Low-density lipoprotein balances T cell metabolism and enhances response to anti-PD-1 blockade in a HCT116 spheroid model
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...
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| Language: | English |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1107484/full |
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| author | Nathalie Babl Joshua Hofbauer Carina Matos Florian Voll Florian Voll Ayse Nur Menevse Michael Rechenmacher Ruth Mair Philipp Beckhove Philipp Beckhove Wolfgang Herr Peter J. Siska Kathrin Renner Marina Kreutz Marina Kreutz Annette Schnell |
| author_facet | Nathalie Babl Joshua Hofbauer Carina Matos Florian Voll Florian Voll Ayse Nur Menevse Michael Rechenmacher Ruth Mair Philipp Beckhove Philipp Beckhove Wolfgang Herr Peter J. Siska Kathrin Renner Marina Kreutz Marina Kreutz Annette Schnell |
| author_sort | Nathalie Babl |
| collection | DOAJ |
| description | 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 μg/ml and LDLhigh = 200 μg/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. |
| first_indexed | 2024-04-10T20:00:25Z |
| format | Article |
| id | doaj.art-665d9c3a8e194fc4aff448d9891a418f |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-10T20:00:25Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-665d9c3a8e194fc4aff448d9891a418f2023-01-27T07:21:20ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-01-011310.3389/fonc.2023.11074841107484Low-density lipoprotein balances T cell metabolism and enhances response to anti-PD-1 blockade in a HCT116 spheroid modelNathalie Babl0Joshua Hofbauer1Carina Matos2Florian Voll3Florian Voll4Ayse Nur Menevse5Michael Rechenmacher6Ruth Mair7Philipp Beckhove8Philipp Beckhove9Wolfgang Herr10Peter J. Siska11Kathrin Renner12Marina Kreutz13Marina Kreutz14Annette Schnell15Department of Internal Medicine III, University Hospital Regensburg, Regensburg, GermanyDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg, GermanyDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg, GermanyDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg, GermanyDivision of Interventional Immunology, Leibniz Institute for Immunotherapy (LIT), Regensburg, GermanyDivision of Interventional Immunology, Leibniz Institute for Immunotherapy (LIT), Regensburg, GermanyDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg, GermanyDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg, GermanyDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg, GermanyDivision of Interventional Immunology, Leibniz Institute for Immunotherapy (LIT), Regensburg, GermanyDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg, GermanyDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg, GermanyDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg, GermanyDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg, GermanyDivision of Interventional Immunology, Leibniz Institute for Immunotherapy (LIT), Regensburg, GermanyDepartment of Internal Medicine III, University Hospital Regensburg, Regensburg, GermanyIntroductionThe 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 μg/ml and LDLhigh = 200 μg/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.https://www.frontiersin.org/articles/10.3389/fonc.2023.1107484/fullcholesterolLDL (low-density lipoprotein)immunotherapyPD-1reactive oxygen speciesCD154 (CD40L) |
| spellingShingle | Nathalie Babl Joshua Hofbauer Carina Matos Florian Voll Florian Voll Ayse Nur Menevse Michael Rechenmacher Ruth Mair Philipp Beckhove Philipp Beckhove Wolfgang Herr Peter J. Siska Kathrin Renner Marina Kreutz Marina Kreutz Annette Schnell Low-density lipoprotein balances T cell metabolism and enhances response to anti-PD-1 blockade in a HCT116 spheroid model Frontiers in Oncology cholesterol LDL (low-density lipoprotein) immunotherapy PD-1 reactive oxygen species CD154 (CD40L) |
| title | Low-density lipoprotein balances T cell metabolism and enhances response to anti-PD-1 blockade in a HCT116 spheroid model |
| title_full | Low-density lipoprotein balances T cell metabolism and enhances response to anti-PD-1 blockade in a HCT116 spheroid model |
| title_fullStr | Low-density lipoprotein balances T cell metabolism and enhances response to anti-PD-1 blockade in a HCT116 spheroid model |
| title_full_unstemmed | Low-density lipoprotein balances T cell metabolism and enhances response to anti-PD-1 blockade in a HCT116 spheroid model |
| title_short | Low-density lipoprotein balances T cell metabolism and enhances response to anti-PD-1 blockade in a HCT116 spheroid model |
| title_sort | low density lipoprotein balances t cell metabolism and enhances response to anti pd 1 blockade in a hct116 spheroid model |
| topic | cholesterol LDL (low-density lipoprotein) immunotherapy PD-1 reactive oxygen species CD154 (CD40L) |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1107484/full |
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