Cannabinoid Receptor Type-2 in B Cells Is Associated with Tumor Immunity in Melanoma

Simple Summary In this study we investigated the role of cannabinoid receptor 2 (CB2R) on immune cells in melanoma and found significantly improved overall survival in patients with high intra-tumoral CB2R gene expression. In human melanoma, CB2R is predominantly expressed in B cells, as shown using a previously published single-cell RNA sequencing (scRNA-seq) dataset and by performing RNAscope. In a murine melanoma model, tumor growth was enhanced in CB2R-deficient mice. In-depth analysis of tumor-infiltrating lymphocytes using scRNA-seq showed less differentiated B cells in CB2R-deficient tumors, favoring the induction of regulatory T cells (T-reg) and an immunosuppressive tumor microenvironment. Taken together, these data indicate a central role of CB2R on B cells in regulating tumor immunity. These results contribute to the understanding of the role of CB2R in tumor immunity and facilitate the development of new CB2R-targeted anti-cancer drugs. Agents targeting the endocannabinoid system (ECS) have gained attention as potential cancer treatments. Given recent evidence that cannabinoid receptor 2 (CB2R) regulates lymphocyte development and inflammation, we performed studies on CB2R in the immune response against melanoma. Analysis of The Cancer Genome Atlas (TCGA) data revealed a strong positive correlation between CB2R expression and survival, as well as B cell infiltration in human melanoma. In a murine melanoma model, CB2R expression reduced the growth of melanoma as well as the B cell frequencies in the tumor microenvironment (TME), compared to CB2R-deficient mice. In depth analysis of tumor-infiltrating B cells using single-cell RNA sequencing suggested a less differentiated phenotype in tumors from Cb2r(-/-) mice. Thus, in this study, we demonstrate for the first time a protective, B cell-mediated role of CB2R in melanoma. This gained insight might assist in the development of novel, CB2R-targeted cancer therapies.

Automated summary

The study highlights the critical role of CB2R in regulating tumor immunity in melanoma, with high CB2R gene expression associated with improved overall survival. Mouse models and in-depth analysis of tumor-infiltrating lymphocytes suggest that CB2R deficiency may lead to an immunosuppressive microenvironment by affecting B cell differentiation. This insight could potentially inform the development of novel CB2R-targeted cancer therapies.