Unlocking the Potential of CD73 Inhibitors: Enhancing CD8+ T Cell Responses and Combating Tumor Growth

Adenosine (ADO) is a key inhibitor of T-cell activation, produced intracellularly from ATP through the action of ecto-nucleotidases CD39 and CD73. Given the role of ADO in immune suppression within tumors, there is significant interest in developing CD73 inhibitors. This study introduces a series of potent small-molecule CD73 inhibitors, with A000830 as a prime example.

A000830 was found to be highly potent and specific, with an IC50 of 1.0 nM against human CD73 and 3 nM against mouse CD73. It effectively blocked ADO production from AMP in human ovarian cancer cells, showing significant selectivity over other ecto-nucleotidases and unrelated enzymes, receptors, and ion channels.

In functional assays, A000830 reversed the suppressive effects of ADO on CD8+ T cells, enhancing their proliferation, CD25 expression, and production of IFNγ and granzyme B. When administered to mice, A000830 was well tolerated and achieved plasma concentrations far exceeding its potency against mouse CD73.

In a tumor model using CT26 cells in Balb/c mice, A000830 in combination with an anti-PD1 antibody led to significant tumor growth inhibition, surpassing the effects of either treatment alone. This therapeutic effect was linked to an increase in the CD8:Treg ratio within tumors.

In summary, the study presents a new class of CD73 inhibitors capable of blocking ADO generation, enhancing T-cell activation, and exhibiting significant anti-tumor effects when combined with PD-1 blockade. These findings support the potential of A000830 and similar compounds as promising candidates for cancer immunotherapy.