CD73: a novel target for cancer immunotherapy

Abstract

The promise of cancer immunotherapy has not been translated into clinical successes, in large part because of tumor-associated immune suppression that blocks effective antitumor immunity. Recent findings show a tumor-induced immunosuppressive mechanism, whereby tumor-derived CD73 functions as an ecto-enzyme to produce extracellular adenosine, which promotes tumor growth by limiting antitumor T-cell immunity via adenosine receptor signaling. Results with small molecule inhibitors, or monoclonal antibodies targeting CD73 in murine tumor models, suggest that targeted CD73 therapy is an important alternative and realistic approach to effective control of tumor growth. In particular, it helps T-cell-based therapy by enhancing the adaptive immune response machinery, which may increase the function of tumor-infiltrating T lymphocytes, and subsequently lead to improved survival in cancer patients.

Figure 1. Schema of extracellular adenosine metabolism in tumor-induced immune suppression

The sequential action of ecto-ATPase (CD39) and ecto-5′-nucleotidase (CD73), both of which can be induced by tumor hypoxia, to degrade ATP represents a primary pathway of extracellular adenosine generation in the tumor microenvironment. It is very likely that coordinated expression and activity of CD39/CD73 (increased) and ecto-adenosine deaminase ADA (decreased) which in human cells can be bound to the cell surface by CD26 contribute to the elevated levels of extracellular adenosine during tumor progression. The exact roles of CD39/CD73 on the non-malignant host cells (e.g. Treg) in the tumor microenvironment remain unclear. High concentrations of adenosine suppress antitumor T cell activation, survival and effector function through A2AR engagement. Meanwhile, adenosine may trigger certain adenosine receptors (AR) on cancer cells to promote tumor cell chemotaxis and metastasis. In addition, adenosine can negatively modulate differentiation and function of dendritic cells (DCs), and further inhibit natural killer (NK) cell proliferation and cytolytic function.