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Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Gillian Griffiths, University of Cambridge, United Kingdom
- Second opponent: Professor Cinzia Anita Maria Progida, University of Oslo
- Third member and chair of the evaluation committee: Professor Erik Dissen, University of Oslo
Chair of the Defence
Professor II Anne Simonsen, University of Oslo
Principal Supervisor
Professor Karl-Johan Malmberg, University of Oslo
Summary
The benefits of cancer immunotherapy are well-established, and NK cells hold promise in overcoming some of the limitations of current cell products. This thesis investigates intracellular mechanisms of NK cell education and provides novel insights into how homeostatic inhibitory signaling translates into a state of superior cytotoxicity.
Through a flow cytometry-based analysis of NK cell repertoires in healthy donors we identified a link between inhibitory killer cell immunoglobulin-like receptor (KIR)-HLA signaling and the intracellular granzyme B content in NK cells. Ultrastructure analysis revealed a distinct pool of electron dense secretory lysosomes associated with education. We found that allelic variation of highly polymorphic KIR and HLA class I genes correlated with lysosomal granzyme B loading and NK cell function. Moreover, the total granzyme B content in the cell combined with expression of the activating NK cell receptor DNAM-1, served as a simple phenotype-based metric predictive of the cytolytic potential of NK cells. The proposed metric captured the variation in functional repertoires among healthy donors and may have clinical implications for donor selection in cancer immunotherapy.
Pharmacological and genetic modulation of lysosomal calcium and the lysosomal calcium channel TRPML1, altered NK cell effector functions and the lysosomal granzyme B payload, phenocopying the educated phenotype. In addition, we found that TRPML1 played an important role in inter-organelle communication, autophagy induction, and mitochondrial fitness in NK cells. Further mapping of the calcium channel landscape in NK cells unveiled that TRPV2 is highly expressed in NK cells and exhibit immunomodulatory properties.
In summary, this thesis sheds light on functional tuning of NK cells during education and uncovers a potential role for inter-organelle communication in maintaining cellular fitness. These findings may impact the design of novel NK-cell based cancer immunotherapy.
Additional information
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