The Coincidence Between Increasing Age, Immunosuppression, and the Incidence of Patients With Glioblastoma
Background: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and is associated with a median overall survival (mOS) of 16–21 months. Our previous work found a negative association between advanced aging and the survival benefit after treatment with immunotherapy in an experime...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-03-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2019.00200/full |
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| author | Erik Ladomersky Denise M. Scholtens Denise M. Scholtens Masha Kocherginsky Masha Kocherginsky Elizabeth A. Hibler Elizabeth T. Bartom Sebastian Otto-Meyer Lijie Zhai Kristen L. Lauing Jaehyuk Choi Jaehyuk Choi Jeffrey A. Sosman Jennifer D. Wu Jennifer D. Wu Bin Zhang Bin Zhang Rimas V. Lukas Rimas V. Lukas Derek A. Wainwright Derek A. Wainwright Derek A. Wainwright Derek A. Wainwright |
| author_facet | Erik Ladomersky Denise M. Scholtens Denise M. Scholtens Masha Kocherginsky Masha Kocherginsky Elizabeth A. Hibler Elizabeth T. Bartom Sebastian Otto-Meyer Lijie Zhai Kristen L. Lauing Jaehyuk Choi Jaehyuk Choi Jeffrey A. Sosman Jennifer D. Wu Jennifer D. Wu Bin Zhang Bin Zhang Rimas V. Lukas Rimas V. Lukas Derek A. Wainwright Derek A. Wainwright Derek A. Wainwright Derek A. Wainwright |
| author_sort | Erik Ladomersky |
| collection | DOAJ |
| description | Background: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and is associated with a median overall survival (mOS) of 16–21 months. Our previous work found a negative association between advanced aging and the survival benefit after treatment with immunotherapy in an experimental brain tumor model. Given the recent phase III clinical success of immunotherapy in patients with many types of cancer, but not for patients with GBM, we hypothesize that aging enhances immunosuppression in the brain and contributes to the lack of efficacy for immunotherapy to improve mOS in patients with malignant glioma. Herein, we compare epidemiological data for the incidence and mortality of patients with central nervous system (CNS) cancers, in addition to immune-related gene expression in the normal human brain, as well as peripheral blood immunological changes across the adult lifespan.Methods: Data were extracted from the National Cancer Institute’s surveillance, epidemiology, and end results (SEER)-, the Broad Institute’s Genotype Tissue Expression project (GTEx)-, and the University of California San Francisco’s 10k Immunomes-databases and analyzed for associations with aging.Results: The proportion of elderly individuals, defined as ≥65 years of age, has predominantly increased for more than 100 years in the United States. Over time, the rise in elderly United States citizens has correlated with an increased incidence and mortality rate associated with primary brain and other CNS cancer. With advanced aging, human mRNA expression for factors associated with immunoregulation including immunosuppressive indoleamine 2,3 dioxygenase 1 (IDO) and programmed death-ligand 1 (PD-L1), as well as the dendritic cell surface marker, CD11c, increase in the brain of normal human subjects, coincident with increased circulating immunosuppressive Tregs and decreased cytolytic CD8+ T cells in the peripheral blood. Strikingly, these changes are maximally pronounced in the 60–69 year old group; consistent with the median age of a diagnosis for GBM.Conclusion: These data demonstrate a significant association between normal human aging and increased immunosuppression in the circulation and CNS; particularly late in life. Our data raise several hypotheses including that, aging: (i) progressively suppresses normal immunosurveillance and thereby contributes to GBM cell initiation and/or outgrowth; (ii) decreases immunotherapeutic efficacy against malignant glioma. |
| first_indexed | 2024-04-14T01:30:00Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-14T01:30:00Z |
| publishDate | 2019-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-745b21c92aef40bba365cd55223a21912022-12-22T02:20:13ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122019-03-011010.3389/fphar.2019.00200447805The Coincidence Between Increasing Age, Immunosuppression, and the Incidence of Patients With GlioblastomaErik Ladomersky0Denise M. Scholtens1Denise M. Scholtens2Masha Kocherginsky3Masha Kocherginsky4Elizabeth A. Hibler5Elizabeth T. Bartom6Sebastian Otto-Meyer7Lijie Zhai8Kristen L. Lauing9Jaehyuk Choi10Jaehyuk Choi11Jeffrey A. Sosman12Jennifer D. Wu13Jennifer D. Wu14Bin Zhang15Bin Zhang16Rimas V. Lukas17Rimas V. Lukas18Derek A. Wainwright19Derek A. Wainwright20Derek A. Wainwright21Derek A. Wainwright22Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesDepartment of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesDepartment of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesDepartment of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesDepartment of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesDepartment of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesDepartment of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesDepartment