Abstract A113: The CD73 Inhibitor, AB680 Enhances Chemotherapy-Induced STING Activation and T Cell-Mediated Tumor Immunity in Pancreatic Ductal Adenocarcinoma
Authors: Premji Alykhan , Link Jason , Rashid Khalid , Zhao Weihang , Abt Evan , Srienc Michael , Zheng Serena , Li Luyi , Wainberg Zev , Radu Caius , Donahue Timothy 
Published: February 2025

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunosuppressive tumor immune microenvironment (TIME) where combinations of chemotherapy and immune checkpoint blockade (ICB) have shown limited efficacy. Standard of care FOLFIRINOX (FFX) chemotherapy promotes replication stress in tumor cells triggering synthesis of 2’-3’ cGAMP, an intercellular mediator of STING activation in nearby leukocytes. STING activation induces Type 1 Interferon (IFN) production and a cascade of anti-tumor immune responses. In parallel, dying tumor cells release ATP that is rapidly converted to immunosuppressive adenosine (Ado) by extracellular ectonucleotidases, widely expressed throughout the PDAC TIME. Accordingly, Ado-related gene expression is associated with worse overall survival in PDAC (P &lt; 0.0002). Using a mouse model of orthotopic PDAC, we demonstrated that FFX was only effective when combined with AB680, a drug in clinical trials that blocks the extracellular ectonucleotidase responsible for Ado production (CD73). FFX+AB680 significantly decreased tumor mass (P &lt; 0.01), reduced liver metastases, and eliminated lung metastases (P &lt; 0.01) compared to treatment with FFX alone. Flow cytometry of tumor-infiltrating leukocytes (TILs) showed that FFX+AB680 enhanced CD8+ T cell activation, reduced CD8+ T cell exhaustion, and increased M1 macrophages. Depleting CD4+ or CD8+ T cells reversed FFX+AB680 efficacy, and CD4+ T cell depletion alone reduced intratumoral CD8+ T cell activation (P &lt; 0.05). scRNA-seq of CD45⁺ TILs confirmed that FFX+AB680, but not FFX alone, increased the frequencies of effector T cells and M1 macrophages and upregulated Type I IFN gene signatures (P &lt; 0.0001). Cell Chat analysis identified significantly stronger ligand-receptor interactions directed from macrophages to T cells after treatment with FFX+AB680 compared to FFX alone. Using murine bone-marrow derived macrophages, we demonstrated that adenosine-receptor agonism could prevent Ifnb1 expression by limiting phosphoactivation of Irf3 downstream of STING activation. These suppressive effects are reversed by Ado receptor blockade, highlighting a regulatory interplay between Ado metabolism and STING signaling that influences immune responses in the PDAC TIME. Ado inhibition of STING signaling was also demonstrated with human PBMCs and an ex vivo living tissue model of PDAC patient tumors. Our data support a model whereby adenosine, generated as a consequence of chemotherapy, can limit tumor-suppressive IFN production by interrupting STING signaling in macrophages in the PDAC TIME. These data reveal CD73 activity as a critical therapeutic vulnerability in PDAC that can improve responses to FFX. An ongoing UCLA clinical trial combining FFX with AB680 dramatically reduces serum adenosine, precludes tumor involvement in lymph nodes and vasculature, and yields exceptionally rare near complete/complete pathologic responses in 50% of patients.

Citation Format: Alykhan Premji, Jason Link, Khalid Rashid, Weihang Zhao, Evan Abt, Michael Srienc, Serena Zheng, Luyi Li, Zev Wainberg, Caius Radu, Timothy Donahue. The CD73 Inhibitor, AB680 Enhances Chemotherapy-Induced STING Activation and T Cell-Mediated Tumor Immunity in Pancreatic Ductal Adenocarcinoma [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A113.