Mechanisms for cell-intrinsic granzyme and/or perforin resistance in ovarian cancer

• Applicant: Dr. Fabian Kraus
• Subject Area: Gynaecology and Obstetrics
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 531961242

Despite recent advances in the targeted therapy of ovarian cancer patients following the introduction of the anti-VEGF antibody bevacizumab or PARP inhibitors, five-year survival rates remain low and only modest changes have been observed in the last decades. Attempts to add immune modulatory agents, mainly checkpoint inhibitors, to standard therapies have failed to provide a significant benefit in prospective clinical phase III trials. The adoptive transfer of genetically engineered, tumor-specific T cells might constitute a promising alternative. Whereas many attempts to improve adoptive cell transfers have focused on how to enhance T cell activation and migration, only limited efforts have been made to investigate cancer cell susceptibility to lytic granule-mediated killing, which relies heavily on granzymes and perforins, and constitutes a major killing mechanism of cytotoxic T cells and natural killer cells. In preliminary experiments, my hosting lab has shown that ovarian cancer cells have selective sensitivity to perforin and granzyme B and, by extension, to T cell cytotoxic activity. Furthermore, it has been demonstrated that ovarian cancer cells can acquire resistance to these cytotoxic granules upon immune exposure. The aim of the outlined research project is to identify factors that mediate the emergence and maintenance of cancer cell-intrinsic granzyme/perforin resistance and to find ways to overcome it. The results of an extensive literature review suggest that certain candidate proteins confer lytic granule resistance to ovarian cancer cells. These candidate proteins include cathepsin B, histone H2B, scinderin and ephrin A1 as potential mediators of perforin resistance, and SERPINB9, SERPINB4, beclin-1 and bcl-2 as factors possibly shielding cancer cells against granzymes. In the first step, a variety of ovarian cancer cell and patient-derived organoid lines will be screened for correlations of their granzyme/perforin susceptibility and their candidate protein expression. Furthermore, drugs of different pharmacological classes, i.e. blocking antibodies, small molecule inhibitors or siRNA expected to modulate candidate protein function will be applied to sensitize tumor cells to granule-mediated toxicity and to assess their therapeutic potential alone or in combination with tumor-specific CD8+ T cells in vitro and in vivo. The relative resistance of solid tumors to cellular therapies remains a major obstacle for adoptive cell transfers in many different cancer entities to date. The relevance of our findings could extend beyond gynecologic malignancies and, indeed, span various current immune oncological treatment approaches, such as checkpoint blockade and adoptive T cell or natural killer cell transfers.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Oladapo Yeku, Ph.D.