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Background: The G protein-coupled receptor 55 (GPR55) is part of an expanded endocannabinoid system (ECS), and plays a pro-tumorigenic role in different cancer models, including pancreatic cancer. Next to cancer cells, various cells of the immune tumor microenvironment (TME) express receptors of the ECS that critically determine tumor growth. The role of GPR55 in cancer cells has been widely described, but its role in the immune TME is not well understood. Methods: We intended to uncover the role of GPR55 in tumor immunity in a model of pancreatic ductal adenocarcinoma (PDAC). To this end, a KPCY tumor cell line or a GPR55-overexpressing KPCY cell line (KPCY55) from murine PDAC were subcutaneously injected into wildtype (WT) and GPR55 knockout (KO) mice, and immune cell populations were evaluated by flow cytometry. Results: Deficiency of GPR55 in the TME led to reduced tumor weight and volume, and altered the immune cell composition of tumors, favoring an anti-tumorigenic environment by increasing the number of CD3+ T cells, particularly CD8+ T cells, and the expression of PDL1 on macrophages. RNA-seq pathway analysis revealed higher T cell activity in KPCY55 tumors of GPR55 KO vs. WT mice. In addition, tumors from GPR55 KO mice displayed increased levels of T cell chemokines Cxcl9 and Cxcl10. Migration of T cells from GPR55 KO mice towards CXCL9 was increased in comparison to T cells from WT mice, suggesting that a CXCR3/CXCL9 axis was involved in T cell influx into tumors of GPR55 KO mice. Notably, anti-PD-1 immunotherapy increased tumor burden in WT mice, while this effect was absent in the GPR55 KO mice. Conclusion: Our study indicates that GPR55 in TME cells may drive tumor growth by suppressing T cell functions, such as migration, in a model of PDAC, making it an interesting target for immunotherapies. [ABSTRACT FROM AUTHOR]

Cannabinoid (CB) receptors (CB 1 and CB 2 ) are expressed on cancer cells and their expression influences carcinogenesis in various tumor entities. Cells of the tumor microenvironment (TME) also express CB receptors, however, their role in tumor development is still unclear. We, therefore, investigated the role of TME-derived CB 1 and CB 2 receptors in a model of non-small cell lung cancer (NSCLC). Leukocytes in the TME of mouse and human NSCLC express CB receptors, with CB 2 showing higher expression than CB 1 . In the tumor model, using CB 1 - (CB 1 -/- ) and CB 2 -knockout (CB 2 -/- ) mice, only deficiency of CB 2 , but not of CB 1 , resulted in reduction of tumor burden vs. wild type (WT) littermates. This was accompanied by increased accumulation and tumoricidal activity of CD8 + T and natural killer cells, as well as increased expression of programmed death-1 (PD-1) and its ligand on lymphoid and myeloid cells, respectively. CB 2 -/- mice responded significantly better to anti-PD-1 therapy than WT mice. The treatment further increased infiltration of cytotoxic lymphocytes into the TME of CB 2 -/- mice. Our findings demonstrate that TME-derived CB 2 dictates the immune cell recruitment into tumors and the responsiveness to anti-PD-1 therapy in a model of NSCLC. CB 2 could serve as an adjuvant target for immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sarsembayeva, Kienzl, Gruden, Ristic, Maitz, Valadez-Cosmes, Santiso, Hasenoehrl, Brcic, Lindenmann, Kargl and Schicho.)