Abstract 1606: Potentiating effect of olaparib on anti-PD-1 treatment in colorectal cancer
Authors: Bhavsar Chintal , John Peter , Abreu Magnolia , Bencosme Laura , Maitra Radhashree , Goel Sanjay , Augustine Titto 
Published: July 2021

Abstract
Immune checkpoint inhibitors (ICIs) are approved for microsatellite unstable colorectal cancer (CRC), however, microsatellite stable (MSS) CRC that make up the majority of tumors in clinical practice have not seen any benefit with ICI. This is in part due to the lack of sufficient tumor infiltrating immune cells, particularly CD8+ T cells, in the milieu. Immunogenic cell death (ICD) is a particular form of cell death that elicits robust cross-priming of CD8 T cells against antigens expressed by dying cells in the absence of exogenous adjuvants. ICD-inducing drugs such as poly (ADP-ribose) polymerase inhibitors (PARPis) are poised to enhance cancer cell killing, boost tumor immunogenicity, increase in vivo immune infiltration, and thereby accelerate a tumor response to ICI treatment.
Here, we tested the combinatorial therapeutic efficacy of a PARPi, olaparib (OLA), and an ICI, anti-PD-1, in in vitro and in vivo conditions. Combined treatment of OLA and anti-mouse PD-1 reduced tumor growth and increased survival in an immunocompetent, syngeneic animal model of BALB/c carrying allograft CT26 tumor that is MSS. Flow cytometry analysis revealed that the combo treatment significantly reduced percentages of anti-inflammatory macrophages and increased inflammatory monocytes. There was no significant difference in dendritic cell populations. We observed increased anti-tumor lymphocyte response via activation of CD4 and CD8 T cell populations upon combo treatment with OLA and anti-mouse PD-1. In addition, we noticed an increased association of expression of PD-L1 and its receptor PD-1 with OLA treatment in CRC cell lines and CT26 tumors. Our preliminary data suggests altered expressions of the CD8+ T cell exhaustion marker TIM-3 and its ligands galectin-9 and high mobility group protein 1 (HMGB1), an indicator of ICD. The pilot studies also revealed increased levels of STING-dependent type I interferon signaling initiator cGAS upon treatment with OLA in vivo. Mechanistically, OLA might induce DNA damage among tumor cells and trigger innate immune signaling including NF-κB activation and STING-dependent type I interferon signaling, both of which contribute to the maturation of myeloid antigen-presenting cells and subsequent activation of T cells.
In conclusion, OLA potentiated the antitumor efficacy of anti-PD-1 in CT26 induced syngeneic CRC mouse model. Our findings indicate that OLA might trigger tumor immunogenicity, and enable a potential targeted-immunotherapeutic angle for exercising ICD and activating cytotoxic T lymphocytes in CT26 syngeneic CRC mouse model; however, further studies are needed to elucidate the mechanism. Despite ICD markers' identification as immuno-stimulating characteristics of dead cells, whether ICD-associated molecules can be used as a prognostic biomarker or therapeutic target, and the rational for such markers on tumor cells in eliciting antitumor immunity are still under investigation.
Citation Format: Chintal Bhavsar, Peter John, Magnolia Abreu, Laura Bencosme, Radhashree Maitra, Sanjay Goel, Titto Augustine. Potentiating effect of olaparib on anti-PD-1 treatment in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1606.