Mast Cell Specific Cyp11a1 Deficiency Promotes T Cell Mediated Immunity and Suppresses Tumour Metastasis in a Mouse Model of Melanoma

Abstract

Mast cells are emerging players in malignant conditions, but the underlying molecular mechanisms remain poorly defined. Based on previous studies showing that steroids can impact on tumour progression in various settings, we here investigated whether mast cell-derived steroid synthesis can have an impact on tumour metastasis in a melanoma model. To this end, we used mice with mast cell-specific ablation of Cyp11a1, a key enzyme in steroid synthesis. We show that lung colonization of melanoma nodules was markedly diminished in mice with mast cell-specific ablation of Cyp11a1, accompanied by reduced infiltration of mast cells into the lungs. Cyp11a1 gene expression was significantly decreased in lungs of mice with mast cell-specific ablation of Cyp11a1, indicating that mast cells account for a substantial fraction of the total Cyp11a1 expression. Our results also revealed that the mast cell-specific deletion of Cyp11a1 led to an overall increase in CD107a/LAMP1 staining intensity of the lung tissue, suggesting that mast cell-derived steroids can suppress immune cell activation and degranulation. A further dissection of this finding by flow cytometry analysis of individual immune cell populations revealed that CD8+ T cells, NK cells and basophils were activated to a higher extent in lungs from mice with mast cell-specific Cyp11a1 ablation. We also demonstrate that both CD8+ and CD4+ T cells in lungs of mice with mast cell-specific deletion of Cyp11a1 expressed elevated levels of IFN-{gamma} in comparison with controls. Altogether, these findings introduce a hitherto unrecognized role of a mast cell-derived steroid axis in regulating tumour metastasis.