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

Abstract

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.

Endocannabinoid System and Tumour Microenvironment: New Intertwined Connections for Anticancer Approaches

“…In particular, CB2R is predominantly expressed in B cells and responsible for their differentiation. The impairment of CB2R expression led to less differentiated B cells, favouring the induction of regulatory T cells (Treg) and the generation of an immunosuppressive microenvironment in Cnr2 −/− mice [ 249 ].…”

Rationalizing a prospective coupling effect of cannabinoids with the current pharmacotherapy for melanoma treatment

“…Recently, significant interest from multidisciplinary research groups worldwide has emerged, trying to utilize nonconventional remedies such as cannabinoids to treat melanoma (Carpi et al, 2017; Gruber et al, 2021; Milanez et al, 2021; Simmerman et al, 2019). Cannabinoids have been shown to manipulate various cell signaling responses that influence an immunogenic tumor's microenvironment.…”

Understanding Cellular, Molecular, and Functional Specificity, Heterogeneity, and Diversity of the Endocannabinoid System

“…The second example is regarding the involvement of cannabinoid receptor type-1 (CB1R/Cnr1) and type-2 (CB2R/Cnr2) in nonalcoholic fatty liver disease (NAFLD) [ 10 ] and melanoma [ 11 ]. Although the deletion of Cnr1 (CB1R KO mice) was hypothesized to prevent the development of NAFLD, scRNA-seq and UMAP analysis did not support the hypothesis and pointed out that Cnr1−/− mice failed to protect the liver from fibrosis.…”