Highlights in Cancer Research: January 2023

Glioblastoma (GBM) is the most aggressive tumor in the central nervous system. Despite pronounced efforts to identify effective therapies, curative options for GBM do not exist, and the survival rate of diagnosed patients is low. In this paper, the authors took an approach of co-targeting and disrupting distinct features of the immunosuppressive glioma microenvironment, aiming to elicit a sustained therapeutic response. To do so they combined a tricyclic antidepressant (TCA) – imipramine – with a drug targeting VEGF-A ligand in mice bearing de novo GBM. While neither drug was efficacious as monotherapy, the combination of IM + anti-VEGF significantly delayed tumor growth. Investigation of the basis for the therapeutic efficacy revealed that the combo accentuated autophagy in cancer cells while modifying the angiogenic tumor vasculature with induction of high endothelial venules, known to facilitate the extravasation of T cells. Imipramine downregulated a pro-tumorigenic phenotype of tumor-associated macrophages via inhibiting histamine receptor, thereby reprogramming them to express chemokines attracting otherwise rare T cells, which demonstrably contributed functionally to the observed efficacy. As such, this co-targeting regimen reprograms GBM, rendering it immuno-stimulatory and provocatively sensitive to immune checkpoint blockade, as evidenced by sustained therapeutic responses when an anti-PD-L1 therapy was included in the mix.