283 TIM-3 blockade modulates the tumor microenvironment improving the outcome of preclinical pediatric diffuse midline glioma models

Background Diffuse Midline Gliomas (DMGs), encompassing Intrinsic Pontine (DIPGs), are the most aggressive pediatric brain tumors. Their meager survival has not changed despite combination of radiotherapy with targeted therapies emphasizing urgent need for effective treatments. Recent research suggested that DIPG tumor microenvironment is neither highly immunosuppressive nor inflammatory. 1 These analyses showed lack infiltrating lymphocytes and abundance CD11b+ cells. TIM-3 a member T-cell immunoglobulin mucin domain protein family expressed on multiple immune cell types, including T cells, Treg, NK monocytes, dendritic microglia, where it potently regulates only adaptive immunity but also innate immunity. 2–3 Therefore, inhibitors could challenge several components in microenvironment, thereby providing potentially treatment DMGs. Methods NP53 XFM murine lines were used animal experiments immunocompetent orthotopic models. The tumors processed by mechanical enzymatic digestion populations analyzed flow cytometry panel. Antibodies against cells (NK1.1), CD4 (GK1.5), CD8 (CD8β) depletion alone or combination. Results In silico assessment expression datasets robust this gene. Moreover, single-cell sequencing biopsies uncover its myeloid compartment (especially microglia). vivo efficacy studies anti-TIM-3 antibody significantly increased overall two models (doubling median), lead to long-term survivors free disease (50%) memory. Analyses CD45+ significant increase granulocytes, CD8+ corresponding activate phenotypes treated-mice. addition, we have substantial decrease Treg population, which causes an CD8/Treg ratio. led total loss efficacy. reduced effectiveness therapy, albeit lesser extent than CD4-CD8 depletion. We currently investigating role microglia outcome treatment. Conclusions Our data uncovered as potential target Inhibition molecule potent antitumor effect mediated profound remodelling. References Lieberman NAP, DeGolier K, Kovar HM, et al . Characterization diffuse intrinsic pontine glioma: implications development immunotherapy. Neuro Oncol 2019; 21 (1):83–94. doi:10.1093/neuonc/noy145. Acharya N, Sabatos-Peyton C, Anderson AC. Tim-3 finds place cancer immunotherapy landscape. J Immunother Cancer 2020; 8 (1):e000911. doi:10.1136/jitc-2020-000911. Wolf Y, AC, Kuchroo VK. TIM3 comes age inhibitory receptor. Nat Rev Immunol 20 (3):173–185. doi:10.1038/s41577-019-0224-6