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- W4308406943 abstract "<h3>Background</h3> The endocannabinoid system is widely expressed in the human body, including the innate and adaptive immune system, where endocannabinoids, Δ9-tetrahydrocannabinol and synthetic ligands regulate immune response. The effects of endocannabinoids on immune regulation are primarily mediated by G-protein coupled cannabinoid CB<sub>2</sub> receptors (CB<sub>2</sub>R) via several mechanisms, including development, migration, proliferation and effector functions. The upregulated expression of CB<sub>2</sub>R and elevated levels of endocannabinoids have been observed in a variety of tumor microenvironments and are associated with the aggressiveness of cancer. <h3>Methods</h3> Membranes prepared from CHO-K1 cells stably expressing human CB<sub>2</sub>R were used for receptor binding assays in the presence of TT-816 and [3H]CP-55,940, and for GTPγS binding assay in the presence of TT-816, 10 μM GDP and 0.3 nM [35S]GTPγS. cAMP assay was performed by incubating the CHO-K-1 cells for 30 min with TT-816, 25 μM forskolin and 12 nM CP-55,940, or with TT-816 and 5 μM forskolin. NK cell function was determined by co-culturing TT-816 pretreated NK cells with K562 cancer cells for 24 hours. The mixed lymphocyte reaction assay was conducted by co-culturing human CD4+ T cells with monocyte-derived dendritic cells. Cell viability was measured by FACS and IFN-γ by MSD. <h3>Results</h3> TT-816 is a competitive and selective CB<sub>2</sub>R antagonist. It bound to human CB<sub>2</sub>R with an IC50 26.2 nM, showing greater than 380-fold selectivity over cannabinoid CB<sub>1</sub> receptors. The ability of TT-816 to inhibit the constitutive activity of CB<sub>2</sub>R was characterized in both GTPγS and cAMP assays. TT-816 concentration-dependently inhibited the basal GTPγS binding response, antagonized CB<sub>2</sub>R agonist-mediated cAMP production and enhanced the forskolin response on basal cAMP level. Consistent with its inhibition of CB<sub>2</sub>R function, TT-816 inhibited the growth of human breast, colorectal and lung cancer cells. In addition, TT-816 concentration-dependently enhanced the functions of NK cells, dendritic cells and T cells. It increased NK cell killing of the human cancer cells and IFN-γ production, significantly stimulated the expression of CD86, HLA-DR, IL-12 and TNF-a in monocyte-derived dendritic cells, and enhanced CD4+ T cell proliferation and IFN-γ production in a mixed lymphocyte reaction assay. <h3>Conclusions</h3> TT-816 is a novel, oral small molecule immune checkpoint inhibitor that selectively blocks CB<sub>2</sub>R on cancer cells and immune cells. Preclinical data have demonstrated that it stimulates antitumor innate and adaptive immune response and inhibits cancer cell proliferation. TT-816 is currently undergoing phase 1 clinical trials for the treatment of a broad range of solid tumors." @default.
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- W4308406943 date "2022-11-01" @default.
- W4308406943 modified "2023-09-25" @default.
- W4308406943 title "960 TT-816, a novel small molecule immune checkpoint inhibitor targeting cannabinoid CB<sub>2</sub>receptor, stimulates innate and adaptive immunity for cancer therapy" @default.
- W4308406943 doi "https://doi.org/10.1136/jitc-2022-sitc2022.0960" @default.
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