Inhibitors of the CD73-adenosinergic checkpoint as promising combinatory agents for conventional and advanced cancer immunotherapy.

Autor: Kurago Z; Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia at Augusta University, Medical College of Georgia, Augusta University, Augusta, GA, United States., Guo G; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, United States.; Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States., Shi H; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, United States.; Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States., Bollag RJ; Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States.; Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA, United States., Groves MW; Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States.; Department of Otolaryngology, Medical College of Georgia, Augusta University, Augusta, GA, United States., Byrd JK; Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States.; Department of Otolaryngology, Medical College of Georgia, Augusta University, Augusta, GA, United States., Cui Y; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, United States.; Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, United States.
Jazyk: angličtina
Zdroj: Frontiers in immunology [Front Immunol] 2023 Jun 26; Vol. 14, pp. 1212209. Date of Electronic Publication: 2023 Jun 26 (Print Publication: 2023).
DOI: 10.3389/fimmu.2023.1212209
Abstrakt: 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) A 2A R, but also enhances the immune inhibitory function of cancer-associated fibroblasts and myeloid cells via A 2B R. 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 A 2A R antagonists, and/or with PD-1/PD-L1 blockade. Recent evidence suggests that the distribution of CD73, A 2A R and A 2B R 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.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Kurago, Guo, Shi, Bollag, Groves, Byrd and Cui.)
Databáze: MEDLINE
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