Interleukin-17 signaling influences CD8 <sup>+</sup> T cell immunity and tumor progression according to the IL-17 receptor subunit expression pattern in cancer cells
Constanza Rodríguez, Cintia L. Araujo Furlan, Jimena Tosello, Sabrina Bossio, Santiago Boccardo, Laura Fozzatti, Fernando P. Canale, Cristian G. Beccaría, Nicolás Gonzalo Núñez, Danilo G. Ceschin, Eliane Piaggio, Adriana Gruppi, Carolina L. Montes, Eva V. Acosta Rodríguez
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.