The environmental stressor ultraviolet B radiation inhibits murine antitumor immunity through its ability to generate platelet-activating factor agonists

Abstract

Ubiquitous pro-oxidative stressor ultraviolet B radiation (UVB) 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. 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 (WT) mice, independent of whether B16F10 cells express PAF-Rs, but do not augment tumor growth in Pafr -/- mice. UVB-mediated augmentation of experimental murine tumor growth was inhibited with antioxidants, demonstrating the importance of Ox-GPC PAF-R agonists produced non-enzymatically. Host immune cells are required as CPAF-induced augmentation of tumor growth which is not seen in immunodeficient NOD SCID mice. Finally, depleting antibodies against IL-10 in WT mice or depletion of CD25-positive cells in FoxP3(EGFP) transgenic mice block UVB and/or CPAF-induced tumor growth supporting a requirement for IL-10 and 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.

Systemic Platelet-activating Factor Receptor Activation Augments Experimental Lung Tumor Growth and Metastasis

“…As shown in Figure 1, exogenous administration of CPAF augments the growth of subcutaneously implanted LLC1 tumors in WT but not in PAFR-KO mice, which indicates that this effect is mediated via the host PAF-R. These results are consistent with our previous reports demonstrating that UVB/CPAF augments the growth of murine B16F10 tumors in a PAF-R-dependent manner 19. These studies also indicate that PAF-R agonist-mediated systemic immunosuppression is not specific in augmenting the growth of experimental melanoma tumors; however, it can also affect the growth of lung cancer.…”

“…Functional PAF-R in LLC1 cells was accessed by intracellular Ca 2+ mobilization assay as described previously 19,20. In brief, LLC1 tumor cells, grown at optimum condition, were loaded with the Ca 2+ - sensitive fura-2-AM dye (4 μM in Hanks’ balanced salt solution [HBSS]) at 37°C for 90 min.…”

Topical Application of a Platelet Activating Factor Receptor Agonist Suppresses Phorbol Ester-Induced Acute and Chronic Inflammation and Has Cancer Chemopreventive Activity in Mouse Skin

“…Similarly, our studies have shown that PAF-induced immunosuppression promotes the growth of syngeneic tumors in mice [19]. Thus, the ability of topical CPAF to suppress chemical carcinogenesis in mice would run counter to previous thoughts regarding the role of PAF in tumorigenesis.…”

Platelets in the immune response: Revisiting platelet-activating factor in anaphylaxis

“…9,105,106 PAF and PAFR agonists are generated after exposure to oxidative stress and inhibit the antitumor immune response. 107 In an animal model of lung cancer, administration of PAFR agonists led to increased tumor growth and lung metastasis. 106 In a recent animal study the oxidative stress of traditional chemotherapy promoted PAF production and subsequent treatment failure, suggesting a role for PAF signaling in treatment outcomes.…”