paired Cas9-Nickases for Primary Hyperoxaluria Type 1 Jan 16, 2024 | Magazine: EMBO Molecular Medicine