Inhibitors of the CD73-adenosinergic checkpoint as promising combinatory agents for conventional and advanced cancer immunotherapy
The cell surface enzyme CD73 is increasingly appreciated as a pivotal non-redundant immune checkpoint (IC) in addition to PD-1/PD-L1 and CTLA-4. CD73 produces extracellular adenosine (eADO), which not only inhibits antitumor T cell activity via the adenosine receptor (AR) A2AR, but also enhances the...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1212209/full |
| _version_ | 1827901447688159232 |
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| author | Zoya Kurago Gang Guo Gang Guo Huidong Shi Huidong Shi Roni J. Bollag Roni J. Bollag Michael W. Groves Michael W. Groves J. Kenneth Byrd J. Kenneth Byrd Yan Cui Yan Cui |
| author_facet | Zoya Kurago Gang Guo Gang Guo Huidong Shi Huidong Shi Roni J. Bollag Roni J. Bollag Michael W. Groves Michael W. Groves J. Kenneth Byrd J. Kenneth Byrd Yan Cui Yan Cui |
| author_sort | Zoya Kurago |
| collection | DOAJ |
| description | The cell surface enzyme CD73 is increasingly appreciated as a pivotal non-redundant immune checkpoint (IC) in addition to PD-1/PD-L1 and CTLA-4. CD73 produces extracellular adenosine (eADO), which not only inhibits antitumor T cell activity via the adenosine receptor (AR) A2AR, but also enhances the immune inhibitory function of cancer-associated fibroblasts and myeloid cells via A2BR. Preclinical studies show that inhibition of the CD73-adenosinergic pathway in experimental models of many solid tumors either as a monotherapy or, more effectively, in combination with PD-1/PD-L1 or CTLA-4 IC blockades, improves antitumor immunity and tumor control. Consequently, approximately 50 ongoing phase I/II clinical trials targeting the CD73-adenosinergic IC are currently listed on https://clinicaltrials.gov. Most of the listed trials employ CD73 inhibitors or anti-CD73 antibodies alone, in combination with A2AR antagonists, and/or with PD-1/PD-L1 blockade. Recent evidence suggests that the distribution of CD73, A2AR and A2BR in tumor microenvironments (TME) is heterogeneous, and this distribution affects CD73-adenosinergic IC function. The new insights have implications for the optimally effective, carefully tailored approaches to therapeutic targeting of this essential IC. In the mini-review, we briefly discuss the cellular and molecular mechanisms of CD73/eADO-mediated immunosuppression during tumor progression and therapy in the spatial context of the TME. We include preclinical data regarding therapeutic CD73-eADO blockade in tumor models as well as available clinical data from completed trials that targeted CD73-adenosinergic IC with or without PD-1/PD-L1 inhibitors and discuss factors that are potentially important for optimal therapeutic outcomes in cancer patients. |
| first_indexed | 2024-03-12T23:46:17Z |
| format | Article |
| id | doaj.art-3e2f3be5d3434e9f97690ddfc6fa6e3d |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-12T23:46:17Z |
| publishDate | 2023-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-3e2f3be5d3434e9f97690ddfc6fa6e3d2023-07-14T04:44:51ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-06-011410.3389/fimmu.2023.12122091212209Inhibitors of the CD73-adenosinergic checkpoint as promising combinatory agents for conventional and advanced cancer immunotherapyZoya Kurago0Gang Guo1Gang Guo2Huidong Shi3Huidong Shi4Roni J. Bollag5Roni J. Bollag6Michael W. Groves7Michael W. Groves8J. Kenneth Byrd9J. Kenneth Byrd10Yan Cui11Yan Cui12Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia at Augusta University, Medical College of Georgia, Augusta University, Augusta, GA, United StatesDepartment of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, United StatesGeorgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United StatesDepartment of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, United StatesGeorgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United StatesGeorgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United StatesDepartment of Pathology, Medical College of Georgia, Augusta University, Augusta, GA, United StatesGeorgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United StatesDepartment of Otolaryngology, Medical College of Georgia, Augusta University, Augusta, GA, United StatesGeorgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United StatesDepartment of Otolaryngology, Medical College of Georgia, Augusta University, Augusta, GA, United StatesDepartment of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, United StatesGeorgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United StatesThe cell surface enzyme CD73 is increasingly appreciated as a pivotal non-redundant immune checkpoint (IC) in addition to PD-1/PD-L1 and CTLA-4. CD73 produces extracellular adenosine (eADO), which not only inhibits antitumor T cell activity via the adenosine receptor (AR) A2AR, but also enhances the immune inhibitory function of cancer-associated fibroblasts and myeloid cells via A2BR. Preclinical studies show that inhibition of the CD73-adenosinergic pathway in experimental models of many solid tumors either as a monotherapy or, more effectively, in combination with PD-1/PD-L1 or CTLA-4 IC blockades, improves antitumor immunity and tumor control. Consequently, approximately 50 ongoing phase I/II clinical trials targeting the CD73-adenosinergic IC are currently listed on https://clinicaltrials.gov. Most of the listed trials employ CD73 inhibitors or anti-CD73 antibodies alone, in combination with A2AR antagonists, and/or with PD-1/PD-L1 blockade. Recent evidence suggests that the distribution of CD73, A2AR and A2BR in tumor microenvironments (TME) is heterogeneous, and this distribution affects CD73-adenosinergic IC function. The new insights have implications for the optimally effective, carefully tailored approaches to therapeutic targeting of this essential IC. In the mini-review, we briefly discuss the cellular and molecular mechanisms of CD73/eADO-mediated immunosuppression during tumor progression and therapy in the spatial context of the TME. We include preclinical data regarding therapeutic CD73-eADO blockade in tumor models as well as available clinical data from completed trials that targeted CD73-adenosinergic IC with or without PD-1/PD-L1 inhibitors and discuss factors that are potentially important for optimal therapeutic outcomes in cancer patients.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1212209/fullCD73NT5ECD39adenosineA2ARA2BR |
| spellingShingle | Zoya Kurago Gang Guo Gang Guo Huidong Shi Huidong Shi Roni J. Bollag Roni J. Bollag Michael W. Groves Michael W. Groves J. Kenneth Byrd J. Kenneth Byrd Yan Cui Yan Cui Inhibitors of the CD73-adenosinergic checkpoint as promising combinatory agents for conventional and advanced cancer immunotherapy Frontiers in Immunology CD73 NT5E CD39 adenosine A2AR A2BR |
| title | Inhibitors of the CD73-adenosinergic checkpoint as promising combinatory agents for conventional and advanced cancer immunotherapy |
| title_full | Inhibitors of the CD73-adenosinergic checkpoint as promising combinatory agents for conventional and advanced cancer immunotherapy |
| title_fullStr | Inhibitors of the CD73-adenosinergic checkpoint as promising combinatory agents for conventional and advanced cancer immunotherapy |
| title_full_unstemmed | Inhibitors of the CD73-adenosinergic checkpoint as promising combinatory agents for conventional and advanced cancer immunotherapy |
| title_short | Inhibitors of the CD73-adenosinergic checkpoint as promising combinatory agents for conventional and advanced cancer immunotherapy |
| title_sort | inhibitors of the cd73 adenosinergic checkpoint as promising combinatory agents for conventional and advanced cancer immunotherapy |
| topic | CD73 NT5E CD39 adenosine A2AR A2BR |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1212209/full |
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