Due to copyright issues, an electronic copy of the thesis must be ordered from the faculty. For the faculty to have time to process the order, the order must be received by the faculty at the latest 2 days before the public defence. Orders received later than 2 days before the defence will not be processed. After the public defence, please address any inquiries regarding the thesis to the candidate.
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Yenan Bryceson, Karolinska Institutet
- Second opponent: Professor Anette Susanne Bøe Wolf, University of Bergen
- Third member and chair of the evaluation committee: Professor Victor Greiff, University of Oslo
Chair of the Defence
Professor Bjørn Steen Skålhegg, University of Oslo
Principal Supervisor
Professor Kjetil Taskén, University of Oslo
Summary
Cancer cells have developed sophisticated strategies to evade immune-mediated destruction. Tumor cells suppress immune activity through multiple mechanisms, including the upregulation of inhibitory ligands, recruitment of immunosuppressive cell populations, and secretion of suppressive cytokines or tumor-derived soluble factors. Although these inhibitory mechanisms serve a role in maintaining immune tolerance in healthy tissues, cancer cells co-opt them to their advantage. Selectively targeting these pathways therefore represents a critical opportunity to improve current cancer therapies.
In this thesis, we investigated multifaceted approaches to enhance anti-tumor immunity by modulating T-cell activity and tolerance. Our work included a search for inhibitors of suppressive regulatory T cells (Tregs), the characterization of a novel PI3Kδ inhibitor, roginolisib, with respect to its effects on Treg and T-cell activity in the context of cancer treatment, and the elucidation of suppressive mechanisms mediated by programmed death-ligand 1 (PD-L1).
First, we employed a high-throughput phenotypic screen to identify compounds capable of downregulating FoxP3 expression. This approach yielded two compounds, along with structural analogs, that effectively suppressed FoxP3 expression and impaired Treg suppressive function by targeting of the MAPK and STAT3 signaling pathways.
Second, we demonstrated that roginolisib more effectively preserved T-cell proliferation and cytotoxic function, while inducing less activation of pro-inflammatory CD4+ T helper cells, compared to the widely used PI3Kδ inhibitor idelalisib. Notably, roginolisib retained comparable efficacy to idelalisib in inhibiting chronic lymphocytic leukemia (CLL) cell viability and downstream cell signaling.
Finally, we made the unexpected observation that PD-L1 exerts both stimulatory and suppressive effects on healthy donor T cells through PD-1-independent mechanisms. Using AlphaFold Multimer, we identified 14 putative novel binding partners of PD-L1. While further investigation is warranted, antibody-mediated blockade of select candidate binding partners was found to modulate PD-L1-mediated effects on T cells.
Overall, this thesis presents a broad exploration of strategies to enhance anti-tumor immunity and underscores the therapeutic potential of targeting T-cell tolerance mechanisms for the further development of cancer immunotherapies.
Additional information
Contact the research support staff.