A Threshold Model for T-Cell Activation in the Era of Checkpoint Blockade Immunotherapy
Continued discoveries of negative regulators of inflammatory signaling provide detailed molecular insights into peripheral tolerance and anti-tumor immunity. Accumulating evidence indicates that peripheral tolerance is maintained at multiple levels of immune responses by negative regulators of proin...
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Frontiers Media S.A.
2019-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.00491/full |
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doaj-7f03ac3257c644a4a2d8b34ee5d2bc9f2020-11-25T02:16:43ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-03-011010.3389/fimmu.2019.00491432353A Threshold Model for T-Cell Activation in the Era of Checkpoint Blockade ImmunotherapyKripa Guram0Sangwoo S. Kim1Victoria Wu2P. Dominick Sanders3Sandip Patel4Stephen P. Schoenberger5Stephen P. Schoenberger6Ezra E. W. Cohen7Si-Yi Chen8Andrew B. Sharabi9Andrew B. Sharabi10Department of Radiation Medicine and Applied Sciences, San Diego Moores Cancer Center, University of California, San Diego, San Diego, CA, United StatesDepartment of Radiation Medicine and Applied Sciences, San Diego Moores Cancer Center, University of California, San Diego, San Diego, CA, United StatesMoores Comprehensive Cancer Center, University of California, San Diego, San Diego, CA, United StatesDepartment of Radiation Medicine and Applied Sciences, San Diego Moores Cancer Center, University of California, San Diego, San Diego, CA, United StatesDivision of Hematology and Oncology, Center for Personalized Cancer Therapy, San Diego Moores Cancer Center, University of California, San Diego, San Diego, CA, United StatesDivision of Hematology and Oncology, Center for Personalized Cancer Therapy, San Diego Moores Cancer Center, University of California, San Diego, San Diego, CA, United StatesLaboratory of Cellular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, United StatesMoores Comprehensive Cancer Center, University of California, San Diego, San Diego, CA, United StatesDepartment of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United StatesDepartment of Radiation Medicine and Applied Sciences, San Diego Moores Cancer Center, University of California, San Diego, San Diego, CA, United StatesMoores Comprehensive Cancer Center, University of California, San Diego, San Diego, CA, United StatesContinued discoveries of negative regulators of inflammatory signaling provide detailed molecular insights into peripheral tolerance and anti-tumor immunity. Accumulating evidence indicates that peripheral tolerance is maintained at multiple levels of immune responses by negative regulators of proinflammatory signaling, soluble anti-inflammatory factors, inhibitory surface receptors & ligands, and regulatory cell subsets. This review provides a global overview of these regulatory machineries that work in concert to maintain peripheral tolerance at cellular and host levels, focusing on the direct and indirect regulation of T cells. The recent success of checkpoint blockade immunotherapy (CBI) has initiated a dramatic shift in the paradigm of cancer treatment. Unprecedented responses to CBI have highlighted the central role of T cells in both anti-tumor immunity and peripheral tolerance and underscored the importance of T cell exhaustion in cancer. We discuss the therapeutic implications of modulating the negative regulators of T cell function for tumor immunotherapy with an emphasis on inhibitory surface receptors & ligands—central players in T cell exhaustion and targets of checkpoint blockade immunotherapies. We then introduce a Threshold Model for Immune Activation—the concept that these regulatory mechanisms contribute to defining a set threshold of immunogenic (proinflammatory) signaling required to elicit an anti-tumor or autoimmune response. We demonstrate the value of the Threshold Model in understanding clinical responses and immune related adverse events in the context of peripheral tolerance, tumor immunity, and the era of Checkpoint Blockade Immunotherapy.https://www.frontiersin.org/article/10.3389/fimmu.2019.00491/fullnegative regulatorantigen presentation attenuatorthreshold modelcheckpoint blockadeimmunotherapyPD-1 |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Kripa Guram Sangwoo S. Kim Victoria Wu P. Dominick Sanders Sandip Patel Stephen P. Schoenberger Stephen P. Schoenberger Ezra E. W. Cohen Si-Yi Chen Andrew B. Sharabi Andrew B. Sharabi |
| spellingShingle |
Kripa Guram Sangwoo S. Kim Victoria Wu P. Dominick Sanders Sandip Patel Stephen P. Schoenberger Stephen P. Schoenberger Ezra E. W. Cohen Si-Yi Chen Andrew B. Sharabi Andrew B. Sharabi A Threshold Model for T-Cell Activation in the Era of Checkpoint Blockade Immunotherapy Frontiers in Immunology negative regulator antigen presentation attenuator threshold model checkpoint blockade immunotherapy PD-1 |
| author_facet |
Kripa Guram Sangwoo S. Kim Victoria Wu P. Dominick Sanders Sandip Patel Stephen P. Schoenberger Stephen P. Schoenberger Ezra E. W. Cohen Si-Yi Chen Andrew B. Sharabi Andrew B. Sharabi |
| author_sort |
Kripa Guram |
| title |
A Threshold Model for T-Cell Activation in the Era of Checkpoint Blockade Immunotherapy |
| title_short |
A Threshold Model for T-Cell Activation in the Era of Checkpoint Blockade Immunotherapy |
| title_full |
A Threshold Model for T-Cell Activation in the Era of Checkpoint Blockade Immunotherapy |
| title_fullStr |
A Threshold Model for T-Cell Activation in the Era of Checkpoint Blockade Immunotherapy |
| title_full_unstemmed |
A Threshold Model for T-Cell Activation in the Era of Checkpoint Blockade Immunotherapy |
| title_sort |
threshold model for t-cell activation in the era of checkpoint blockade immunotherapy |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Immunology |
| issn |
1664-3224 |
| publishDate |
2019-03-01 |
| description |
Continued discoveries of negative regulators of inflammatory signaling provide detailed molecular insights into peripheral tolerance and anti-tumor immunity. Accumulating evidence indicates that peripheral tolerance is maintained at multiple levels of immune responses by negative regulators of proinflammatory signaling, soluble anti-inflammatory factors, inhibitory surface receptors & ligands, and regulatory cell subsets. This review provides a global overview of these regulatory machineries that work in concert to maintain peripheral tolerance at cellular and host levels, focusing on the direct and indirect regulation of T cells. The recent success of checkpoint blockade immunotherapy (CBI) has initiated a dramatic shift in the paradigm of cancer treatment. Unprecedented responses to CBI have highlighted the central role of T cells in both anti-tumor immunity and peripheral tolerance and underscored the importance of T cell exhaustion in cancer. We discuss the therapeutic implications of modulating the negative regulators of T cell function for tumor immunotherapy with an emphasis on inhibitory surface receptors & ligands—central players in T cell exhaustion and targets of checkpoint blockade immunotherapies. We then introduce a Threshold Model for Immune Activation—the concept that these regulatory mechanisms contribute to defining a set threshold of immunogenic (proinflammatory) signaling required to elicit an anti-tumor or autoimmune response. We demonstrate the value of the Threshold Model in understanding clinical responses and immune related adverse events in the context of peripheral tolerance, tumor immunity, and the era of Checkpoint Blockade Immunotherapy. |
| topic |
negative regulator antigen presentation attenuator threshold model checkpoint blockade immunotherapy PD-1 |
| url |
https://www.frontiersin.org/article/10.3389/fimmu.2019.00491/full |
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1724889512806449152 |