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TGF-beta and CSF-1 as mediators of GALR2-induced immunosuppression in Head and Neck Cancer (HNC)

Abstract

Modulation of the immune system by head and neck cancer (HNC) is critically relevant for tumor progression, prognosis and response to treatment. Interfering with tumor-meditated immune modulation and/or rescuing anti-tumor immune competency are actively studied as promising therapeutic approaches. Macrophages are the most prevalent immune cell type in HNC and increased infiltration of macrophages is associated with worse prognosis. Our research group has shown that HNC cell-secreted products suppress immune cells in vitro, which may not only favor tumor evasion but also subvert the immune response to enhance tumor invasion. Studies from the collaborator in this proposal demonstrate that Galanin receptor 2 (GALR2) is an oncogene in HNC, as it is associated with increased cancer cell proliferation, survival and invasion; however the immune-related influences of increased GALR2 expression by cancer cells are largely unknown. Increased expression of GALR2 in cancer cells influences the expression of immune-relevant mediators, such as COX-2, VEGF and IL-6. These changes in the cancer cell-secreted products can affect the phenotype of macrophages in the tumor microenvironment, favoring progression and invasion. Transforming growth factor (TGF)-beta and Colony stimulating factor (CSF)-1 are two cancer-derived mediators that are associated with worse prognosis of epithelial cancers and that also affect macrophages directly, enhancing the M2-like phenotype associated with more aggressive tumors. In this proposal we will dissect the intersection between GALR2 expression and regulation of TGF-beta and CSF-1 in HNC cells and the effects of these mediators on macrophages, specifically looking into changes in the macrophage phenotype and tumor growth and invasion in vitro and vivo. The central hypothesis is that GALR2 activity in HNC cells increases expression of TGF-beta and CSF-1, which influences the phenotype of macrophages favoring HNC growth and invasion. (AU)

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