In many types of cancer, presence of eosinophils in tumors correlate with an improved disease outcome. In line with this, activated eosinophils have been shown to reduce tumor growth in colorectal cancer (CRC). Interleukin (IL)-33 has recently emerged as a cytokine that is able to inhibit the development of tumors through eosinophils and other cells of the tumor microenvironment thereby positively influencing disease progress. Here, we asked whether eosinophils are involved in the effects of IL-33 on tumor growth in CRC. In models of CT26 cell engraftment and colitis-associated CRC, tumor growth was reduced after IL-33 treatment. The growth reduction was absent in eosinophil-deficient ΔdblGATA-1 mice but was restored by adoptive transfer of ex vivo-activated eosinophils indicating that the antitumor effect of IL-33 depends on the presence of eosinophils. In vitro, IL-33 increased the expression of markers of activation and homing in eosinophils, such as CD11b and Siglec-F, and the degranulation markers CD63 and CD107a. Increased expression of Siglec-F, CD11b and CD107a was also seen in vivo in eosinophils after IL-33 treatment. Viability and cytotoxic potential of eosinophils and their migration properties toward CCL24 were enhanced indicating direct effects of IL-33 on eosinophils. IL-33 treatment led to increased levels of IL-5 and CCL24 in tumors. Our data show that the presence of eosinophils is mandatory for IL-33-induced tumor reduction in models of CRC and that the mechanisms include eosinophil recruitment, activation and degranulation. Our findings also emphasize the potential use of IL-33 as an adjuvants in CRC immunotherapy.
Monoacylglycerol lipase (MGL) expressed in cancer cells influences cancer pathogenesis but the role of MGL in the tumor microenvironment (TME) is less known. Using a syngeneic tumor model with KP cells (Kras LSL-G12D /p53 fl/fl ; from mouse lung adenocarcinoma), we investigated whether TME-expressed MGL plays a role in tumor growth of non-small cell lung cancer (NSCLC). In sections of human and experimental NSCLC, MGL was found in tumor cells and various cells of the TME including macrophages and stromal cells. Mice treated with the MGL inhibitor JZL184 as well as MGL knock-out (KO) mice exhibited a lower tumor burden than the controls. The reduction in tumor growth was accompanied by an increased number of CD8 + T cells and eosinophils. Naïve CD8 + T cells showed a shift toward more effector cells in MGL KOs and an increased expression of granzyme-B and interferon-γ, indicative of enhanced tumoricidal activity. 2-arachidonoyl glycerol (2-AG) was increased in tumors of MGL KO mice, and dose-dependently induced differentiation and migration of CD8 + T cells as well as migration and activation of eosinophils in vitro . Our results suggest that next to cancer cell-derived MGL, TME cells expressing MGL are responsible for maintaining a pro-tumorigenic environment in tumors of NSCLC.
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.
Myeloperoxidase (MPO) is a heme peroxidase that is mainly expressed and secreted by neutrophils. The role of MPO in inflammatory diseases has been highlighted in recent years, but its role in tumor development remains unclear. Therefore, we investigated the role of MPO in non-small cell lung cancer (NSCLC). In silico analysis revealed a survival benefit in patients with NSCLC and low MPO expression. Furthermore, a syngeneic tumor model using MPO knockout (KO) mice revealed that mice lacking MPO had lower tumor growth than controls. The reduction in tumor size was accompanied by an increase in lymphoid populations, including natural killer cells and CD8+ T cells, suggesting a shift to a more anti-tumorigenic immune environment in MPO-KO mouse tumors. The T cell induced interferon-gamma (IFN-γ) expression was increased in MPO- KO tumors, indicating increased tumoricidal activity. CD8 depletion abolished the previously observed reduction in tumor size in MPO-KO mice, indicating that CD8+ T cells play an important role. In vitro, T cells treated with MPO showed reduced proliferation and IFN-γ expression. Furthermore, MPO could be internalized into T cells. Heparin pretreatment of T cells blocked MPO binding and internalization into T cells and reversed MPO-induced proliferation reduction. Interestingly, MPO+ lymphocytes were found in tumor samples from patients with NSCLC. Our findings suggest that MPO plays an immunosuppressive role in NSCLC.
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