Adenosine A2a receptor inhibition increases the anti-tumor efficacy of anti-PD1 treatment in murine hepatobiliary cancers

• Published in: JHEP reports Vol. 6; no. 1; p. 100959
• Main Authors: Myojin, Yuta, McCallen, Justin D., Ma, Chi, Bauer, Kylynda C., Ruf, Benjamin, Benmebarek, Mohamed-Reda, Green, Benjamin L., Wabitsch, Simon, McVey, John C., Fu, Claude, Xie, Changqing, Greten, Tim F.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2024; Elsevier
• Subjects: adenosine receptor; immunotherapy; Liver cancer; CCA; Tregs; TACE; HCC; PBMCs; ICI; Liver cancer; immunotherapy; adenosine receptor; CTLA4; A2aR; PD1; NK
• ISSN: 2589-5559; 2589-5559
• DOI: 10.1016/j.jhepr.2023.100959

The efficacy of immune checkpoint inhibitor (ICI) therapy for liver cancer remains limited. As the hypoxic liver environment regulates adenosine signaling, we tested the efficacy of adenosine A2a receptor (A2aR) inhibition in combination with ICI treatment in murine models of liver cancer. RNA expression related to the adenosine pathway was analyzed from public databases. Peripheral blood mononuclear cells of 13 patients with hepatocellular carcinoma (HCC) were examined by flow cytometry. The following murine cell lines were used: SB-1, RIL175, and Hep55.1c (liver cancer), CT26 (colon cancer), and B16–F10 (melanoma). C57BL/6 and BALB/c mice were used for orthotopic tumor models and were treated with SCH58261, an A2aR inhibitor, in combination with anti-PD1 therapy. RNA expression of ADORA2A in tumor tissues derived from patients with HCC was higher than in tissues from other cancer types. A2aR+ T cells in peripheral blood from patients with HCC were highly proliferative after immunotherapy. Likewise, in an orthotopic murine model, A2aR expression on T cells increased following anti-PD1 treatment, and the expression of A2aR on T cells increased more in tumor-bearing mice compared with tumor-free mice. The combination of SCH58261 and anti-PD1 led to activation of T cells and reductions in tumor size in orthotopic liver cancer models. In contrast, SCH58261 monotherapy was ineffective in orthotopic liver cancer models and the combination was ineffective in the subcutaneous tumor models tested. CD4+ T-cell depletion attenuated the efficacy of the combination therapy. A2aR inhibition and anti-PD1 therapy had a synergistic anti-tumor effect in murine liver cancer models. Adenosine A2a receptor (A2aR)-expressing T cells in the liver increased in tumor-bearing mice and after anti-PD1 treatment. The combination of an A2aR inhibitor and anti-PD1 treatment had potent anti-tumor effects in two murine models of orthotopic liver cancer. Adenosine A2a receptor blockade promotes immunotherapy efficacy in murine models, highlighting putative clinical benefits for advanced stage liver cancer patients. [Display omitted] •Adenosine-related genes are highly expressed in patients with liver cancer.•A2aR expression on T cells increases in tumor-bearing and ICI-treated mice.•A2aR blockade enhances the anti-tumor effect of ICIs.