Introduction: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a profoundly immunosuppressive microenvironment. Innovative therapeutic strategies are urgently needed to stop the progression of precancerous lesions into aggressive PDAC, which remains a lethal malignancy. The goal of this research project is to test immunopreventive strategies by targeting the 5’ ectonucleotidase enzyme, CD73, one of the gatekeeper enzymes responsible for conversion of adenosine monophosphate (AMP), to an immunosuppressive metabolite, adenosine, in the tumor microenvironment (TME). We hypothesize that inhibition of CD73 will prevent pancreatic intraepithelial neoplasia (PanIN) formation and progression to PDAC by reversing adenosine directed immunosuppression. This research explores immunopreventive strategies aimed to restore tumor immune surveillance to prevent cancer initiation or progression.

Materials and methods: We used two models: a syngeneic model of PDAC using cells derived from KrasG12D;Trp53R172H/+;PdxCre (KPC) mice and a KrasG12D;PdxCre (KC) genetically engineered mouse model (GEM) of PDAC. Oral gavage of AB680 (small molecule CD73 inhibitor) was given three days/week at 10mg/kg starting the day after KPC injections and tumor sizes were measured weekly. In the GEM model, the same treatment regimen began when the mice were between 6 and 9 weeks old and were euthanized either between 15 and 20 weeks of age or around 27 weeks of age, and pancreas tissue was harvested. Histology was analyzed and 6 fields per mouse were quantified using ImageJ.

Results: As we have described (Singh, et al, bioRxiv), in the syngeneic model, there was a significant reduction in tumor growth and significant increase in activated CD8-positive T cells, dendritic cells, and macrophages from AB680 treated mice. The intratumoral adenosine levels were significantly decreased in AB680 treated mice compared to vehicle treated mice. In the KC GEM model, we quantified significantly fewer early PanIN lesions (p=0.0328), a trend in decreased advanced PanIN (p=0.0641), and significant decrease in PDAC (p=0.0058) in the AB680 treated mice when compared to the vehicle treated mice. We quantified abundance of collagen deposition as a marker of fibrosis and observed significantly decreased collagen (p<0.0001) in AB680 treated KC mice. In addition, we quantified abundance of CK19+ lesions and observed a significant decrease in CK19+ lesions in AB680 treated mice (p=0.0061) compared to vehicle treated mice.

Conclusion: Inhibiting CD73 restructures TME and reduces PanIN incidence and progression to PDAC. CD73 inhibition may be a candidate immunoprevention strategy in pancreatic cancer. [Supported by NCI 75N91019D00021/75N91020F00002]

Citation Format: Lincoln N. Strickland, Erika Y. Faraoni, Nicolette R. Mardik, Lana Vornik, Michelle I. Savage, Shizuko Sei, Mark S. Miller, Holger K. Eltzschig, Powel H. Brown, Florencia McAllister, Jennifer M. Bailey-Lundberg. Preclinical testing of CD73 inhibitor AB680 for pancreatic cancer immunoprevention. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5258.