Specialty: Oncology 

Keywords: Pancreatic ductal adenocarcinoma, FOLFIRINOX Chemotherapy, CD73 inhibition, STING Pathway

Background:
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, with a 5-year survival rate of ~13%.1 Its poor prognosis is largely driven by a highly immunosuppressive tumor microenvironment (TME) where standard chemotherapy, such as FOLFIRINOX (FFX), has limited efficacy.2 Tumor cell death induced by FFX releases extracellular ATP into the TME, triggering an inflammatory response that promotes anti-tumor immunity.3 ATP also enhances leukocyte uptake of cGAMP, a second messenger that activates the Stimulator of Interferon Genes (STING) pathway.4 However, these immune-stimulatory effects are short-lived, as ectonucleotidases CD39 and CD73-abundant in the TME-rapidly convert ATP into immunosuppressive adenosine (Ado).5,6 In a Phase I clinical trial for borderline resectable PDAC, we show the enhanced therapeutic efficacy of neoadjuvant chemoimmunotherapy with CD73 inhibition, supporting further investigation of this strategy.

Objective:
To examine how CD73 inhibition in combination with chemotherapy modulates the PDAC TME using patient-derived samples and metastatic mouse models.

Methods:
To counteract adenosine-mediated immunosuppression, we combined FFX with AB680, a selective CD73 inhibitor currently under clinical trials. Bulk and single-cell RNA (scRNA) sequencing was performed on samples from Phase I trial patients stratified by CD73 expression and neoadjuvant treatment (NAT). In addition, orthotopic PDAC mouse models were used to evaluate the therapeutic effects of FFX versus FFX+AB680 (20 mg/kg). Tumors were dissociated for scRNA-seq with lymphoid and myeloid cell-type annotations. STING pathway activation was assessed via Western blot by measuring IFNβ1 expression under adenosine signaling activation.

Results:
In the Phase I trial, neoadjuvant chemoimmunotherapy with CD73 inhibition was associated with improved clinical outcomes and increased expression of adenosine-related genes. In mouse models, combination treatment with AB680+FFX resulted in significantly smaller primary tumors (p < 0.01) and reduced liver and lung metastases. This therapeutic effect was reversed upon depletion of CD4+ and CD8+ T cells, indicating a T cell–dependent mechanism. scRNA-seq revealed a significant upregulation of Type I interferon signaling in the FFX+AB680 group compared to FFX alone (p < 0.0001). Western blot analysis showed that adenosine signaling suppressed STING activation by downregulating IFNβ1 transcription. Such suppression was reversed by adenosine receptor blockade.

Conclusion:
CD73 inhibition with AB680 enhances the anti-tumor efficacy of FFX chemotherapy by reactivating STING-mediated Type I interferon signaling and reversing adenosine-induced immunosuppression. These findings support CD73 blockade as a promising therapeutic strategy in PDAC and provide a strong rationale for ongoing clinical evaluation of AB680 in combination with chemoimmunotherapy for borderline resectable PDAC patients at UCLA.

References:

1. Mizrahi JD, Surana R, Valle JW, Shroff RT. Pancreatic cancer. The Lancet. 2020;395(10242):2008-2020. doi:10.1016/S0140-6736(20)30974-0

2. Falcomatà C, Bärthel S, Schneider G, Rad R, Schmidt-Supprian M, Saur D. Context-Specific Determinants of the Immunosuppressive Tumor Microenvironment in Pancreatic Cancer. Cancer Discov. 2023;13(2):278-297. doi:10.1158/2159-8290.CD-22-0876

3. Aymeric L, Apetoh L, Ghiringhelli F, et al. Tumor Cell Death and ATP Release Prime Dendritic Cells and Efficient Anticancer Immunity. Cancer Res. 2010;70(3):855-858. doi:10.1158/0008-5472.CAN-09-3566

4. Abt ER, Le TM, Dann AM, et al. Reprogramming of nucleotide metabolism by interferon confers dependence on the replication stress response pathway in pancreatic cancer cells. Cell Rep. 2022;38(2). doi:10.1016/j.celrep.2021.110236

5. Wurm M, Schaaf O, Reutner K, et al. A Novel Antagonistic CD73 Antibody for Inhibition of the Immunosuppressive Adenosine Pathway. Mol Cancer Ther. 2021;20(11):2250-2261. doi:10.1158/1535-7163.MCT-21-0107

6. Allard D, Allard ,Bertrand, Gaudreau ,Pierre-Olivier, Chrobak ,Pavel, and Stagg J. CD73–Adenosine: A Next-Generation Target in Immuno-Oncology. Immunotherapy. 2016;8(2):145-163. doi:10.2217/imt.15.106