T cell-derived interleukin-22 drives the expression of CD155 by cancer cells to suppress NK cell function and promote metastasis

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 can...

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Published in:	Immunity (Cambridge, Mass.) Vol. 56; no. 1; pp. 143 - 161.e11
Main Authors:	Briukhovetska, Daria, Suarez-Gosalvez, Javier, Voigt, Cornelia, Markota, Anamarija, Giannou, Anastasios D., Schübel, Maryam, Jobst, Jakob, Zhang, Tao, Dörr, Janina, Märkl, Florian, Majed, Lina, Müller, Philipp Jie, May, Peter, Gottschlich, Adrian, Tokarew, Nicholas, Lücke, Jöran, Oner, Arman, Schwerdtfeger, Melanie, Andreu-Sanz, David, Grünmeier, Ruth, Seifert, Matthias, Michaelides, Stefanos, Hristov, Michael, König, Lars M., Cadilha, Bruno Loureiro, Mikhaylov, Oleg, Anders, Hans-Joachim, Rothenfusser, Simon, Flavell, Richard A., Cerezo-Wallis, Daniela, Tejedo, Cristina, Soengas, María S., Bald, Tobias, Huber, Samuel, Endres, Stefan, Kobold, Sebastian
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 10-01-2023 Cell Press
Subjects:	Animals Antigens, Differentiation, T-Lymphocyte - metabolism breast carcinoma CD155 CD226 Humans Interleukin-22 Interleukins - genetics Interleukins - metabolism Killer Cells, Natural - metabolism lung adenocarcinoma metastasis Mice Neoplasms - metabolism NK cells poliovirus receptor Protein Binding PVR Receptors, Virus T helper T-Lymphocytes, Helper-Inducer - metabolism NK cells poliovirus receptor metastasis breast carcinoma lung adenocarcinoma CD226 interleukin-22 PVR T helper CD155
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Summary:	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. [Display omitted] •IL-22 from Th cells acts on IL-22RA1+ tumor cells to promote lung metastases•Mechanistically, IL-22 induces overexpression of CD155 on tumor cells•Excessive CD155 promotes internalization of CD226 in NK cells, rendering them inert•IL-22-CD155 signature governs early-stage lung and breast cancer patients’ survival Metastatic disease is the terminal and most lethal stage of cancer. Briukhovetska et al. find that interleukin-22 produced by Th cells increases the expression of CD155 in cancer cells, which in turn abrogates NK cell function by promoting the internalization of the activating receptor CD226. This axis promotes an immunosuppressive niche that enables lung metastases.
Bibliography:	These authors contributed equally Lead contact
ISSN:	1074-7613 1097-4180
DOI:	10.1016/j.immuni.2022.12.010