The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.
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1. Cancer cell autophagy, reprogrammed macrophages, and remodeled vasculature in glioblastoma triggers tumor immunity
Chryplewicz, A. et al. Cancer Cell. 40(10):1111-1127. (2022).
doi: 10.1016/j.ccell.2022.08.014.
Summary of the findings
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.
A combination of tricyclic antidepressants (TCA) and anti-VEGF treatment increases autophagic flux, reprogrammes tumour-associated macrophages and remodels vascular in glioblastoma rendering the tumour susceptible to immunotherapy such as anti-PD-L1 therapy.
Future impact
This investigation has revealed a provocative new therapeutic approach involving clinically approved drugs that unleashed a potent anti-tumoral immune response in a tumor type that is otherwise refractory to immune intervention. Given the transient response and the dismal prognosis of GBM patients on standard-of-care therapies, these findings motivate consideration of proof-of-concept clinical trials aimed to evaluate the translational potential of TCAs combined with VEGF pathway inhibitors and immune checkpoint blockade. Notably, this study has motivated the Mark Foundation to support a clinical trial in GBM patients progressing on first-line treatment.
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The Cancer Researcher is an online magazine for the cancer research community from the European Association for Cancer Research.
The EACR, a registered charity, is a global community for those working and studying in cancer research. Our mission is “The advancement of cancer research for the public benefit: from basic research to prevention, treatment and care.”
