Cannabinoid receptor 2 plays a pro-tumorigenic role in non-small cell lung cancer by limiting anti-tumor activity of CD8+ T and NK cells

Abstract

Cannabinoid (CB) receptors (CB₁ and CB₂) 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 CB₁ and CB₂ receptors in a model of non-small cell lung cancer (NSCLC). Leukocytes in the TME of mouse and human NSCLC express CB receptors, with CB₂ showing higher expression than CB₁. In the tumor model, using CB₁- (CB₁ ^-/-) and CB₂-knockout (CB₂ ^-/-) mice, only deficiency of CB₂, but not of CB₁, 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. CB₂ ^-/- mice responded significantly better to anti-PD-1 therapy than WT mice. The treatment further increased infiltration of cytotoxic lymphocytes into the TME of CB₂ ^-/- mice. Our findings demonstrate that TME-derived CB₂ dictates the immune cell recruitment into tumors and the responsiveness to anti-PD-1 therapy in a model of NSCLC. CB₂ could serve as an adjuvant target for immunotherapy.

Keywords: CB1; CB2; CD8+ T cells; NK cells; cannabinoid receptors; immunotherapy; non-small cell lung cancer; tumor microenvironment.