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

Abstract

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.

Posttranslational protein modifications as gatekeepers of cancer immunogenicity

“…CD73 is expressed in various solid tumors in humans, and its presence often correlates with unfavorable cancer progression, including metastasis and angiogenesis ( 7 ). Its immunosuppressive effects encompass inhibition of T cell activation by disrupting T cell receptor signaling and cytokine production, induction of regulatory T cells, suppression of proinflammatory cytokine production, and, in some instances, inhibition of antigen-presenting cells ( 8 ). These effects primarily stem from CD73’s enzymatic activity.…”

CAR T cells recognizing CD276 and Dual-CAR T cells against CD276/FGFR4 promote rhabdomyosarcoma clearance in orthotopic mouse models

“…TIM-3, T cell immunoglobulin and mucin domain 3, is predominantly expressed at higher levels by CD8 + tumor-infiltrating lymphocytes (TILs) and CD4 + Tregs (63). CD39, an ectonucleoside triphosphate diphosphohydrolase expressed on the T cell surface, dephosphorylates ATP released from damaged cells, generating extracellular adenosine and driving the suppression of immune-stimulatory effects downstream (64).…”

CD276-CAR T cells and Dual-CAR T cells targeting CD276/FGFR4 promote rhabdomyosarcoma clearance in orthotopic mouse models

“…TIM-3, T cell immunoglobulin and mucin domain 3, is predominantly expressed at higher levels by CD8 + tumor-infiltrating lymphocytes (TILs) and CD4 + T regs [ 63 ]. CD39, an ectonucleoside triphosphate diphosphohydrolase expressed on the T cell surface, dephosphorylates ATP released from damaged cells, generating extracellular adenosine and driving the suppression of immune-stimulatory effects downstream [ 64 ].…”