Blocking the CB2 cannabinoid receptor triggered a strong anti-tumor immune response against brain cancer in mice

CB2 receptor antagonist AM630 induced a potent antitumor response in glioblastoma-bearing mice, with 50% survival at day 40 when all control mice (median survival 28 days) and CB2 agonist-treated mice (median survival 21 days) had died. AM630 caused an 83% decrease in spleen monocytes/macrophages and 1.8- and 1.6-fold increases in CD8+ and CD4+ T cells respectively, with corresponding changes in the tumor microenvironment.

Bioinformatics analysis of human glioblastoma databases plus in vivo mouse model using luciferase-expressing GL261 glioblastoma cells with CB2 receptor agonist (GW405833) or antagonist (AM630) treatment. Immune cell populations assessed by FACS and immunocytochemistry.

Glioblastoma is among the deadliest cancers partly because it suppresses the immune system. This study reveals that the endocannabinoid system plays a key role in that immunosuppression and identifies CB2 receptor blockade as a potential way to unleash immune attack against the tumor.

If endocannabinoid signaling through CB2 receptors helps glioblastomas evade the immune system, CB2 antagonists could potentially be combined with existing immunotherapies to improve outcomes for a cancer type where immune checkpoint therapy has largely failed.

Mouse model with a single glioblastoma cell line. CB2 antagonist AM630 may have off-target effects. Human glioblastoma is more heterogeneous than mouse models. Survival follow-up was limited to 40 days.