Due to their capacity to eliminate virus-infected and malignant cells without prior sensitization, Natural Killer (NK) cells are promising effector cells for tumour therapy. However, NK cell functions are often impaired in the tumour microenvironment (TME) of solid tumours. One prominent factor mediating tumour-associated immunosuppression in the TME is transforming growth factor β (TGF-β). In this project, we aimed to investigate how long-term TGF-β exposure shapes NK cell responsiveness.
To this end, we analyzed in-vitro TGF-β kinetics and conducted phenotypic and functional characterizations of TGF-β-exposed NK cell. Moreover, we established an experimental setup where NK cells were challenged with TGF-β for several days and then left to recover and employed a multi-omics approach to deconstruct and reconstruct the complex impact of TGF-β on NK cells.
We found remarkable TGF-β driven alterations on the functional, epigenetic and transcriptional level, with some genes and functions showing persistent changes upon TGF-β exposure, whereas others were only transiently regulated. Interestingly, regions with persistent epigenetic remodeling showed enrichment for a distinct set of transcription factor motifs, suggesting discrete transcriptional regulation of these regions.
In summary, we provide an in-depth analysis of the diverse functional and epigenetic effects of TGF-β on NK cells. The insights gained here will be crucial for developing therapies aimed at overriding TGF-β-mediated NK cell suppression in solid tumours.