During solid
tumor progression, the tumor microenvironment (TME) evolves into a highly immunosuppressive milieu. Key players in the immunosuppressive environment are regulatory myeloid cells, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), which are recruited and activated via
tumor-secreted
cytokines such as
colony-stimulating factor 1 (CSF-1). Therefore, the depletion of
tumor-secreted
cytokines is a leading anticancer strategy. Here, we found that
CSF-1 secretion by
melanoma cells is decreased following treatment with Cannabis extracts.
Cannabigerol (
CBG) was identified as the bioactive
cannabinoid responsible for the effects.
Conditioned media from cells treated with pure
CBG or the high-
CBG extract reduced the expansion and macrophage transition of the monocytic-MDSC subpopulation. Treated MO-MDSCs also expressed lower levels of iNOS, leading to restored CD8+ T-cell activation.
Tumor-bearing mice treated with
CBG presented reduced
tumor progression, lower TAM frequencies and reduced TAM/M1 ratio. A combination of
CBG and αPD-L1 was more effective in reducing
tumor progression, enhancing survival and increasing the infiltration of activated cytotoxic T-cells than each treatment separately. We show a novel mechanism for
CBG in modulating the TME and enhancing
immune checkpoint blockade therapy, underlining its promising therapeutic potential for the treatment of a variety of
tumors with elevated
CSF-1 expression.