The combined action of mast cell chymase, tryptase and carboxypeptidase A3 protects against melanoma colonization of the lung

Abstract

Mast cell secretory granules are densely packed with various bioactive mediators including proteases of chymase, tryptase and CPA3 type. Previous studies have indicated that mast cells can affect the outcome of melanoma but the contribution of the mast cell granule proteases to such effects has not been clear. Here we addressed this issue by assessing mice lacking either the chymase Mcpt4, the tryptase Mcpt6 or carboxypeptidase A3 (Cpa3), as well as mice simultaneously lacking all three proteases, in a model of melanoma dissemination from blood to the lung. Although mice with individual deficiency in the respective proteases did not differ significantly from wildtype mice in the extent of melanoma colonization, mice with multiple protease deficiency (Mcpt4/Mcpt6/Cpa3-deficient) exhibited a higher extent of melanoma colonization in lungs as compared to wildtype animals. This was supported by higher expression of melanoma-specific genes in lungs of Mcpt4/Mcpt6/CPA3-deficient vs. wildtype mice. Cytokine profiling showed that the levels of CXCL16, a chemokine with effects on T cell populations and NKT cells, were significantly lower in lungs of Mcpt4/Mcpt6/Cpa3-deficient animals vs. controls, suggesting that multiple mast cell protease deficiency might affect T cell or NKT cell populations. In line with this, we found that the Mcpt4/Mcpt6/Cpa3-deficiency was associated with a reduction in cells expressing CD1d, a MHC class 1-like molecule that is crucial for presenting antigen to invariant NKT (iNKT) cells. Together, these findings indicate a protective role of mast cell-specific proteases in melanoma dissemination, and suggest that this effect involves a CXCL16/CD1d/NKT cell axis.

Protective role of mouse mast cell tryptase Mcpt6 in melanoma

“…However, it is notable that our findings are in line with a previous study where we showed that the collective absence of all of the proteases expressed by connective tissue‐type MCs led to a higher colonization of lungs with melanoma cells following their i.v. administration (Grujic et al, ). Moreover, our findings are consistent with clinical evidence in support of a correlation between MC protease expression and protection against melanoma (Crincoli et al, ; Siiskonen et al, ; Stieglitz et al, ).…”

“…In that study, we found that MCs had an overall detrimental impact (Öhrvik et al, ) and to dissect the underlying mechanism we assessed mice lacking all of the MC proteases in the same model. Strikingly, we found that mice with global MC protease deficiency, contrary to the mice lacking MCs altogether, developed larger tumors than did WT mice (Grujic et al, ). This suggests that the combined action of the MC proteases serves a protective function in this model of melanoma, that is, despite the overall negative impact of MCs.…”

“…This suggests that the combined action of the MC proteases serves a protective function in this model of melanoma, that is, despite the overall negative impact of MCs. Further, the data indicated that the protective function of the MC proteases could be related to CXCL16/CD1d‐dependent effects on iNKT cell populations (Grujic et al, ).…”

Killer Immunoglobulin-Like Receptor 2DL4 (CD158d) Regulates Human Mast Cells both Positively and Negatively: Possible Roles in Pregnancy and Cancer Metastasis

“…Mast cells are a major source of histamine, and histamine was shown to inhibit tumor growth by promoting the development of monocyte-derived DCs [93]. The combined deficiency in mast cell chymase, tryptase, and carboxypeptidase A3 was associated with reduced invariant NKT cells and increased melanoma dissemination [94]. Contrary to these reports on suppressive roles of mast cells in tumor progression, there are reports on enhancing roles of mast cells.…”

“…Mast cells produce Th2 cytokines which contributes to M2 (pro-tumor) polarization of tumor-associated macrophages, and the cells produce TNF-α and IL-10 which promote the Treg-mediated immune tolerance and immune tolerance against tumors [4][5][6]. Mast cells produce TGF-β, CXCL8, and TNF-α, promoting epithelial-to-mesenchymal transition in tumor invasion and metastasis [94][95][96]. Mast-cell-produced histamine was shown to inhibit hypoxia inducible factor-1 alpha expression and the followed growth suppression in melanoma [97].…”