Abstract B013: Elevation of immune cell infiltration and interferon-stimulated gene expression is associated with niraparib treatment in murine syngeneic tumor models
Authors: Wang Sarah , Sun Kaiming , Xiao Yonghong , Mikule Keith , Ramaswamy Sridhar , Hanke Jeffrey , Wang Jing Yu 
Published: August 2018

Abstract
Introduction: Niraparib is an orally available and selective poly (ADP-ribose) polymerase (PARP)-1/-2 inhibitor approved for maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in complete or partial response to platinum-based chemotherapy. Here, we evaluated the effects of niraparib treatment on tumor-immune microenvironment and assessed the efficacy of niraparib in combination with anti-PD-1 therapy in mouse-derived syngeneic transplant models. Experimental Procedures: Mouse Apcmin/+ syngeneic skin squamous carcinoma model was established by subcutaneously transplanting tumor spontaneously developed from C57BL/6J-Apcmin mouse model into immunocompetent mice with similar genetic background. Niraparib was administered orally at 50mg/kg or 25mg/kg daily as single-agent or in combination with intraperitoneally administered anti-PD-1 antibody (RMP1-14) at 5mg/kg twice weekly after tumors reach 100-200mm3. The tumor growth was monitored twice per week post randomization. At the end of the study, tumors were collected for immunophenotyping and transcriptome profiling. Summary: Anti-PD-1 monotherapy demonstrated minimal effect in Apcmin/+ syngeneic tumors, which were sensitive to niraparib daily treatment at 50mg/kg. Upon niraparib treatment, numbers of infiltrating CD8+ and CD4+ cells were significantly elevated within intratumoral regions. Interferon response gene signatures were identified by gene set enrichment analysis (GSEA) as top differentially expressed gene sets upon niraparib treatment. Several immune-related transcripts were also found to be upregulated, including STING, PDL1, CXCL9, and CXCL10. The activation of STING pathway was further evaluated in BRCA-deficient MDA-MB-436 human triple-negative breast cancer cells, where levels of p-STING(Ser366) and p-TBK1(Ser172) were elevated following niraparib treatments. Consistent with the niraparib-induced changes in tumor microenvironments, combining niraparib treatment at suboptimal dose (25mg/kg) with anti-PD-1 antibody resulted in enhanced antitumor activity as compared to niraparib or anti-PD-1 antibody alone in Apcmin/+ syngeneic tumors. Conclusions: Niraparib treatment increased CD4+ and CD8+ immune cell infiltration and upregulated the expression of interferon-stimulated genes in Apcmin/+ syngeneic tumors. Elevated levels of STING transcription and phosphorylation were associated with niraparib treatment in niraparib-sensitive models. Niraparib and anti-PD-1 combination was well tolerated and demonstrated enhanced antitumor activities as compared to niraparib or anti-PD1 monotherapy.
Citation Format: Sarah Wang, Kaiming Sun, Yonghong Xiao, Keith Mikule, Sridhar Ramaswamy, Jeffrey Hanke, Jing Yu Wang. Elevation of immune cell infiltration and interferon-stimulated gene expression is associated with niraparib treatment in murine syngeneic tumor models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B013.