Publication: T cell-derived interleukin-22 drives the expression of CD155 by cancer cells to suppress NK cell function and promote metastasis.
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Abstract
Although T cells can exert potent anti-tumor immunity, a subset of T helper (Th) cells producing interleukin-22 (IL-22) in breast and lung tumors is linked to dismal patient outcome. Here, we examined the mechanisms whereby these T cells contribute to disease. In murine models of lung and breast cancer, constitutional and T cell-specific deletion of Il22 reduced metastases without affecting primary tumor growth. Deletion of the IL-22 receptor on cancer cells decreases metastasis to a degree similar to that seen in IL-22-deficient mice. IL-22 induced high expression of CD155, which bound to the activating receptor CD226 on NK cells. Excessive activation led to decreased amounts of CD226 and functionally impaired NK cells, which elevated the metastatic burden. IL-22 signaling was also associated with CD155 expression in human datasets and with poor patient outcomes. Taken together, our findings reveal an immunosuppressive circuit activated by T cell-derived IL-22 that promotes lung metastasis.
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This study was supported by the international doctoral program i-Target: Immunotargeting of Cancer funded by the Elite Network of Bavaria (S.K. and S.E.); Melanoma Research Alliance grant 409510 (to S.K.); the MarieSklodowska-Curie Program Training Network for the Immunotherapy of Cancer funded by the H2020 Program of the European Union (grant 641549 to S.E. and S.K.); the Marie-Sklodowska-Curie Program Training Network for Optimizing Adoptive T Cell Therapy of Cancer funded by the H2020 Program of the European Union (grant 955575 to S.K.); the Else Kroner-Fresenius-Stiftung (to S.K.); the German Cancer Aid (to S.K.); the Wilhelm Sander-Stiftung (to S.K.); the Ernst-Jung-Stiftung (to S.K.); LMU Excellent within the framework of the German Excellence Initiative (to S.E. and S.K.); Bundesministerium fur Bildung und Forschung (to S.E. and S.K.); the Go-Bio-initiative (to S.K.); the m4 award of the Bavarian Ministry of Economic Affairs (to S.E. and S.K.); the European Research Council grant 756017, ARMOR-T (to S.K.); the ERC proof-of-concept grant 101100460 (to S.K.); the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG, KO5055-2-1 and 510821390 to S.K. and H.J.A as AN372/30-1); the SFB-TRR 338/1 2021-452881907 (to S.K.); the SFB/TRR 205 associated project C11 (S.K. and D.B.); the Hector Foundation (to S.K.); the Fritz Bender Foundation and the Deutsche Jose Carreras Leukamie-Stiftung (to S.K.); The Einheit fur Klinische Pharmakologie (EKLIP), Helmholtz Zentrum Munchen, Neuherberg, Germany (to S.R. and S.E.); DFG (391217598) and SFB/TR-237-B14 (404450088 to S.R.); and the InCa Research Award by Novartis (to D.B.). T.B. is funded by DFG under Germany's Excellence Strategy - EXC2151-390873048. S.H. was supported in part by the European Research Council (CoG 865466). S.H. has an endowed Heisenberg-Professorship awarded by DFG. A.D.G. was supported by Else Kroner Memorial Stipendium and the Jung Foundation for Science and Research (Ernst Jung Career Development Award 2022).
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Immunity . 2023 Jan 10;56(1):143-161