BackgroundHigh expression of CD155 (poliovirus receptor, PVR) is associated with a poor prognosis of lung adenocarcinoma (LUAD) and triple-negative breast cancer (TNBC) patients. When overexpressed, this molecule inhibits the antitumor function of NK and cytotoxic T cells through binding to its inhibitory co-receptors TIGIT and CD96, and downregulation of stimulatory CD226 (DNAM-1). However, the exact mechanism of CD155 overexpression on the tumor cells remains unclear. Here we demonstrate that interleukin-22 (IL-22), a cytokine known to promote cancer progression, induces upregulation of CD155 on tumor cells in mouse models of breast and lung cancer and may, thus, inhibit antitumor immunity and promote lung metastasis.Materials and MethodsTo study the influence of IL-22 on antitumor immunity, we utilize IL-22-deficient animals in syngeneic mouse models of metastatic breast and lung cancer. For this purpose, we generated tumor cells deficient in IL-22 receptor (IL-22R) or in CD155 and tumor cells, that constantly express CD155 independent of its natural regulation. Here, we determine the incidence of metastasis and antitumor NK and T cell responses in the lung, the primary site of metastasis.ResultsWe demonstrate that murine cancer cells upregulate CD155 surface expression upon treatment with recombinant IL-22, whereas this effect is abolished in the absence of IL-22R. Furthermore, IL-22-deficient animals have a lower metastatic burden in the lung and demonstrate a dramatic increase in IFN-γ production in NK, and, to a lower extent, cytotoxic T cells. Moreover, this effect is reversed when CD155 is expressed on the tumor cells independent of its natural regulation, which enables lung metastases in IL-22 deficient animals. Phenotypically, NK cells in IL-22 knockout mice have a higher expression of co-stimulatory receptor CD226, which is linked to the antitumor potential of these cells.ConclusionsHere we demonstrate a novel pathway of cytokine-mediated cancer progression, where IL-22 is capable of inducing CD155 on the tumor cells and, therefore, promotes an immunosuppressive tumor microenvironment. This highlights the potential of IL-22 as a target for immunotherapy considering the complexity of the CD155-dependent immunoregulatory network.Disclosure InformationD. Briukhovetska: None. J. Suarez-Gosalvez: None. M. Schübel: None. A. Markota: None. J. Jobst: None. J. Dörr: None. F. Märkl: None. M. Schwerdtfeger: None. A. Öner: None. M. Seifert: None. A. Gottschlich: None. S. Endres: None. S. Kobold: None.