Babl, Nathalie and Hofbauer, Joshua and Matos, Carina and Voll, Florian and Menevse, Ayse Nur and Rechenmacher, Michael and Mair, Ruth and Beckhove, Philipp and Herr, Wolfgang and Siska, Peter J. and Renner, Kathrin and Kreutz, Marina and Schnell, Annette (2023) Low-density lipoprotein balances T cell metabolism and enhances response to anti-PD-1 blockade in a HCT116 spheroid model. FRONTIERS IN ONCOLOGY, 13: 1107484. ISSN 2234-943X,
Full text not available from this repository. (Request a copy)Abstract
IntroductionThe discovery of immune checkpoints and the development of their specific inhibitors was acclaimed as a major breakthrough in cancer therapy. However, only a limited patient cohort shows sufficient response to therapy. Hence, there is a need for identifying new checkpoints and predictive biomarkers with the objective of overcoming immune escape and resistance to treatment. Having been associated with both, treatment response and failure, LDL seems to be a double-edged sword in anti-PD1 immunotherapy. Being embedded into complex metabolic conditions, the impact of LDL on distinct immune cells has not been sufficiently addressed. Revealing the effects of LDL on T cell performance in tumor immunity may enable individual treatment adjustments in order to enhance the response to routinely administered immunotherapies in different patient populations. The object of this work was to investigate the effect of LDL on T cell activation and tumor immunity in-vitro. MethodsExperiments were performed with different LDL dosages (LDLlow = 50 mu g/ml and LDLhigh = 200 mu g/ml) referring to medium control. T cell phenotype, cytokines and metabolism were analyzed. The functional relevance of our findings was studied in a HCT116 spheroid model in the context of anti-PD-1 blockade. ResultsThe key points of our findings showed that LDLhigh skewed the CD4(+) T cell subset into a central memory-like phenotype, enhanced the expression of the co-stimulatory marker CD154 (CD40L) and significantly reduced secretion of IL-10. The exhaustion markers PD-1 and LAG-3 were downregulated on both T cell subsets and phenotypical changes were associated with a balanced T cell metabolism, in particular with a significant decrease of reactive oxygen species (ROS). T cell transfer into a HCT116 spheroid model resulted in a significant reduction of the spheroid viability in presence of an anti-PD-1 antibody combined with LDLhigh. DiscussionFurther research needs to be conducted to fully understand the impact of LDL on T cells in tumor immunity and moreover, to also unravel LDL effects on other lymphocytes and myeloid cells for improving anti-PD-1 immunotherapy. The reason for improved response might be a resilient, less exhausted phenotype with balanced ROS levels.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CHOLESTEROL-METABOLISM; CANCER; PATHWAY; DIFFERENTIATION; PROLIFERATION; AUTOIMMUNITY; EFFECTOR; IL-15; CD154; cholesterol; LDL (low-density lipoprotein); immunotherapy; PD-1; reactive oxygen species; CD154 (CD40L); central memory (T) CM; spheroid model |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) Medicine > Zentren des Universitätsklinikums Regensburg > Regensburger Centrum für Interventionelle Immunologie (RCI) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 08 Mar 2024 13:00 |
| Last Modified: | 08 Mar 2024 13:00 |
| URI: | https://pred.uni-regensburg.de/id/eprint/59152 |
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