Metabolic stress in cancer cells induces immune escape through a PI3K-dependent blockade of IFNγ receptor signaling
Abstract Background T-cell mediated immunotherapy brought clinical success for many cancer patients. Nonetheless, downregulation of MHC class I antigen presentation, frequently occurring in solid cancers, limits the efficacy of these therapies. Unraveling the mechanisms underlying this type of immun...
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doaj-85c217c823ff441f83eae360b029fc7a2020-11-25T01:43:58ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262019-06-017111210.1186/s40425-019-0627-8Metabolic stress in cancer cells induces immune escape through a PI3K-dependent blockade of IFNγ receptor signalingKoen A. Marijt0Marjolein Sluijter1Laura Blijleven2Sofie H. Tolmeijer3Ferenc A. Scheeren4Sjoerd H. van der Burg5Thorbald van Hall6Department of Medical Oncology, Oncode Institute, C7-P, Leiden University Medical CenterDepartment of Medical Oncology, Oncode Institute, C7-P, Leiden University Medical CenterDepartment of Medical Oncology, Oncode Institute, C7-P, Leiden University Medical CenterDepartment of Medical Oncology, Oncode Institute, C7-P, Leiden University Medical CenterDepartment of Medical Oncology, Oncode Institute, C7-P, Leiden University Medical CenterDepartment of Medical Oncology, Oncode Institute, C7-P, Leiden University Medical CenterDepartment of Medical Oncology, Oncode Institute, C7-P, Leiden University Medical CenterAbstract Background T-cell mediated immunotherapy brought clinical success for many cancer patients. Nonetheless, downregulation of MHC class I antigen presentation, frequently occurring in solid cancers, limits the efficacy of these therapies. Unraveling the mechanisms underlying this type of immune escape is therefore of great importance. We here investigated the immunological effects of metabolic stress in cancer cells as a result of nutrient deprivation. Methods TC1 and B16F10 tumor cell lines were cultured under oxygen- and glucose-deprivation conditions that mimicked the tumor microenvironment of solid tumors. Presentation of peptide antigens by MHC class I molecules was measured by flow cytometry and via activation of tumor-specific CD8 T cell clones. The proficiency of the IFNy-STAT1 pathway was investigated by Western blots on phosphorylated proteins, transfection of constitutive active STAT1 constructs and qPCR of downstream targets. Kinase inhibitors for PI3K were used to examine its role in IFNy receptor signal transduction. Results Combination of oxygen- and glucose-deprivation resulted in decreased presentation of MHC class I antigens on cancer cells, even in the presence of the stimulatory cytokine IFNy. This unresponsiveness to IFNy was the result of failure to phosphorylate the signal transducer STAT1. Forced expression of constitutive active STAT1 fully rescued the MHC class I presentation. Furthermore, oxygen- and glucose-deprivation increased PI3K activity in tumor cells. Pharmacological inhibition of this pathway not only restored signal transduction through IFNy-STAT1 but also improved MHC class I presentation. Importantly, PI3K inhibitors also rendered tumor cells sensitive for recognition by CD8 T cells in culture conditions of metabolic stress. Conclusions These data revealed a strong impact of metabolic stress on the presentation of tumor antigens by MHC class I and suggest that this type of tumor escape takes place at hypoxic areas even during times of active T cell immunity and IFNy release.http://link.springer.com/article/10.1186/s40425-019-0627-8Cancer metabolismTumor microenvironmentImmune-escape |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Koen A. Marijt Marjolein Sluijter Laura Blijleven Sofie H. Tolmeijer Ferenc A. Scheeren Sjoerd H. van der Burg Thorbald van Hall |
spellingShingle |
Koen A. Marijt Marjolein Sluijter Laura Blijleven Sofie H. Tolmeijer Ferenc A. Scheeren Sjoerd H. van der Burg Thorbald van Hall Metabolic stress in cancer cells induces immune escape through a PI3K-dependent blockade of IFNγ receptor signaling Journal for ImmunoTherapy of Cancer Cancer metabolism Tumor microenvironment Immune-escape |
author_facet |
Koen A. Marijt Marjolein Sluijter Laura Blijleven Sofie H. Tolmeijer Ferenc A. Scheeren Sjoerd H. van der Burg Thorbald van Hall |
author_sort |
Koen A. Marijt |
title |
Metabolic stress in cancer cells induces immune escape through a PI3K-dependent blockade of IFNγ receptor signaling |
title_short |
Metabolic stress in cancer cells induces immune escape through a PI3K-dependent blockade of IFNγ receptor signaling |
title_full |
Metabolic stress in cancer cells induces immune escape through a PI3K-dependent blockade of IFNγ receptor signaling |
title_fullStr |
Metabolic stress in cancer cells induces immune escape through a PI3K-dependent blockade of IFNγ receptor signaling |
title_full_unstemmed |
Metabolic stress in cancer cells induces immune escape through a PI3K-dependent blockade of IFNγ receptor signaling |
title_sort |
metabolic stress in cancer cells induces immune escape through a pi3k-dependent blockade of ifnγ receptor signaling |
publisher |
BMJ Publishing Group |
series |
Journal for ImmunoTherapy of Cancer |
issn |
2051-1426 |
publishDate |
2019-06-01 |
description |
Abstract Background T-cell mediated immunotherapy brought clinical success for many cancer patients. Nonetheless, downregulation of MHC class I antigen presentation, frequently occurring in solid cancers, limits the efficacy of these therapies. Unraveling the mechanisms underlying this type of immune escape is therefore of great importance. We here investigated the immunological effects of metabolic stress in cancer cells as a result of nutrient deprivation. Methods TC1 and B16F10 tumor cell lines were cultured under oxygen- and glucose-deprivation conditions that mimicked the tumor microenvironment of solid tumors. Presentation of peptide antigens by MHC class I molecules was measured by flow cytometry and via activation of tumor-specific CD8 T cell clones. The proficiency of the IFNy-STAT1 pathway was investigated by Western blots on phosphorylated proteins, transfection of constitutive active STAT1 constructs and qPCR of downstream targets. Kinase inhibitors for PI3K were used to examine its role in IFNy receptor signal transduction. Results Combination of oxygen- and glucose-deprivation resulted in decreased presentation of MHC class I antigens on cancer cells, even in the presence of the stimulatory cytokine IFNy. This unresponsiveness to IFNy was the result of failure to phosphorylate the signal transducer STAT1. Forced expression of constitutive active STAT1 fully rescued the MHC class I presentation. Furthermore, oxygen- and glucose-deprivation increased PI3K activity in tumor cells. Pharmacological inhibition of this pathway not only restored signal transduction through IFNy-STAT1 but also improved MHC class I presentation. Importantly, PI3K inhibitors also rendered tumor cells sensitive for recognition by CD8 T cells in culture conditions of metabolic stress. Conclusions These data revealed a strong impact of metabolic stress on the presentation of tumor antigens by MHC class I and suggest that this type of tumor escape takes place at hypoxic areas even during times of active T cell immunity and IFNy release. |
topic |
Cancer metabolism Tumor microenvironment Immune-escape |
url |
http://link.springer.com/article/10.1186/s40425-019-0627-8 |
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