Abstract LB-B03: PARP and PI3K inhibitor combination therapy eradicates c-MYC-driven murine prostate cancers via cGAS/STING pathway activation within tumor-associated macrophages
Authors: Duttagupta Priyanka , Chaudagar Kiranj , Sharma-Saha Sweta , Bynoe Kaela , Parkes Eileen , Patnaik Akash 
Published: March 2020

Abstract
While immune checkpoint blockade (ICB) targeting CTLA-4 and PD-1/PD-L1 has shown remarkable success across a wide range of malignancies, the majority of prostate cancer (PC) patients do not demonstrate clinically meaningful responses to these therapies. Therefore, there is a critical unmet need to discover combinatorial therapeutic strategies that enhance immune-responsiveness in ICB-refractory cancers, such as PC. Here, we show that DNA damage induced by PARP inhibitor (PARPi), rucaparib, in combination with PI3K inhibitor (PI3Ki), buparlisib, resulted in STING activation within myeloid suppressive cells within the TME. Strikingly, this myeloid reprogramming induced by rucaparib/buparlisib combination was accompanied by enhanced T cell infiltration and tumor regression of myc-driven murine PCs in vivo. Furthermore, the anti-tumor mechanism of the rucaparib/buparlisib combination was non-tumor cell autonomous and immune-mediated, as the effect was abrogated in immunodeficient NOD/SCID mice. Critically, rucaparib/buparlisib-mediated tumor regression in myc-driven murine models was abrogated with concomitant clodronate treatment in vivo, which depletes macrophages. To unravel the mechanism for activation of macrophage-mediate anti-cancer immunity elicited by DNA damage, we performed co-culture assays, which revealed that STING pathway activation elicited within macrophages was mediated by double-stranded (ds) DNA-containing microvesicles (MVs) released from tumor cells treated with PARP inhibitors, coupled with c-GAS de-repression induced by PI3K inhibition within macrophages. Interestingly, ex vivo exosome reconstitution studies revealed that DNAse treatment of the MVs completely abolished the STING activation response elicited within macrophages, thus demonstrating that the DNA fragments on the surface of exosomes drives STING pathway activation within macrophages. Strikingly, the combination of rucaparib/buparlisib with immune checkpoint blockade enhanced macrophage and T cell activation/infiltration, resulting in durable tumor clearance. Taken together, these results demonstrate that the DNA damage elicited by PARPi/PI3Ki can reprogram the myeloid tumor microenvironment (TME) to enhance anti-tumor immunity, resulting in effective tumor eradication in ICB-refractory cancers. Preliminary immune profiling of paired metastatic biopsies from a combination co-clinical trial in castrate-resistant prostate cancer patients, showed decreased immunosuppression and T cell activation within the TME following 4 weeks of treatment with rucaparib/nivolumab, thus supporting the preclinical data described above.
Citation Format: Priyanka Duttagupta, Kiranj Chaudagar, Sweta Sharma-Saha, Kaela Bynoe, Eileen Parkes, Akash Patnaik. PARP and PI3K inhibitor combination therapy eradicates c-MYC-driven murine prostate cancers via cGAS/STING pathway activation within tumor-associated macrophages [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-B03. doi:10.1158/1535-7163.TARG-19-LB-B03