Accessing the specific capacity of TIL-derived CD8 T-cells to suppress tumor recurrence in resectable HBV-HCC patients

Kah, J.; Staffeldt, L.; Mattert, G.; Volz, T.; Schulze, K.; Heumann, A.; Voss, M.; Hoell, M. C.; Goebel, M.; Peine, S.; Dandri, M.; Lueth, S.

doi:10.1101/2024.12.05.626571

bioRxiv · 10.1101/2024.12.05.626571

Accessing the specific capacity of TIL-derived CD8 T-cells to suppress tumor recurrence in resectable HBV-HCC patients

Kah, J.·Staffeldt, L.·Mattert, G.·Volz, T.·Schulze, K.·Heumann, A.·Voss, M.·Hoell, M. C.·Goebel, M.·Peine, S.·Dandri, M.·Lueth, S.

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Abstract

BackgroundHepatocellular carcinoma represents a significant global health challenge, affecting over a million patients annually, arising mainly from chronic liver diseases, with a majority being related to viral infections. However, despite the groundbreaking clinical results of immune checkpoint blockades and adoptive cell therapies, we still face non-responders accompanied by high rebound rates after resection. Considering that the main concern is to overcome a highly specialized immunosuppressive tumor microenvironment of the individual patient, the characterization of the particular tumor microenvironment and the source of the immune cells used in ACT is of immense importance. Approved ACT therapies mainly use modified peripheral blood cells from individuals. At the same time, tumor-infiltrating lymphocytes are underrepresented even if they have garnered interest due to their potential to target tumor-specific antigens more effectively. MethodsIn this study, we employed allogenic and autologous immune cell sources for expansion and stimulation, resulting in adoptive T-cell transfer experiments determining the effector cell differentiation and the related anti-tumor effects by the possible implementation of re-stimulation. ResultsWe determined a high success rate in expanding and stimulating tumor-infiltrating lymphocytes with consistent CD8 T-cell fractions from HCC patients. To showcase the effectiveness of stimulated T-cells from different sources, we generated cell lines derived from the margin and center of an HBV-induced HCC with a highly immune-suppressive TME. We found effective immune responses supported by cell death induction, ferroptosis, proptosis and apoptosis triggered by all sources of T-cells depending on the area of derived tumor cells. ConclusionEffector T-cell fractions derived from tumor-infiltrating lymphocytes present a viable source for cell-based immune therapy combined with immune checkpoint inhibitors in HCC patients, especially after resection, to suppress rebound strategies of the parental tumor on an individual level.

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Kah, J., Staffeldt, L., Mattert, G., Volz, T., Schulze, K., Heumann, A., Voss, M., Hoell, M. C., Goebel, M., Peine, S., Dandri, M., Lueth, S.. 2024-12-09. Accessing the specific capacity of TIL-derived CD8 T-cells to suppress tumor recurrence in resectable HBV-HCC patients. https://doi.org/10.1101/2024.12.05.626571

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