Abstract B40: Co-targeting autophagy, macrophages and vasculature in glioma tumors triggers tumor immunity

Abstract Glioblastoma (GBM) is the most common primary tumor arising in the central nervous system (CNS). The currently approved standard of care has transient clinical benefit as GBM tends to be exceedingly aggressive. Despite pronounced efforts to identify novel therapies, curative options for GBM do not exist, and the survival rate of diagnosed patients is very low. Therefore, there is an urgent need for new treatment strategies. One approach would be to co-target and thereby disrupt distinct hallmarks of cancer, aiming to elicit sustained therapeutic responses. We have assessed this concept by combining a tricyclic antidepressant -imipramine - with drugs targeting VEGF-A ligand or VEGF-Receptor in mice bearing de novo GBM. All monotherapies were ineffective. In notable contradistinction, we found that combinatorial regimens significantly increased survival benefit and regressed established tumors. Investigation of the basis for the therapeutic efficacy revealed that combining the VEGF pathway inhibitor with imipramine accentuated autophagy while modifying the angiogenic tumor vasculature to be more normal-like with induction of high endothelial venules. In addition, imipramine downregulated an M2-like phenotype of tumor-associated macrophages via histamine receptor and reprogramed them to express chemokines attracting otherwise rare CD8 T cells, which demonstrably contributed to the observed efficacy. As such, these hallmark co-targeting combinations reprogram the GBM microenvironment from immunosuppressive to pro-inflammatory, thereby rendering it immunogenic and sensitizing the tumors to immune checkpoint blockade, as evidenced by enhanced responses when an anti-PD-L1 therapy was included in the mix. The results to be presented will elaborate on a provocative new therapeutic approach for glioblastoma that has the prospect of motivating clinical evaluation in this daunting form of human cancer. Citation Format: Agnieszka Chryplewicz, Julie Scotton, Mélanie Tichet, Douglas Hanahan. Co-targeting autophagy, macrophages and vasculature in glioma tumors triggers tumor immunity [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B40.