Functional differences between PD-1⁺ and PD-1⁻CD4⁺ effector T cells in healthy donors and patients with glioblastoma multiforme
mmune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) have been highly successful in the treatment of cancer. While PD-1 expression has been widely investigated, its role in CD4⁺ effector T cells in the setting of health and cancer remains unclear, particularly in the setting...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Public Library of Science
2017
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| Online Access: | http://hdl.handle.net/1721.1/111673 https://orcid.org/0000-0002-5962-9570 https://orcid.org/0000-0003-0921-3144 |
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| author | Hernandez, Amanda L. Lowther, Daniel E. Lucca, Liliana E. Lerner, Benjamin A. Gunel, Murat Raddassi, Khadir Coric, Vlad Hafler, David A. Thomas, Brittany A. Love, John C |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Hernandez, Amanda L. Lowther, Daniel E. Lucca, Liliana E. Lerner, Benjamin A. Gunel, Murat Raddassi, Khadir Coric, Vlad Hafler, David A. Thomas, Brittany A. Love, John C |
| author_sort | Hernandez, Amanda L. |
| collection | MIT |
| description | mmune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) have been highly successful in the treatment of cancer. While PD-1 expression has been widely investigated, its role in CD4⁺ effector T cells in the setting of health and cancer remains unclear, particularly in the setting of glioblastoma multiforme (GBM), the most aggressive and common form of brain cancer. We examined the functional and molecular features of PD-1⁺ CD4⁺ CD25—CD127⁺ Foxp3—effector cells in healthy subjects and in patients with GBM. In healthy subjects, we found that PD-1⁺ CD4⁺ effector cells are dysfunctional: they do not proliferate but can secrete large quantities of IFNγ. Strikingly, blocking antibodies against PD-1 did not rescue proliferation. RNA-sequencing revealed features of exhaustion in PD-1⁺ CD4 effectors. In the context of GBM, tumors were enriched in PD-1⁺ CD4⁺ effectors that were similarly dysfunctional and unable to proliferate. Furthermore, we found enrichment of PD-1⁺ TIM-3⁺ CD4⁺ effectors in tumors, suggesting that co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial. RNA-sequencing of blood and tumors from GBM patients revealed distinct differences between CD4⁺ effectors from both compartments with enrichment in multiple gene sets from tumor infiltrating PD-1[superscript —]CD4⁺ effectors cells. Enrichment of these gene sets in tumor suggests a more metabolically active cell state with signaling through other co-receptors. PD-1 expression on CD4 cells identifies a dysfunctional subset refractory to rescue with PD-1 blocking antibodies, suggesting that the influence of immune checkpoint inhibitors may involve recovery of function in the PD-1[superscript —]CD4⁺ T cell compartment. Additionally, co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial. |
| first_indexed | 2024-09-23T12:11:11Z |
| format | Article |
| id | mit-1721.1/111673 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:11:11Z |
| publishDate | 2017 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/1116732022-09-28T00:41:10Z Functional differences between PD-1⁺ and PD-1⁻CD4⁺ effector T cells in healthy donors and patients with glioblastoma multiforme Hernandez, Amanda L. Lowther, Daniel E. Lucca, Liliana E. Lerner, Benjamin A. Gunel, Murat Raddassi, Khadir Coric, Vlad Hafler, David A. Thomas, Brittany A. Love, John C Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Chemical Engineering Koch Institute for Integrative Cancer Research at MIT Love, Christopher J. Thomas, Brittany A. Love, John C mmune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) have been highly successful in the treatment of cancer. While PD-1 expression has been widely investigated, its role in CD4⁺ effector T cells in the setting of health and cancer remains unclear, particularly in the setting of glioblastoma multiforme (GBM), the most aggressive and common form of brain cancer. We examined the functional and molecular features of PD-1⁺ CD4⁺ CD25—CD127⁺ Foxp3—effector cells in healthy subjects and in patients with GBM. In healthy subjects, we found that PD-1⁺ CD4⁺ effector cells are dysfunctional: they do not proliferate but can secrete large quantities of IFNγ. Strikingly, blocking antibodies against PD-1 did not rescue proliferation. RNA-sequencing revealed features of exhaustion in PD-1⁺ CD4 effectors. In the context of GBM, tumors were enriched in PD-1⁺ CD4⁺ effectors that were similarly dysfunctional and unable to proliferate. Furthermore, we found enrichment of PD-1⁺ TIM-3⁺ CD4⁺ effectors in tumors, suggesting that co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial. RNA-sequencing of blood and tumors from GBM patients revealed distinct differences between CD4⁺ effectors from both compartments with enrichment in multiple gene sets from tumor infiltrating PD-1[superscript —]CD4⁺ effectors cells. Enrichment of these gene sets in tumor suggests a more metabolically active cell state with signaling through other co-receptors. PD-1 expression on CD4 cells identifies a dysfunctional subset refractory to rescue with PD-1 blocking antibodies, suggesting that the influence of immune checkpoint inhibitors may involve recovery of function in the PD-1[superscript —]CD4⁺ T cell compartment. Additionally, co-blockade of PD-1 and TIM-3 in GBM may be therapeutically beneficial. Daniel Lowther 2017-10-02T18:23:29Z 2017-10-02T18:23:29Z 2017-09 2017-02 Article http://purl.org/eprint/type/JournalArticle 1932-6203 http://hdl.handle.net/1721.1/111673 Goods, Brittany A. et al. “Functional differences between PD-1⁺ and PD-1⁻CD4⁺ effector T cells in healthy donors and patients with glioblastoma multiforme.” Edited by Derya Unutmaz. PLOS ONE 12, 9 (September 2017): e0181538 © 2017 Goods et al. https://orcid.org/0000-0002-5962-9570 https://orcid.org/0000-0003-0921-3144 en_US http://dx.doi.org/10.1371/journal.pone.0181538 PLOS ONE Creative Commons Attribution 4.0 International License http://creativecommons.org/licenses/by/4.0/ application/pdf Public Library of Science Prof. Love |
| spellingShingle | Hernandez, Amanda L. Lowther, Daniel E. Lucca, Liliana E. Lerner, Benjamin A. Gunel, Murat Raddassi, Khadir Coric, Vlad Hafler, David A. Thomas, Brittany A. Love, John C Functional differences between PD-1⁺ and PD-1⁻CD4⁺ effector T cells in healthy donors and patients with glioblastoma multiforme |
| title | Functional differences between PD-1⁺ and PD-1⁻CD4⁺ effector T cells in healthy donors and patients with glioblastoma multiforme |
| title_full | Functional differences between PD-1⁺ and PD-1⁻CD4⁺ effector T cells in healthy donors and patients with glioblastoma multiforme |
| title_fullStr | Functional differences between PD-1⁺ and PD-1⁻CD4⁺ effector T cells in healthy donors and patients with glioblastoma multiforme |
| title_full_unstemmed | Functional differences between PD-1⁺ and PD-1⁻CD4⁺ effector T cells in healthy donors and patients with glioblastoma multiforme |
| title_short | Functional differences between PD-1⁺ and PD-1⁻CD4⁺ effector T cells in healthy donors and patients with glioblastoma multiforme |
| title_sort | functional differences between pd 1⁺ and pd 1⁻cd4⁺ effector t cells in healthy donors and patients with glioblastoma multiforme |
| url | http://hdl.handle.net/1721.1/111673 https://orcid.org/0000-0002-5962-9570 https://orcid.org/0000-0003-0921-3144 |
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