2. Academic Validation
  3. Cancer cell autophagy, reprogrammed macrophages, and remodeled vasculature in glioblastoma triggers tumor immunity

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

  • Cancer Cell. 2022 Oct 10;40(10):1111-1127.e9. doi: 10.1016/j.ccell.2022.08.014.
Agnieszka Chryplewicz 1,  Julie Scotton 2,  Mélanie Tichet 3,  Anoek Zomer 4,  Ksenya Shchors 2,  Johanna A Joyce 5,  Krisztian Homicsko 5,  Douglas Hanahan 6
Affiliations

Affiliations

  • 1 Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland; Agora Translational Cancer Research Center, Lausanne, Switzerland.
  • 2 Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
  • 3 Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland; Agora Translational Cancer Research Center, Lausanne, Switzerland; Lausanne Branch, Ludwig Institute for Cancer Research, Lausanne, Switzerland.
  • 4 Agora Translational Cancer Research Center, Lausanne, Switzerland; Lausanne Branch, Ludwig Institute for Cancer Research, Lausanne, Switzerland.
  • 5 Agora Translational Cancer Research Center, Lausanne, Switzerland; Lausanne Branch, Ludwig Institute for Cancer Research, Lausanne, Switzerland; Department of Oncology, University of Lausanne, Lausanne, Switzerland; Swiss Cancer Center Leman (SCCL), Lausanne/Geneva, Switzerland.
  • 6 Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland; Agora Translational Cancer Research Center, Lausanne, Switzerland; Lausanne Branch, Ludwig Institute for Cancer Research, Lausanne, Switzerland; Swiss Cancer Center Leman (SCCL), Lausanne/Geneva, Switzerland. Electronic address: [email protected].
PMID: 36113478 DOI: 10.1016/j.ccell.2022.08.014
Abstract

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.

Keywords

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.

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