Abstract 6398: Targeting ENPP1 to boost anti-tumor immunity during PARP inhibition

Abstract

Abstract Homologous recombination (HR) deficiency confers sensitivity to poly (ADP-ribose) polymerase inhibitors (PARPi), which have been approved for use in ovarian and triple negative breast cancers (TNBC) carrying loss-of-function mutations in HR pathway genes, most commonly BRCA1/2. Preclinical studies in BRCA1-deficient tumor models have demonstrated that the immune compartment is required for PARPi efficacy through the ability of PARPi to cause micronuclei formation and activate cGAS in tumors cells. The production of the 2’3’-cGAMP secondary intermediate stimulates STING in neighboring tumor-infiltrating immune cells to promote an anti-tumor response. Despite this evidence of immune stimulation, PARPi does not extend overall survival in TNBC patients, suggesting that immune suppression remains a significant barrier for efficacy. Here we sought to evaluate the role of ectonucleotide pyrophosphatase/phosphodiesterase 1(ENPP1), a type II transmembrane glycoprotein that hydrolyzes extracellular 2’3’-cGAMP. We generated Brca1/Pten/Trp53-deficient TNBC cell lines from a genetically engineered mouse model and found that these expressed higher levels of ENPP1 than Brca1-proficient TNBC and non-TNBC cell lines. Knocking out Enpp1 via CRISPR/Cas9 increased 2’3’-cGAMP production during Niraparib treatment but did not affect cellular proliferation in vitro. Critically, knocking out Enpp1 significantly reduced the growth of orthotopic Brca1-deficient tumors, with no change in growth observed for orthotopic E0771 or PyMT models, suggesting an important role for ENPP1 in HR-deficient tumors. Therapeutic dosing of Niraparib further reduced the growth of Enpp1 knockout tumors in a manner that was dependent upon host STING and correlated with higher CD8+ T cell infiltration and effector function. These findings demonstrate that ENPP1 suppresses anti-tumor immunity in Brca1-deficient tumors, suggesting that blocking the enzymatic activity of ENPP1 may provide therapeutic benefits during PARPi treatment for TNBC patients. Citation Format: Jie Li, Charlotte Mason, Kay Hanggi, Vincent Luca, Brian Ruffell. Targeting ENPP1 to boost anti-tumor immunity during PARP inhibition. [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 6398.