Overcoming Adenosine-Mediated Immunosuppression: The Therapeutic Potential of AB928

The study delves into the role of adenosine, a molecule produced from AMP by the enzyme CD73, in suppressing the immune system during cancer progression. It highlights that adenosine's impact on immune cells is mainly mediated through two receptors, A2aR and A2bR. The research introduces AB928, a dual antagonist for these receptors, which has been shown to counteract the suppressive effects of adenosine on T-cells.

The methodology involved assessing AB928's effect on dendritic cell function using human monocyte-derived dendritic cells (moDC), which were treated with various agents and then subjected to gene expression analysis and a mixed lymphocyte reaction (MLR). Mouse models with mammary tumor AT3-OVA or melanoma B16-F10 cells were also utilized to examine AB928's impact on tumor growth when combined with chemotherapy or α-PD-1 therapy.

Findings indicate that several types of human tumors, including non-small cell lung, renal, triple-negative breast, ovarian, colorectal, and gastroesophageal cancers, express high levels of adenosine processing enzymes, making them potential targets for adenosine pathway interventions. The study also discovered a strong correlation between CD73 transcript and protein levels, validating the reliability of the techniques used.

In vitro, moDC treated with adenosine exhibited reduced capacity to stimulate IFN-γ secretion from CD4+ T-cells in an MLR, an effect that was significantly reversed by AB928. Additionally, gene expression profiling identified 39 genes influenced by adenosine during moDC differentiation, with AB928 rescuing these changes, underscoring the antagonist's role in mitigating adenosine's suppressive effects.

In vivo, AB928 demonstrated antitumor efficacy, particularly when combined with anthracycline chemotherapy, resulting in significantly reduced tumor volumes. This combination also led to an enhanced immune cell infiltrate and stromal response within tumors. Furthermore, AB928 was effective in inhibiting B16-F10 tumor growth, either as a monotherapy or in conjunction with α-PD-1.

The study concludes that targeting both A2aR and A2bR receptors with AB928 is crucial for alleviating adenosine-induced immunosuppression in cancer. AB928 not only boosts the antitumor immune response but also leads to reduced tumor growth and increased immune cell infiltration in mouse tumors. The compound has completed a phase 1 clinical trial in healthy individuals and is now being tested in cancer patients.