Cancer cell autophagy, reprogrammed macrophages, and remodeled vasculature in glioblastoma triggers tumor immunity

• DOI: 10.1016/j.ccell.2022.08.014
• Publication Date: 2022-09-15T14:58:41Z
• Authors: Agnieszka Chryple...; Julie Scotton; Mélanie Tichet; Anoek Zomer; Ksenya Shchors; Johanna A. Joyce; Krisztian Homicsko; Douglas Hanahan
• Keywords: Vascular Endothelial Growth Factor A; Imipramine; randomized phase-3; enhance; Programmed Cell Death 1 Receptor; bevacizumab; Antidepressive Agents, Tricyclic; adjuvant temozolomide; Article; B7-H1 Antigen; Mice; Animals; Antidepressive Agents, Tricyclic/metabolism; Antidepressive Agents, Tricyclic/therapeutic use; Autophagy; B7-H1 Antigen/metabolism; Glioblastoma/pathology; Imipramine/metabolism; Imipramine/therapeutic use; Immune Checkpoint Inhibitors; Immunotherapy; Macrophages/metabolism; Mice; Neoplasm Recurrence, Local/drug therapy; Programmed Cell Death 1 Receptor; Tumor Microenvironment; Vascular Endothelial Growth Factor A/metabolism; VEGF inhibitors; anti-PD-L1 immune checkpoint blockade; glioblastoma immunotherapy; high endothelial venules; histamine receptor signaling; immunostimulatory autophagy; multi-targeted cancer therapy; remodeling tumor vasculature; reprogramming immunosuppressive macrophages; repurposing tricyclic antidepressants; Autophagy; Tumor Microenvironment; Animals; microenvironmental landscape; concomitant; Immune Checkpoint Inhibitors; t-cells; radiotherapy; Macrophages; trial; 3. Good health; immunotherapy; Immunotherapy; Neoplasm Recurrence, Local; Glioblastoma

Glioblastoma (GBM) is poorly responsive to therapy and invariably lethal. One conceivable strategy to circumvent this intractability is to co-target distinctive mechanistic components of the disease, aiming to concomitantly disrupt multiple capabilities required for tumor progression and therapeutic resistance. We assessed this concept by combining vascular endothelial growth factor (VEGF) pathway inhibitors that remodel the tumor vasculature with the tricyclic antidepressant imipramine, which enhances autophagy in GBM cancer cells and unexpectedly reprograms immunosuppressive tumor-associated macrophages via inhibition of histamine receptor signaling to become immunostimulatory. While neither drug is efficacious as monotherapy, the combination of imipramine with VEGF pathway inhibitors orchestrates the infiltration and activation of CD8 and CD4 T cells, producing significant therapeutic benefit in several GBM mouse models. Inclusion up front of immune-checkpoint blockade with anti-programmed death-ligand 1 (PD-L1) in eventually relapsing tumors markedly extends survival benefit. The results illustrate the potential of mechanism-guided therapeutic co-targeting of disparate biological vulnerabilities in the tumor microenvironment.