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.
Highlights
Mast cells (MCs) are hematopoietic cells that are present as resident populations in virtually all tissues of the body, with preponderance at sites close to the exterior such as skin and mucosal surfaces of the lung and gut [1]
We found that the Mcpt4/Mcpt6/carboxypeptidase A3 (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 cells
Our data suggest that the enhanced melanoma colonization seen in Mcpt4/Mcpt6/Cpa3-deficient animals is associated with a defective CXCL16/CD1d/invariant NKT (iNKT) cell axis
Summary
Mast cells (MCs) are hematopoietic cells that are present as resident populations in virtually all tissues of the body, with preponderance at sites close to the exterior such as skin and mucosal surfaces of the lung and gut [1]. The MC-restricted proteases encompass tryptases, chymases and carboxypeptidase A3 (CPA3), of which the former two are serine proteases whereas CPA3 is a Zn-containing metalloprotease [3,4,5] These proteases are all stored in enzymatically active form and when MCs are activated to degranulate, e.g. by IgE receptor crosslinking [6] or by engagement of the MRGPRX2/MRGPRB2 receptor [7], large amounts of these proteases are released to the cell exterior and can exert massive proteolytic action in the tissue [3, 4]. We show that melanoma colonization of the lungs is enhanced in animals with simultaneous absence of chymase, tryptase and CPA3, suggesting a protective role of the MC-restricted proteases. Our data suggest that the enhanced melanoma colonization seen in Mcpt4/Mcpt6/Cpa3-deficient animals is associated with a defective CXCL16/CD1d/iNKT cell axis
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