Decreased melanoma CSF-1 secretion by Cannabigerol treatment reprograms regulatory myeloid cells and reduces tumor progression

ABSTRACT

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.

KEYWORDS:

• Tumor Microenvironment
• Regulatory Myeloid Cells
• CSF-1 (M-CSF)
• MDSC
• TAM
• Cannabis
• Cannabinoids
• CBG
• immune checkpoint inhibitors
• αPD-L1

Acknowledgments

The authors would like to thank Cannasoul Analytics and especially Dr Rotem Perry Feigenbaum for the isolation of the phytocannabinoid compounds; Ohad Guberman for the extraction and sample preparation of the Cannabis extracts; the Flow cytometry unit at the Technion Life Sciences and Engineering Infrastructure Center for the help with data analyses; and Yonathan Nissan at the Pre-Clinical Research Authority for help with the animal care. Diagrams were created with Biorender.

Author contributions

IW, HNK and DM, Conceptualization and design; IW, MS, AG, RR, YEM and LS, Acquisition of data; IW and HNK, Analysis and interpretation of data; IW and SP Figure preparation; IW, HNK, SP and DM Writing, review, and/or revision of the manuscript, HNK and DM, Study supervision.

Disclosure statement

D.M. is an active member of the scientific advisory board and co-founder of Cannasoul Analytics.

The rest of the authors have declared that no conflict of interest exists.

Data and materials availability

All data analyzed during this study are included in this published article and its supplementary information files. The datasets generated during the current study are available from the corresponding authors on reasonable request.

Consent for publication

All authors give their consent to publish this manuscript.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2219164

Additional information

Funding

This study was not supported by external funding.