Myeloid Cell-Derived Thrombospondin-1 Mediates Anti-Metastatic Effects of Histamine Dihydrochloride in B16 Melanoma

Introduction: Histamine dihydrochloride (HDC) has been shown to reduce metastatic spread of tumors by modulating myeloid cells, including immunosuppressive monocytes. Thrombospondin-1 (TSP-1), a matricellular glycoprotein present in the pre-metastatic niche, has also been implicated in limiting tumor metastasis. Microarray analyses have identified THBS1 , encoding TSP-1, as an HDC-induced gene in human myeloid cells. This study investigated the mechanisms underlying HDC-induced TSP-1 expression and assessed whether TSP-1 contributes to the anti-metastatic effects of HDC in melanoma progression. Methods: TSP-1 expression and secretion were analyzed in human and murine myeloid cell subsets following HDC stimulation. Patient datasets were used to assess the clinical relevance of THBS1 expression in melanoma tissue. The functional significance of TSP-1 for HDC-mediated metastasis control was investigated in the B16F10 melanoma model of hematogenous lung metastasis in wild-type and TSP-1 knockout (KO) mice. Results: HDC robustly induced TSP-1 expression and secretion across multiple myeloid cell populations, including human and murine myeloid-derived suppressor cells. This effect was mediated via histamine type-2 receptors (H 2 Rs) and downstream cAMP-PKA signaling. Analysis of human melanoma datasets revealed reduced THBS1 expression in tumor tissue and an association between high THBS1 expression and improved overall survival. In addition, THBS1 expression correlated with the histamine synthesis gene histidine decarboxylase in human melanoma samples. In vivo, systemic HDC treatment increased lung TSP-1 levels and reduced pulmonary metastasis in wild-type but not in TSP-1 KO mice. Discussion: We identify TSP-1 as a downstream effector of HDC in myeloid cells and show that its induction is mediated by H 2 R-dependent cAMP-PKA signaling. The association between THBS1 expression and favorable survival in human melanoma supports a protective role for TSP-1. These findings suggest a previously unrecognized myeloid-cell mediated mechanism of HDC with potential relevance for metastasis control. The diagram illustrates the effect of histamine on myeloid cells and its impact on metastatic burden in the lungs. On the left, a myeloid cell is shown with histamine interacting with the histamine type 2 receptor, leading to activation of AC, cAMP and PKA, which subsequently increases THBS1 production. This process results in the release of TSP-1. On the right, two scenarios are depicted: ’No histamine’ shows lungs with a higher metastatic burden, while ’Histamine’ shows lungs with a reduced metastatic burden. The diagram highlights the role of histamine in reducing metastatic burden through its action on myeloid cells.Diagram of histamine’s effect on myeloid cells and metastatic burden in lungs.