Anti-melanoma immunity promoted by cutaneous genetic immunizations requires agonistic signaling via the nerokinin-1 receptor (131.6)

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Abstract In spite of initial enthusiasm provided by melanoma immunizations, the incidence of melanoma has increased in the past decade. To improve current melanoma vaccines is imperative that we understand the mechanisms involved in effective immunity to self-melanocyte Ags. The pro-inflammatory and immune functions of the skin are ideal for administration of cancer vaccines able to bias anti-tumor type-1 immunity. Pro-inflammatory neuropeptides that signal via the neurokinin-1 receptor (NK1R) expressed in skin cells, promote CD4+Th1 and CD8+Tc1 immunity to foreign Ag. Here, we analyzed the effects of signaling the NK1R during a skin genetic vaccination for melanoma. We utilized the gene gun to deliver plasmid DNA encoding murine TRP-2 with or without the NK1R agonist [Sar9Met O2)11]-SP (SarSP) to C57BL/6 mice. The need of the NK1R for anti-melanoma immunity was addressed by administration of our vaccine to NK1R-/- mice. GG immunizations in the presence of SarSP promoted TRP-2 immunity including short term-effector-, central- and effector- memory Th1 and CTLs resulting in the prevention of melanoma growth and long term survival of mice. Administration of TRP-2 vaccines to NK1R-/- mice showed an impaired ability to initiate anti-TRP-2 immunity. Our results shed light on the mechanisms involved in induction of self-Ag specific immune responses capable of overcoming tumor growth, and provide the foundation for the development of an effective melanoma vaccine.