Abstract
Abstract Ultraviolet B (UVB)-irradiation to human or mouse skin generates Platelet-activating factor (PAF) and novel oxidatively-modified glycerophosphocholines (Ox-GPCs) with PAF-receptor (PAF-R) agonistic activity. These lipids mediate systemic immunosuppression in a process involving IL-10. The current studies sought to determine the functional significance of UVB-mediated systemic immunosuppression in an established model of murine melanoma progression. As our studies demonstrated that B16F10 tumors do not express functional PAF-Rs, retroviral-mediated transduction of the PAF-R was used to create PAF-R-positive B16F10 melanoma tumor cells. We show that UVB irradiation augments B16F10 tumor growth and is dependent on host, but not melanoma cell, PAF-R-expression as UVB or the PAF-R agonist, carbamoyl- PAF (CPAF), both promote B16F10 tumor growth in wild-type mice, independent of whether B16F10 cells express PAF-Rs, but do not augment tumor growth in PAF-R deficient (Pafr -/-) mice. Systemic antioxidant treatment ameliorated UVB-mediated augmentation of tumor growth, indicating involvement of Ox-GPC PAF-R agonists produced non-enzymatically. Host immune cells are required as CPAF-induced augmentation of tumor growth is not seen in immunodeficient NOD SCID mice. Finally, depleting antibodies against IL-10 in WT mice, or depletion of CD25-positive cells (suggestive of FoxP3 directed regulatory T cells) in FoxP3EGFP transgenic mice block UVB/CPAF-induced tumor growth, supporting a requirement for IL-10 and regulatory T cells (Tregs) in this process. These findings indicate that UVB-generated Ox-GPCs with PAF-R agonistic activity enhance experimental murine melanoma tumor growth through targeting host immune cells, most notably Tregs, to mediate systemic immunosuppression. These studies describe a previously unrecognized mechanism by which melanoma tumor cells can escape antitumor immunity. Inasmuch as other pro-oxidative stressors could potentially generate PAF-R agonists, this pathway could have clinical relevance in terms of devising better strategy for melanoma immunotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1548. doi:1538-7445.AM2012-1548
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