Interleukin-17 signaling influences CD8⁺ T cell immunity and tumor progression according to the IL-17 receptor subunit expression pattern in cancer cells

ABSTRACT

IL-17 immune responses in cancer are controversial, with both tumor-promoting and tumor-repressing effects observed. To clarify the role of IL-17 signaling in cancer progression, we used syngeneic tumor models from different tissue origins. We found that deficiencies in host IL-17RA or IL-17A/F expression had varying effects on the in vivo growth of different solid tumors including melanoma, sarcoma, lymphoma, and leukemia. In each tumor type, the absence of IL-17 led to changes in the expression of mediators associated with inflammation and metastasis in the tumor microenvironment. Furthermore, IL-17 signaling deficiencies in the hosts resulted in decreased anti-tumor CD8⁺ T cell immunity and caused tumor-specific changes in several lymphoid cell populations. Our findings were associated with distinct patterns of IL-17A/F cytokine and receptor subunit expression in the injected tumor cell lines. These patterns affected tumor cell responsiveness to IL-17 and downstream intracellular signaling, leading to divergent effects on cancer progression. Additionally, we identified IL-17RC as a critical determinant of the IL-17-mediated response in tumor cells and a potential biomarker for IL-17 signaling effects in tumor progression. Our study offers insight into the molecular mechanisms underlying IL-17 activities in cancer and lays the groundwork for developing personalized immunotherapies.

KEYWORDS:

• Angiogenesis
• CD8+ lymphocytes
• IL-17RC
• inflammation
• interleukin 17 (IL-17)
• tumor immunology

Acknowledgments

We thank the staff from Cytometry Core, Animal, Cell culture, and Molecular biology facilities from CIBICI-CONICET at Facultad de Ciencias Quimicas, UNC. We would also like to acknowledge Thomas Gajewski, Mercedes Fuertes, and Ximena Raffo for providing the cell lines and protocols for cell culture. Finally, we would like to thank Editage (www.editage.com) for English language editing.

Disclosure statement

E.P. is co-founder of Egle-Tx. E.P. and J.T. are consultants for Egle-Tx. Other authors report there are no competing interests to declare. This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number R01AI169482.

Author contributions

CR designed and performed most of the experiments, analyzed data, and wrote the manuscript. CLAF, JTB, SNB, SB, FPC, and CGB performed experiments and commented on the manuscript. JTB performed and participated in the analysis of the RNAseq experiment. DGC analyzed RNAseq data and commented on the manuscript. NGN participated in TCGA data analysis. LF participated in western blot and proteome array experiments. EP provided funding for RNAseq and commented on the manuscript. CLM and AG provided intellectual contributions and commented on the manuscript. EVAR supervised the research, designed the experiments, wrote the manuscript, and provided funding.

CR, SB, and SNB thank CONICET for the fellowship awarded. LF, DGC, CM, AG, and EVAR are members of the Scientific career of CONICET. EP and JT are supported by the LabEx DCBIOL (ANR-10-IDEX-0001-02 PSL; ANR-11-LABX-0043); SIRIC INCa-DGOS-Inserm 1255; and Center of Clinical Investigation (CIC IGR-Curie 1428).

Data availability statement

The datasets generated for this study can be found in the NIH repository under accession number PRJNA855854 (https://www.ncbi.nlm.nih.gov/search/all/?term=PRJNA855854).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2261326

Additional information

Funding

This work was supported by Agencia Nacional de la Investigación, el Desarrollo Tecnológico y la Innovación under grants [PICT 2018-01791 and PICT 2020-0487], Secretaría de Ciencia y Técnica-Universidad Nacional de Córdoba under grant [33620180100594CB] and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number [R01AI169482]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.