Progression of Glioblastoma Is Impaired by VEGF Inhibition and Imipramine

Current treatments for glioblastoma (GBM) do not lead to sustained clinical benefit, but combination therapies that cotarget distinct tumor-promoting pathways have been proposed to overcome this issue. Previous studies have indicated that the repurposing of the tricyclic antidepressant imipramine (IM) in glioma can elevate autophagy levels leading to an autophagy-dependent survival advantage, indicating that combining IM with other drugs may be beneficial. As the VEGF inhibitor bevacizumab has already been approved for use in GBM, Chryplewicz and colleagues sought to determine if dual IM and VEGF pathway inhibitor treatment in a newly engineered mouse model of GBM (the HrasV12 shp53 lentivirus-based model) that is comparable to human GBM could show therapeutic efficacy. Minimal effects were observed after use of VEGF inhibitor monotherapy, but addition of IM led to delayed tumor growth, reduced tumor burden, and improved survival. Consistent with previous studies suggesting that autophagy in tumors can be immunogenic, IM plus anti-VEGF therapy induced a robust accumulation of CD8⁺ and CD4⁺ T cells in tumors that could be inhibited by blocking autophagy. Conversely, therapeutic responses were not observed in immunodeficient mice, indicating the role of the adaptive immune system in mediating this phenotype. Characterization of these CD8⁺ and CD4⁺ T cells revealed an increase in activation markers, especially IFNγ, which, when blocked, reversed therapeutic efficacy of the combination therapy. Furthermore, IM treatment, as well as the combination treatment, reprogrammed tumor-associated macrophages (TAM), leading to the downregulation of the M2-like (protumorigenic) program through a mechanism involving inhibition of the histamine receptor HRH1. Upregulation of the CD8⁺ T-cell chemoattractants CXCL9 and CXCL10, which are predominantly expressed by TAMs, was also observed after combination treatment, and blocking of their receptor, CXCR3, reduced efficacy of the combination treatment as well as impaired both CD8⁺ and CD4⁺ T-cell proliferation. Additionally, as resistance occurs with this combination, relapsing tumors were observed to have high PD-L1 expression, and addition of PD-L1 blockade to this combination strategy improved CD8⁺ T-cell abundance and overall survival. In conclusion, this study provides a potential cotargeting strategy for GBM and provides preclinical support for testing this combination strategy in a proof-of-concept clinical trial for GBM.

Chryplewicz A, Scotton J, Tichet M, Zomer A, Shchors K, Joyce JA, et al. Cancer cell autophagy, reprogrammed macrophages, and remodeled vasculature in glioblastoma triggers tumor immunity. Cancer Cell 2022 Sep 15 [Epub ahead of print].

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