Project Details
Projekt
Harnessing the immunogenic potential of ferroptosis to improve immunotherapy in liver cancer
Applicant
Dr. Linda Hammerich
Subject Area
Cell Biology
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 461704718
Ferroptosis is a recently identified form of programmed cell death that is dysregulated in many diseases including cancer, and emerging studies indicate that ferroptosis might be more immunogenic than other types of programmed cell death, which could prove beneficial in cancer treatment. Therefore, we aim to study the immunogenicity of ferroptosis in the context of liver cancer, where new and more efficient therapies are urgently needed. Primary liver cancer - mainly hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA) - is the fourth leading cause of cancer-related death and typically occurs in patients with chronic inflammatory liver diseases. Immunotherapies are emerging as new treatment strategies for many types of cancer, but the response rates in liver cancer are still very low. It has become increasingly clear that efficacy of immunotherapy highly depends on an inflamed tumor phenotype with high infiltration of tumor-reactive T cells. Therefore, therapies that can convert an uninflamed tumor microenvironment to a more inflamed environment have a strong potential to boost efficacy of immunotherapy. Prior work suggests that induction of immunogenic cell death, which is characterized by the release of mediators that can activate the immune system, can induce strong tumor-specific immune responses. Ferroptosis is a type of programmed cell death that occurs as a result of iron accumulation and oxidative stress and there is increasing evidence that ferroptosis might have immunogenic potential and could be targeted to improve immunotherapy. While the molecular pathways and actors involved in the regulation of ferroptosis have been thoroughly investigated, the role of immune cells in a ferroptotic context/environment and how ferroptosis can influence the immune system remains poorly understood. This proposal aims to characterize the influence of ferroptosis on the immune system, especially in the context of anticancer immunotherapy. We propose that ferroptosis of hepatic tumor cells can induce a tumor-specific immune response and that this activation of the immune system will synergize with and increase the (currently insufficient) efficacy of immunotherapy in liver cancer. We will use in vitro culture systems and mouse models of liver cancer to characterize the mechanisms by which ferroptosis elicits an immune response. The immunological changes induced by ferroptosis will be analyzed using innovative multiplex technologies (spectral flow cytometry, imaging mass cytometry). Based on the results, we will also combine ferroptosis induction with other immunotherapies, such as checkpoint blockade. Finally, we will validate the pre-clinical results using human liver and serum samples from patients with liver cancer to facilitate the translation of the results to clinical trials. The results of our studies will establish how ferroptosis may be incorporated into therapeutic strategies against HCC and CCA.
DFG Programme
Priority Programmes
