Abstract
The Helicobacter pylori Neutrophil Activating Protein (HP-NAP) is endowed with immunomodulatory properties that make it a potential candidate for anticancer therapeutic applications. By activating cytotoxic Th1 responses, HP-NAP inhibits the growth of bladder cancer and enhances the anti-tumor activity of oncolytic viruses in the treatment of metastatic breast cancer and neuroendocrine tumors. The possibility that HP-NAP exerts its anti-tumor effect also by modulating the activity of innate immune cells has not yet been explored. Taking advantage of the zebrafish model, we examined the therapeutic efficacy of HP-NAP against metastatic human melanoma, limiting the observational window to 9 days post-fertilization, well before the maturation of the adaptive immunity. Human melanoma cells were xenotransplanted into zebrafish embryos and tracked in the presence or absence of HP-NAP. The behavior and phenotype of macrophages and the impact of their drug-induced depletion were analyzed exploiting macrophage-expressed transgenes. HP-NAP administration efficiently inhibited tumor growth and metastasis and this was accompanied by strong recruitment of macrophages with a pro-inflammatory profile at the tumor site. The depletion of macrophages almost completely abrogated the ability of HP-NAP to counteract tumor growth. Our findings highlight the pivotal role of activated macrophages in counteracting melanoma growth and support the notion that HP-NAP might become a new biological therapeutic agent for the treatment of metastatic melanomas.
Highlights
Melanoma is a cancer that develops from the uncontrolled proliferation of melanocytes, the pigment-producing cells
We demonstrated that Helicobacter pylori Neutrophil Activating Protein (HP-NAP) efficiently inhibits melanoma growth and metastasis, and we propose that macrophages play a pivotal role in this process
With the aim to assess the capacity of HP-NAP to affect melanoma growth, we took advantage of a xenograft model of human melanoma in zebrafish [16,17]
Summary
Melanoma is a cancer that develops from the uncontrolled proliferation of melanocytes, the pigment-producing cells. Surgery is no longer effective in treating metastatic melanoma and the long-term prognosis is dismal, despite combined immune checkpoint inhibitors with targeted therapy drugs (for cancers with BRAF gene changes) and/or with radiation are able to extend life expectancy by some years [3]. The tumor microenvironment is a complex system in which tumor cells dictate the profile of recruited immune cells. T regulatory cells, myeloid-derived suppressor cells (MDSC) and macrophages with a pro-tumoral profile populate the tumor stroma, and altogether may limit the antitumor immunity, contributing to the failure of the therapy [4,5]. Recruited macrophages with a pro-tumoral profile overwhelm proinflammatory macrophages in all stages of melanoma [6], and macrophage infiltration has been found to directly correlate with melanoma thickness and poor prognosis [7,8]
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