Journal Article

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

Kurago, Zoya, Groves, Michael W., Guo, Gang, Cui, Yan, Byrd, J. Kenneth, Bollag, Roni J., Shi, Huidong

2023

Overview

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.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: A2AR / A2BR / Adenosine / Anesthetics, Local / Angiogenesis / Anti-Infective Agents / B7-H1 Antigen / Cancer / Cancer immunotherapy / Cancer therapies / CD39 / CD73 / CD73 antigen / Cell growth / Cell surface / Clinical outcomes / Clinical trials / CTLA-4 Antigen / CTLA-4 protein / Cytotoxicity / Endothelium / Enzymes / Fibrinolytic Agents / Fibroblasts / Humans / Hypoxia / Immune checkpoint / Immunity (Disease) / Immunology / Immunosuppression / Immunotherapy / Inflammation / Kinases / Lymphocytes / Lymphocytes T / Metastasis / Molecular modelling / Myeloid cells / Neoplasms - drug therapy / NT5E / PD-1 protein / PD-L1 protein / Penicillins / Programmed Cell Death 1 Receptor / Pulmonary Surfactants / Roles / Solid tumors / Therapeutic targets / Tumor Microenvironment / Tumors