CD4+ T cell-derived IL-22 enhances liver metastasis by promoting angiogenesis

TAO ZHANG ; RAMEZ WAHIB ; DIMITRA E ZAZARA 3; JÖRAN LÜCKE ; AHMAD MUSTAFA SHIRI ; JAN KEMPSKI ; LILAN ZHAO ; THEODORA AGALIOTI ; ANDRES PABLO MACHICOTE; OLYMPIA GIANNOU; IOANNIS BELIOS ; RONGRONG JIA ; SIWEN ZHANG ; JOSEPH TINTELNOT ; HANNES SEESE; JULIA KRISTIN GRASS; BARIS MERCANOGLU ; LOUISA STERN ; PASQUALE SCOGNAMIGLIO; MOHAMMAD FARD-AGHAIE ; PHILIPP SEEGER ; JONAS WAKKER; MARIUS KEMPER ; BENJAMIN BRUNSWIG; ANNA DUPRÉE ; PANAGIS M LYKOUDIS ; ANASTASIA PIKOULI ; EMMANOUIL GIORGAKIS ; PABLO STRINGA ; NATALIA LAUSADA ; MARIA VIRGINIA GENTILINI ; GABRIEL E GONDOLESI ; KAI BACHMANN ; PHILIPP BUSCH ; RAINER GROTELÜSCHEN ; IOANNIS C MAROULIS ; PETRA C ARCK; RYOSUKE NAKANO ; ANGUS W THOMSON; TARIK GHADBAN ; MICHAEL TACHEZY ; NATHANIEL MELLING; EIKE-GERT ACHILLES ; VICTOR G PUELLES ; FELIX NICKEL ; THILO HACKERT ; OLIVER MANN; JAKOB R IZBICKI; JUN LI ; ,NICOLA GAGLIANI; SAMUEL HUBER; ANASTASIOS D GIANNOU

OncoImmunology

Taylor and Francis Ltd.

Año: 2023 vol. 12

Metastasis is a cancer-related systemic disease and is responsible for the greatest mortality rate among cancer patients. Interestingly, the interaction between the immune system and cancer cells seems to play a key role in metastasis formation in the target organ. However, this complex network is only partially understood. We previously found that IL-22 produced by tissue resident iNKT17 cells promotes cancer cell extravasation, the early step of metastasis. Based on these data, we aimed here to decipher the role of IL-22 in the last step of metastasis formation. We found that IL-22 levels were increased in established metastatic sites in both human and mouse. We also found that Th22 cells were the key source of IL-22 in established metastasis sites, and that deletion of IL-22 in CD4+ T cells was protective in liver metastasis formation. Accordingly, the administration of a murine IL-22 neutralizing antibody in the establishment of metastasis formation significantly reduced the metastatic burden in a mouse model. Mechanistically, IL-22-producing Th22 cells promoted angiogenesis in established metastasis sites. In conclusion, our findings highlight that IL-22 is equally as important in contributing to metastasis formation at late metastatic stages, and thus, identify it as a novel therapeutic target in established metastasis.