Strategies to enhance T cell-mediated tumor cell killing in PDAC

• Applicant: Dr. Abdallah Gaballa
• Subject Area: Gastroenterology ; Immunology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 563407570

Pancreatic ductal adenocarcinoma (PDAC) remains a formidable challenge in oncology with a 5-year survival rate of 11%. Despite the success of immunotherapy in many solid tumors, PDAC has shown remarkable resistance to current approaches, including immune checkpoint blockade (ICB). However, our previous work has shown that depletion of the transcription elongation factor PAF1c significantly upregulates the expression of MHC class I genes in PDAC cells, enhancing their recognition and killing by T cells, that resulted in a significant survival benefit in PDAC-bearing mice. In addition, previous work from my host (Saur) lab has shown that the combinatorial treatment with the MEK inhibitor trametinib and the multi-kinase inhibitor nintedanib is highly effective against highly aggressive mesenchymal PDAC, and that this effect is dependent on the infiltration of cytotoxic and effector T cells. Thus, accumulating evidence highlights the importance of T cell-mediated cytotoxicity in PDAC. The PDAC tumor immune microenvironment (TiME) is highly heterogeneous, with different subtypes showing unique infiltration of different immune cell populations and different responses to the same treatment. My host lab (Saur) has systematically analyzed and characterized TiME profiles in human PDAC patients and mouse PDAC models, revealing diverse immune cell compositions that accurately recapitulate human PDAC heterogeneity. These unique resources allow us, for the first time, to study immune escape mechanisms of PDAC subtypes. In the proposed project, we aim to improve T cell-mediated cytotoxicity in PDAC through two distinct objectives. Objective 1: Perform a comprehensive genome-wide CRISPR knockout screen in PDAC cell lines representing different TiME subtypes to identify genes that enhance or inhibit T cell-mediated cytotoxicity in vitro. Followed by a targeted in vivo CRISPR screen of the top hits with subsequent validation and elucidation of the mechanism of action. Objective 2: Validate and characterize the role and mode of action of Gpaa1 and Otulin (identified hits of a targeted in vivo CRISPR screen) in driving tumor immune evasion of PDAC. By systematically investigating PDAC cell-intrinsic factors that modulate T cell-mediated killing in different PDAC subtypes, we hope to develop more effective, personalized immunotherapeutic strategies for this challenging cancer. The results of this study could significantly advance our understanding of PDAC biology and contribute to the development of innovative treatment approaches, potentially improving outcomes for PDAC patients.

• DFG Programme: WBP Position