Deciphering the Crosstalk between Apoptosis and Immunogenic Cell Death as a Vulnerability in Pancreatic Ductal Adenocarcinoma.

• Applicant: Dr. Matthias Wirth
• Subject Area: Gastroenterology ; Hematology, Oncology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 529255113

Pancreatic ductal adenocarcinoma (PDAC) is expected to emerge as the second leading cause of cancer-related death in the Western world in the next 5-10 years. Existing therapies are ineffective in the majority of cases and cause significant secondary effects and morbidity. A hallmark of PDAC is its highly immunosuppressive and highly desmoplastic tumor microenvironment (TME), which explains why it is also referred to as an "immune desert". Several features contribute to low immunogenicity, including loss of HLA class I, cytotoxic T cells that inhibit immune checkpoints such as CTLA-4, and production of immunosuppressive cytokines. These factors contribute to the lack of efficacy of the current immunotherapies. Reprogramming the TME is a possible option to achieve improved T cell infiltration and allow tumor cell recognition. This would allow immunotherapies such as immune checkpoint blockade to emerge as an effective treatment option. We recently demonstrated that the pro-apoptotic BH3-only protein NOXA plays a distinct role in aggressive PDAC. In the aggressive basal-like subtype, we observed markedly increased expression of NOXA. Based on our own preliminary data, we hypothesize that NOXA both promotes immunosuppressive caspase-induced apoptosis and exhibits a crosstalk to the highly immunogenic necroptosis pathway. Resolving the crosstalk between apoptosis and immunogenic cell death (ICD) may allow this tumor, known as an "immune desert," to be susceptible to immunotherapeutic intervention. Our goal is to identify novel biomarkers and combination partners for ICD-centric mechanism-based therapeutic options using unbiased genome-wide and focused genetic screens as well as candidate-based approaches. Candidate therapeutic combinations will be evaluated in primary patient-derived organoids (PDOs) and in preclinical in vivo models. Our ultimate goal is to develop effective ICD-based combination immunotherapies that overcome the current limitations of (immuno)therapy in PDAC and can be tested in clinical proof-of-concept studies.

• DFG Programme: Research Grants