Abstract
Immunotherapy has emerged as groundbreaking in cancer treatment showing improved overall survival of patients with advanced cancers. However, its application for diffuse midline glioma (DMG) is still challenging due to the non-inflammatory immune environment with lack of T lymphocyte infiltration, low mutation burden associated with low or absence of neo-antigen expression and suppressive immune microenvironment in DMG. Therefore, determination of novel factors that not only trigger the immune response but also evading the tumor immunosuppression is imperative. The cGAS-STING pathway was shown to elicit the maturation and activation of dendritic cells (DCs) in response to the release of double stranded DNA (dsDNA) from tumor cells leading to effective cytotoxic T-cell infiltration and activity. Here, we aimed to determine the effects of a small molecule PTC596 (BMI-1 modulator and tubulin biding molecule) in cGAS-STING pathway activation and induction of antitumor immunity. We have previously reported the single agent efficacy for PTC596 in controlling tumor growth and improving survival compared to vehicle-treated mice. Our preliminary results using PTC596, indicate the presence of multinucleated cells and the formation of micronuclei, colocalizing with cGAS and induction of STAT1 activation (marker of inflammation through type 1 IFN). We are currently evaluating purified DCs post-PTC596 treatment for the activation of the cGAS-STING pathway and interferon-stimulated genes (ISGs) and determining their cross-priming capacity. In vivo, using our established syngeneic orthotopic DIPG models, we are evaluating the T cell infiltration (CD3, CD4 and CD8), and characterizing the tumor microenvironment in response to PTC596. Data collected from the above experiments will be presented and discussed.