Targeting T regulatory cells in cancer immunotherapy with anti-CD73

In the era of immunotherapy, a major focus of the field is to identify new targets that may improve the immune response to solid tumors. Recently, CD73 has been identified as a novel target for cancer immunotherapy. CD73, also known as ecto-5’-nucleotidase, is an enzyme that is involved in purinergic signaling.¹ CD73 is part of a conserved pathway in immune cells that begins with the activity of CD39 (also known as ENTPD1). Together, CD39 and CD73 are responsible for the breakdown of purines by immune cells. CD39 catalyzes the breakdown of ATP and ADP into AMP, and CD73 then converts AMP to adenosine. CD73 is the only known enzyme to have this function.² Both CD39 and CD73 are located at the cell surface and exert their enzymatic functions on extracellular adenosines.³

In the era of immunotherapy, a major focus of the field is to identify new targets that may improve the immune response to solid tumors. Recently, CD73 has been identified as a novel target for cancer immunotherapy. CD73, also known as ecto-5’-nucleotidase, is an enzyme that is involved in purinergic signaling.¹ CD73 is part of a conserved pathway in immune cells that begins with the activity of CD39 (also known as ENTPD1). Together, CD39 and CD73 are responsible for the breakdown of purines by immune cells. CD39 catalyzes the breakdown of ATP and ADP into AMP, and CD73 then converts AMP to adenosine. CD73 is the only known enzyme to have this function.² Both CD39 and CD73 are located at the cell surface and exert their enzymatic functions on extracellular adenosines.³

Co-expression of CD39 and CD73 defines a specific subset of regulatory T cells (Treg), which are CD4+ CD25+ FoxP3+.⁴ CD73 is also expressed by CD25- so-called "precursor" helper T cells that do not have suppressive function.⁵ While the expression of CD73 is limited to just these two subsets of T cells, the suppressive effect of the adenosine produced by the Tregs is broadly acting. Naïve and activated CD4+ Th1 and Th2 cells and cytotoxic CD8+ T cells can all be suppressed by adenosine. Adenosine can bind to the A2a adenosine receptor (A2AR) on the surface of CD4+ and CD8+ effector T cells, and this inhibits cytokine production and proliferation by the effector T cells. Simultaneously, checkpoint blockade molecules including CTLA-4 and PD-1 are upregulated on the surface of the effector T cells.³ The cytolytic function of NK cells is also inhibited by A2AR signaling.⁶

In the tumor microenvironment, CD73 creates an immunosuppressive niche through the local production of adenosine. In a mouse model, the deletion of A2AR allowed for the rejection of immunogenic tumors, and antagonism of A2AR enhances the efficacy of adoptively transferred anti-tumor CD8+ T cells.⁷ In a study of human ovarian cancer samples, nearly all samples expressed CD73 and the amount of CD4+ and CD8+ T cell infiltration was correlated with the expression of CD73 by the tumor stroma.⁸ An anti-CD73 antibody, MEDI9447/oleclumab entered clinical trials for the treatment of advanced colorectal and pancreatic cancers.⁹ Treatment was shown to decrease the expression of CD73 on peripheral T cells while increasing the amount of CD8+ T cells in the tumor microenvironment. Furthermore, several patients exhibited partial remission or stable disease for 28-322 days. In a later study, combination of an anti-CD73 antibody (BMS0986179) with the anti-PD1 treatment nivolumab in patients with a variety of solid tumors led to 28% of patients exhibiting either a partial response or stable disease.¹⁰ In both clinical trials, the anti-CD73 treatments were well-tolerated in comparison to existing immunotherapies. These results demonstrate a need for the continued study of CD73 as an immunotherapeutic target in both preclinical models and clinical trials to further understand the best way to target CD73 in solid tumors.