The anti-inflammatory cytokine IL-37 improves the NK cell-mediated anti-tumor response

ABSTRACT

IL-37 is a member of the IL-1 superfamily exerting anti-inflammatory functions in a number of diseases. Extracellular IL-37 triggers the inhibitory receptor IL-1R8 that is known to regulate different NK cell pathways and functional activities including their anti-tumor effect. However, the effect of IL-37 on human NK cell functions is still to be unveiled. This study aimed to investigate the functional effect of IL-37 in human NK cells activated with IL-15. We found that IL-37 enhanced both NK cell cytotoxic activity against different tumor cell lines and cytokines production. These effects were associated with increased phosphorylation of ERK and NF-Kb. The improved NK cell activity was also strictly related to a time-dependent GSK3β-mediated degradation of IL-1R8. The enhanced activation profile of IL-37 treated NK cells possibly due to IL-1R8 degradation was confirmed by the results with IL-1R8-silenced NK cells. Lastly, in line with these data, through the analysis of the TNM plot database of a large group of patients, IL-37 mRNA expression was found to be significantly lower in colon and skin cancers than in normal tissues. Colon adenocarcinoma and neuroblastoma patients with higher IL-37 mRNA levels had significantly higher overall survival, suggesting that the presence of IL-37 might be considered an independent positive prognostic factor for this tumor. Our results provide novel information on the mechanisms regulating IL-1R8 function in human NK cells, highlighting the IL-37-IL-1R8 axis as a potential new target to improve the anti-tumor immune response.

KEYWORDS:

• Cancer
• IL-1R8
• IL-37
• immunotherapy
• natural killer cells

Acknowledgments

This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (project no. 5 × 10002018 Id 21147, project no. IG 2017 Id 19920 to LM and project n IG2022 Id 27065 to PV). The project leading to these results has received funding from AIRC and from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 800924NL. FRM is supported by Fondazione Umberto Veronesi. This work was supported also by the Italian Ministry of Health with “Current research funds” Ministero della Salute (grant no. RC-2020 OPBG to LM and EM) and Ministero della Salute‐Ricerca 5 × 10002023 to FRM and with grant RF GR-2018-12365485 to AP.

Authors’ contributions

Designed experiments NL, FRM EM; Performed the experiments NL, FRM, AP, VD, CA, TI; Analyzed the data NL, FRM, NL, AP, CA, VD; TI; Interpreted the results EM, NL, FRM, AP; Wrote and edited the manuscript NL, FRM, EM; Provided intellectual input and critically revised the manuscript LM, PV, EM. All authors read and approved the final manuscript.

Disclosure statement

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

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2297504.

Additional information

Funding

The work was supported by the Associazione Italiana per la Ricerca sul Cancro (project no. 5 × 10002018 Id 21147, project no. IG 2017 Id 19920 to LM and project n IG2022 Id 27065 to PV) and by the Italian Ministry of Health with “Current research funds” Ministero della Salute (grant no. RC-2020 OPBG to LM and EM) and Ministero della Salute‐Ricerca 5 × 10002023 to FRM and with grant RF GR-2018-12365485 to AP.