The PARP inhibitor ABT-888 impairs the suppressive capacity of regulatory T cells through modulation of FoxP3 and CTLA-4.

Abstract

Abstract Immune checkpoint blockade (ICB) has achieved long-term survival in melanoma but results remain limited in other solid malignancies including ovarian cancer. Combination treatments are a promising strategy to optimize responses to ICB. We have previously shown that the PARP inhibitor (PARPi) ABT-888 synergizes with CTLA-4 ICB to achieve long-term survival in a preclinical model of ovarian cancer. While the role of PARPi on DNA repair is well established, the impact on T cells is unclear. Published data using PARP1-KO mice suggests that PARP impairs regulatory T cell (Treg) function through modulation of FoxP3. Tregs suppress conventional T cell responses using multiple mechanisms including consumption of co-stimulatory molecules via the inhibitory receptor CTLA-4. Here we sought to define the impact of ABT-888 on the suppressive function of Tregs using FoxP3-eGFP transgenic mice. Using flow cytometry, we examined the levels of FoxP3 and CTLA-4 in Tregs stimulated in the presence of increasing doses of ABT-888 (0 – 50μM). Independent of stimulation, the GMFI of FoxP3 and CTLA-4 were significantly reduced by ABT-888 in a dose-dependent manner (P < 0.05). To test suppressive function, we pre-treated Tregs with increasing doses of ABT-888 prior to use in a standard proliferation assay. Similarly, ABT-888 pre-treatment significantly reduced the suppressive capacity of Tregs in a dose-dependent manner (P < 0.05). Taken together, these data identify a potentially novel area of synergy between PARPi and ICB. Furthermore, these data highlight the immunomodulatory effects of PARPi which are independent of their role in DNA repair. Future studies will focus on the impact of ABT-888 on tumor-associated Tregs and optimization of ICB therapy. This research was supported by NCI R37CA229221 (PI: Adams) and UNM Comprehensive Cancer Center Support Grant NCI P30CA11810. D.F. was supported by the Academic Science Education and Research Training program at the University of New Mexico Health Sciences Center (NIGMS Institutional Research and Academic Career Development Award; K12-GM088021).