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

The takeaway

In a mouse glioblastoma model, blocking the CB2 cannabinoid receptor with AM630 reduced tumor growth and improved survival to 50% by shifting the immune response from suppressive macrophages to cancer-killing T cells.

Neuro-oncology researchers studying glioblastoma immunotherapy; scientists investigating the endocannabinoid system in cancer immunology.

50% survival at day 40 vs 0% in controls at day 28

What the researchers found

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.

Why it matters

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.

The numbers in context

AM630-treated mice: 50% survival at day 40. Control median survival: 28 days. CB2 agonist median survival: 21 days. Spleen monocytes/macrophages decreased 83%. CD8+ T cells increased 1.8-fold. CD4+ T cells increased 1.6-fold. Higher perforin and granzyme B in CD8+ cells.

How the study worked

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.

What this study cannot tell us

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.

How to read the evidence

Preclinical mouse model with bioinformatics support from human databases. Compelling but needs human validation.

When this study was published

2024 study

The bigger picture

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.

Questions still open

Would CB2 blockade enhance the effectiveness of immune checkpoint inhibitors in glioblastoma? Do endocannabinoid levels in patient tumors predict immunotherapy resistance?

Common questions

Does this mean cannabis causes brain cancer to grow?

The study focused on the endocannabinoid system, which the body produces naturally regardless of cannabis use. Whether external cannabis use affects glioblastoma progression through CB2 receptors is a separate question not addressed here.

What are tumor-associated macrophages?

Immune cells that tumors recruit and reprogram to suppress anti-cancer immunity. Instead of fighting the tumor, they help it hide from T cells that would otherwise attack it.

Read the original research

Endocannabinoid Receptor 2 Function is Associated with Tumor-Associated Macrophage Accumulation and Increases in T Cell Number to Initiate a Potent Antitumor Response in a Syngeneic Murine Model of Glioblastoma.

Cannabis and cannabinoid research, 9(6), 1524-1536

View on PubMed ↗Publisher’s paper ↗

Citation

Duan, Jin; Chen, Jieling; Lin, Yilin; Lin, Stanley L; Wu, Jie. (2024). Endocannabinoid Receptor 2 Function is Associated with Tumor-Associated Macrophage Accumulation and Increases in T Cell Number to Initiate a Potent Antitumor Response in a Syngeneic Murine Model of Glioblastoma.. Cannabis and cannabinoid research, 9(6), 1524-1536. https://doi.org/10.1089/can.2024.0063