Immunomodulatory function of cannabinoid receptor 2 and its agonist osteogenic growth peptide in health and cancer: a study in mice and humans

Colon carcinoma is among the most prevalent malignant tumors, with inflammation being the primary risk factor. Cannabinoid receptor 2 (CB2/CNR2) has complex immunomodulatory functions. Therefore, we investigated the role of osteogenic growth peptide (OGP), an endogenous selective CB2 agonist, in colon carcinogenesis and immune modulation in transgenic mice (Apc^Min/+).We injected 8-week-old (progression phase) or five-week-old (initiation phase) Apc^Min/+ mice with OGP or vehicle weekly for 8 weeks or 4 weeks, respectively. During the progression phase, OGP-treated mice displayed significantly fewer tumors in the large intestine and smaller tumors in the small intestine. During the initiation phase, OGP significantly attenuated adenomagenesis in both the small and large intestine, decreased IL-6 and IL-4 levels, increased splenic anti-tumor CD8+ T cells, and diminished populations of tumor-promoting myeloid-derived suppressor cells. Further, we used exomic analyses of UKBiobank patients to determine the relationship between CNR2 polymorphisms and tumor-associated myeloid cells in humans. We found that the common CNR2-Q63R polymorphism is associated with monocyte count. Our results suggest that CB2 activation via OGP attenuates tumorigenesis and adenoma growth by modulating immune cells, corroborated by a significant association between CNR2 polymorphisms and monocytopoiesis in humans. (Figure presented.)