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

Rodriguez, C.; Araujo Furlan, C. L.; Tosello Boari, J.; Bossio, S. N.; Boccardo, S.; Fozzatti, L.; Canale, F. P.; Beccaria, C. G.; Nunez, N. G.; Ceschin, D. G.; Piaggio, E.; Gruppi, A.; Montes, C. L.; Acosta Rodriguez, E. V.

doi:10.1101/2022.12.16.520754

bioRxiv · 10.1101/2022.12.16.520754

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

Rodriguez, C.·Araujo Furlan, C. L.·Tosello Boari, J.·Bossio, S. N.·Boccardo, S.·Fozzatti, L.·Canale, F. P.·Beccaria, C. G.·Nunez, N. G.·Ceschin, D. G.·Piaggio, E.·Gruppi, A.·Montes, C. L.·Acosta Rodriguez, E. V.

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Abstract

The role of IL-17 mediated immune responses in cancer is conflicting as pre-clinical and clinical results show tumor-promoting as wel as tumor-repressing functions. Herein, we used syngeneic tumor models from different tissue origins as a tool to evaluate the role of IL-17 signaling in cancer progression, dissecting the effects in cancer cell growth and tumor immunity. We show that absence of IL-17RA or IL-17A/F expression in the host has contrasting effects in the in vivo growth of different tumor types. We observed that lack of IL-17A/F-IL-17RA signaling in host cells changed the expression pattern of several mediators within the tumor microenvironment in a cancer-type specific manner. Deficiencies in host IL-17RA or IL-17A/F expression resulted in reduced antitumor CD8+ T cell immunity in all cancer models and in tumor-specific changes in several lymphoid cell populations. These findings were associated to particular patterns of expression of cytokines (IL-17A and IL-17F) and receptor subunits (IL-17RA, IL-17RC and IL-17RD) of the IL-17 family in the injected tumor cell lines that, in turn, dictated tumor cell responsiveness to IL-17. We identified IL-17RC as an important determinant of the IL-17-mediated transcriptional response in tumor cells and; consequently, as a predictive biomarker of the overall effect of IL-17 signaling in tumor progression. Our findings contribute to unraveling the molecular mechanisms underlying the divergent activities of IL-17 in cancer and provide rational targets for immunotherapies based on personalized approaches.

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Rodriguez, C., Araujo Furlan, C. L., Tosello Boari, J., Bossio, S. N., Boccardo, S., Fozzatti, L., Canale, F. P., Beccaria, C. G., Nunez, N. G., Ceschin, D. G., Piaggio, E., Gruppi, A., Montes, C. L., Acosta Rodriguez, E. V.. 2022-12-19. Interleukin-17 signaling influences CD8+ T cell immunity and tumor progression according to the IL-17 receptor subunit expression pattern in cancer cells. https://doi.org/10.1101/2022.12.16.520754

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