Abstract 703: The anti-cancer drug BPM 31510 elicits immune-modulatory effects through regulation of IL-10

Abstract

Abstract Mitochondria have emerged as important immune-regulatory organelles, supporting biosynthetic and bioenergetic needs of immune cells and controlling cytokine production. BPM31510 is a clinical stage, nanodispersion of the mitochondrial electron transfer molecule ubidecarenone (CoQ10). Given that cytokine secretion orchestrates immune cell effector function in the tumor microenvironment and importance of mitochondria in this process, the ability of BPM31510 to modulate cytokine secretion was investigated. An ex vivo model using phytohemagglutinin-activated healthy donor peripheral blood mononuclear cells (PBMCs) treated with increasing concentrations of BPM31510 was used to assess cytokine secretion profiles. Analysis of supernatants by multi-analyte ELISA platform revealed effector cytokines IL-2 and IFN-γ to be dose-dependently increased with BPM31510 treatment while IL-10, a key immune-regulatory cytokine, was decreased. Analysis of monocyte depleted PBMCs compared to monocytes alone demonstrated that the observed changes in IL-2 and IFN-γ secretion occur only when both lymphocytes and monocytes are present; however, monocytes alone were identified as the significant source for IL-10. To define the mechanism of BPM31510-induced IL-10 attenuation, two monocytic lineage models were employed in vitro, LPS-stimulated THP-1 monocytes and PMA-differentiated U937 macrophages. Similar to monocytes isolated from PBMCs, treatment of LPS-stimulated THP-1 monocytes with increasing doses of BPM 31510, resulted in a decrease in IL-10 secretion as did treatment of U937 macrophages. The contribution of canonical IL-10 regulatory pathways, ERK, PI3K and STAT3, was assessed by co-treating U937 macrophages with BPM31510 and inhibitors of these pathways (U0126, Wortmannin, and Stattic, respectively). Co-treatment resulted in a further decrease in IL-10 secretion than any inhibitor treatment alone, suggesting that regulation of IL-10 secretion by BPM31510 is not exclusively through canonical signaling pathways. Nevertheless, further investigation into the activation status of these pathways revealed a decrease in STAT3 phosphorylation with BPM31510 treatment, but not of ERK or Akt. Consistent with decreased STAT3 activation, levels of IL-10 transcript, a STAT3 target gene, were also decreased in these samples, indicating that BPM31510 partially regulates IL-10 secretion via inhibition of the STAT3 signaling cascade. Taken together, these data demonstrate BPM31510 attenuates IL-10 secretion from the monocytic lineage through both canonical and non-canonical IL-10 regulatory pathways; this may have important implications for macrophage-mediated immunosuppression and immune cell crosstalk in the tumor microenvironment more broadly upon treatment with BPM31510. Citation Format: Louisa Dowal, Maria D. Nastke, Nidhi Gaur, Richa Singh, Samantha Fowler, Shyamali Jayashankar, Anne R. Diers, Stephane Gesta, Vivek Vishnudas, Niven R. Narain, Rangaprasad Sarangarajan. The anti-cancer drug BPM 31510 elicits immune-modulatory effects through regulation of IL-10 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 703.