Abstract 2247: Adenosine production suppression and PD-1 immune check point inhibitor for treatment of malignant pleural mesothelioma. (MPM)

Abstract Background: Although immune-checkpoint inhibitors (ICIs) have positively impacted the treatment of some tumors, several evidences clearly suggest that the actual relevance of these treatments has not been fully unraveled yet Hypoxic tumors activate the purinergic pathway, which acts as a major immunosuppressive mechanism. CD39 and CD73 are enzymes involved into ATP degradation to AMP and AMP degradation to the immune-suppressive adenosine, respectively thus the inhibitors of these pathways are progressively attracting the attention as actionable targets for immunotherapy in many solid tumors MPM is a highly aggressive malignancy whose treatment challenging for different reasons, including among others acidic and hypoxic tumor microenvironment (TME). Hypoxic TME and the expression of purinergic receptors and enzymes on tumor cells are considered criteria to select patients for immunotherapy with adenosine pathway inhibitor. We have already shown the expression of adenosine receptor 2 B (ADORA2b) and CD73 enzyme on MMP cells is inversely related to patients' survival and that MMP cells degrade AMP to adenosine via CD73. Aim of our study was assessing if ADORA2B and or CD73 with or without PD-1 ICi were able to curb tumor cells growth in a syngeneic mouse MPM model. Methods: For orthotopic mouse models of MPM, CD73 ADORA2B positive 105 AB1B-LUC cells were injected intraperitoneally (i.p.) in immunocompetent BALB/C mice. After three weeks we started monitoring tumor growth and the animals were randomized into five groups of three mice each for treatment with PBS 100 μl (control), Pembro (anti murine PD-1; MCE ) 4.4 mg/Kg, TT-4 (ADORA2 Inhibitor Portage), 3 mg/Kg, Pembro+TT-4, AB-680 (CD73 inhibitor, MCE, HY-125286) 20 mg kg) and Pembro+AB-680 were injected every two days for three weeks. Disease was measured with IVIS® Lumina XR in vivo imaging system, thus facilitating non-invasive longitudinal monitoring of disease progression or regression. Results: after 21 days AB680 and TT4 resulted to be the most effective single treatments (fluorescence reduction vs control p<0.01) whereas Pembro+TT4 Pembro+AB680 did not differ significantly from the single treatments. IHC of murine samples from mice treated as above revealed infiltration of CD8 T cells mostly with AB680 single agent or in combo compared to the cold pattern of the control samples. No relevant toxicity was recorded. Conclusions: Inhibition of the purinergic pathway exerts a significant immune-mediated MPM growth inhibition Citation Format: luciano Mutti, Antonio Giordano, Pierpaolo Correale, Caterina Costa. Adenosine production suppression and PD-1 immune check point inhibitor for treatment of malignant pleural mesothelioma. (MPM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2247.