Regulation of tumor antigen presentation by urocanic acid

Urocanic acid (UCA) accumulates in the epidermis after deamination of histidine. UCA isomerizes from the trans to the cis form upon exposure to environmental UV radiation. Cis-UCA is immunosuppressive in several models. Topically applied cis-UCA was reported to enhance the cutaneous tumor yield in chronically UV-irradiated mice, suggesting involvement of cis-UCA in photocarcinogenesis. Since Langerhans cells (LC) are capable of presenting tumor-associated Ags (TAA) for primary and secondary tumor-immune responses, we examined the effects of trans- and cis-UCA on LC tumor Ag presentation in a model of immunity to the S1509a spindle cell tumor (H-2a). In this system, induction of immunity requires exposure of LC to granulocyte-macrophage CSF. Naive CAF1 (H-2(a/d)) mice were immunized against S1509a by injection with granulocyte-macrophage CSF-exposed and TAA-pulsed epidermal cells (EC), as assessed by growth inhibition of inoculated tumor cells. Incubation of EC in cis-, but not trans-UCA completely inhibited Ag presentation in this system. Neither histamine antagonists nor indomethacin reversed these effects of cis-UCA. The ability of trans- and cis-UCA to modulate EC presentation of TAA for secondary immune responses was also examined. EC were pulsed with TAA in vitro and then injected into hind footpads of tumor-immune mice. After 24 h, footpad swelling was assessed as a measure of delayed-type hypersensitivity. Incubation with cis-, but again not trans-UCA before TAA exposure significantly inhibited elicitation of delayed-type hypersensitivity. These data indicate that cis-UCA may be an important regulator of LC Ag-presenting function in tumor-immune responses, and thus may play a role in photocarcinogenesis.