Abstract 967: Anti-tumor and immune effects of olaparib +/- anti-PD-L1 in preclinical BRCA1mut tumor models
Authors: Staniszewska Anna , Armenia Joshua , King Matthew , Michaloglou Chrysiis , Singh Maneesh , Martin Maryann San , Wilson Zena , Proia Theresa , Delpuech Oona , O'Connor Mark , Leo Elisabetta , Valge-Archer Viia 
Published: September 2020

Abstract
PARP inhibitor treatments are synthetically lethal with BRCA1/2 mutations and, in this setting, accumulation of DNA damage leads ultimately to cell death. Increases in DNA damage are also associated with increased levels of cytosolic DNA and consequently signalling through the cGAS-STING pathway, which can lead to increased inflammatory gene expression and Type I interferon response.
We sought to evaluate the benefit of combining the PARP inhibitor olaparib with immune checkpoint blockade (ICB) in a mouse syngeneic ovarian model, BR5, which lacks BRCA1. We show that olaparib combination with anti-PD-L1 prolonged duration of anti-tumor response vs. either monotherapy. The combination increased durable complete responses (CRs) with 6/10 animals tumor free at 77 days, compared with 1/9 and 2/9 tumor-free animals for olaparib and anti-PD-L1 monotherapies, respectively. Similar results were observed for combination of olaparib with anti-CTLA-4. Furthermore, mice treated with olaparib + ICB demonstrated immunological memory, with 100% of mice with CRs successfully rejecting tumor growth upon rechallenge with BR5. Olaparib treatment of human T cells in vitro and mouse T cells in vitro and in vivo did not show inhibition of T cell activation or proliferation. Moreover, olaparib treatment led to changes in tumor immune infiltrate in the BR5 tumors, including approximately 2-fold increased CD8 T cells and 1.5-fold increased NK cells relative to vehicle.
Differential gene expression analysis of olaparib or anti-PD-L1treated BR5 tumors revealed broad upregulation of immune pathways. Interestingly, type I IFN and STING pathways showed a more pronounced upregulation with Olaparib than with anti-PD-L1 treatment. Moreover, a dose-dependent upregulation of immune pathways, including JAK-STAT, STING and type I IFN was observed in a tumor cell-centric analysis from a BRCA1mut breast PDX model treated with olaparib. In contrast, no significant upregulation of STING or type I IFN pathways is observed in response to olaparib in a BRCAwt breast PDX model.
In vitro mechanistic studies demonstrated that co-culture of olaparib-treated human BRCA1mut MDA-MB-436 tumor cells with human dendritic cells (DC) resulted in an approximately 2-fold upregulation of CD86 expression on DCs. Comparison of isogenic DLD-1 tumor cells showed CD86 upregulation on DCs only following co-culture with olaparib-treated BRCA2-/- DLD-1 cells, but not wt DLD-1 cells. Similarly, increased PD-L1 expression was only observed in BRCA2-/- DLD-1 cells treated with olaparib and following co-culture with DC. These observations suggest a basis for increased immune priming following olaparib treatment of BRCAmut tumors, which can be consolidated with ICB, such as anti-PD-L1, treatment.
Citation Format: Anna Staniszewska, Joshua Armenia, Matthew King, Chrysiis Michaloglou, Maneesh Singh, Maryann San Martin, Zena Wilson, Theresa Proia, Oona Delpuech, Mark O'Connor, Elisabetta Leo, Viia Valge-Archer. Anti-tumor and immune effects of olaparib +/- anti-PD-L1 in preclinical BRCA1mut tumor models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 967.