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

ABSTRACT

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.

KEYWORDS:

• IL-22
• liver metastasis
• Th22

Acknowledgments

The authors thank Cathleen Haueis, Sandra Wende and Tom Blankenburg for technical assistance, the in vivo Optical Imaging Core Facility, the UKE Microscopy Imaging Facility and the FACS Core Sorting Unit at the University Medical Center Hamburg-Eppendorf for their technical assistance.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

T.Z., R.W. conceived, designed and carried out most experiments, analyzed data, and wrote the paper; D.E.Z., JÖ.L., A.M.S., J.K., L.Z., T.A., A.P.M., I.B., R.J., J.T., P.S., SW.Z. carried out in vivo experiments, immunofluorescence and flow cytometry assays; O.G. carried out statistical analysis and provided critical intellectual input and edited the paper H.S., J.K.G., B.M., L.S., M.F.A., P.S., J.W., M.K., B.B., A.D., K.B., P.B., R.G., T.G., M.T., N.M:, E.G.A., F.N, T.H, O.M., J.R.I., J.L. provided the human liver metastasis specimens, provided critical intellectual input and edited the paper; P.M.L., A.P., E.G., P.S., N.L., M.V.G, G.E.G, I.C.M, P.C.A, R.N., V.G.P and A.W.T. provided critical intellectual input and edited the paper; N.G. designed experiments, provided critical intellectual input and edited the paper; S.H. and A.D.G conceived the idea and supervised the study, designed and carried out experiments, analyzed the data, and wrote the paper. All authors reviewed and concur with the submitted manuscript.

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2269634

Additional information

Funding

This work was supported in part by the Deutsche Forschungsgemeinschaft (grant SFB841 to S.H., N.G., grant SFB1328 to S.H., N.G. and grant 50,552–1), the European Research Council (CoG 865,466 to S.H. and StG 756,017 to S.K.), European Respiratory Society/short term fellowship (to A.D.G), Else Kröner Memorial Stipendium (to A.D.G), Werner Otto Stiftung (to A.D.G), Erich und Gertrud Roggenbuck Stiftung (to A.D.G), Hamburger Krebsgesellschaft Stiftung (to A.D.G), the Jung Foundation for Science and Research (Ernst Jung Career Development Award 2022) (to A.D.G). the China Scholarship Council (to T.Z.). S.H. has an endowed Heisenberg-Professorship awarded by the Deutsche Forschungsgemeinschaft.