of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesDepartment of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesDepartment of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesDepartment of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesDepartment of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesDepartment of Medicine-Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesDepartment of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesDepartment of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesDepartment of Medicine-Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesDepartment of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesRobert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, United States0Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesDepartment of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesDepartment of Medicine-Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesDepartment of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesRobert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, United StatesBackground: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and is associated with a median overall survival (mOS) of 16–21 months. Our previous work found a negative association between advanced aging and the survival benefit after treatment with immunotherapy in an experimental brain tumor model. Given the recent phase III clinical success of immunotherapy in patients with many types of cancer, but not for patients with GBM, we hypothesize that aging enhances immunosuppression in the brain and contributes to the lack of efficacy for immunotherapy to improve mOS in patients with malignant glioma. Herein, we compare epidemiological data for the incidence and mortality of patients with central nervous system (CNS) cancers, in addition to immune-related gene expression in the normal human brain, as well as peripheral blood immunological changes across the adult lifespan.Methods: Data were extracted from the National Cancer Institute’s surveillance, epidemiology, and end results (SEER)-, the Broad Institute’s Genotype Tissue Expression project (GTEx)-, and the University of California San Francisco’s 10k Immunomes-databases and analyzed for associations with aging.Results: The proportion of elderly individuals, defined as ≥65 years of age, has predominantly increased for more than 100 years in the United States. Over time, the rise in elderly United States citizens has correlated with an increased incidence and mortality rate associated with primary brain and other CNS cancer. With advanced aging, human mRNA expression for factors associated with immunoregulation including immunosuppressive indoleamine 2,3 dioxygenase 1 (IDO) and programmed death-ligand 1 (PD-L1), as well as the dendritic cell surface marker, CD11c, increase in the brain of normal human subjects, coincident with increased circulating immunosuppressive Tregs and decreased cytolytic CD8+ T cells in the peripheral blood. Strikingly, these changes are maximally pronounced in the 60–69 year old group; consistent with the median age of a diagnosis for GBM.Conclusion: These data demonstrate a significant association between normal human aging and increased immunosuppression in the circulation and CNS; particularly late in life. Our data raise several hypotheses including that, aging: (i) progressively suppresses normal immunosurveillance and thereby contributes to GBM cell initiation and/or outgrowth; (ii) decreases immunotherapeutic efficacy against malignant glioma.https://www.frontiersin.org/article/10.3389/fphar.2019.00200/fullagingbiomarkerIDOimmunosuppressionPD-L1immunotherapy |
| spellingShingle | Erik Ladomersky Denise M. Scholtens Denise M. Scholtens Masha Kocherginsky Masha Kocherginsky Elizabeth A. Hibler Elizabeth T. Bartom Sebastian Otto-Meyer Lijie Zhai Kristen L. Lauing Jaehyuk Choi Jaehyuk Choi Jeffrey A. Sosman Jennifer D. Wu Jennifer D. Wu Bin Zhang Bin Zhang Rimas V. Lukas Rimas V. Lukas Derek A. Wainwright Derek A. Wainwright Derek A. Wainwright Derek A. Wainwright The Coincidence Between Increasing Age, Immunosuppression, and the Incidence of Patients With Glioblastoma Frontiers in Pharmacology aging biomarker IDO immunosuppression PD-L1 immunotherapy |
| title | The Coincidence Between Increasing Age, Immunosuppression, and the Incidence of Patients With Glioblastoma |
| title_full | The Coincidence Between Increasing Age, Immunosuppression, and the Incidence of Patients With Glioblastoma |
| title_fullStr | The Coincidence Between Increasing Age, Immunosuppression, and the Incidence of Patients With Glioblastoma |
| title_full_unstemmed | The Coincidence Between Increasing Age, Immunosuppression, and the Incidence of Patients With Glioblastoma |
| title_short | The Coincidence Between Increasing Age, Immunosuppression, and the Incidence of Patients With Glioblastoma |
| title_sort | coincidence between increasing age immunosuppression and the incidence of patients with glioblastoma |
| topic | aging biomarker IDO immunosuppression PD-L1 immunotherapy |
| url | https://www.frontiersin.org/article/10.3389/fphar.2019.00200/full |
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