Semaphorin 3A induces cytoskeletal paralysis in tumor-specific CD8+ T cells

Barnkob, M. B.; Michaels, Y. S.; Andre, V.; Macklin, P. S.; Gileadi, U.; Valvo, S.; Rei, M.; Kulicke, C.; Chen, J.-L.; Jain, V.; Woodcock, V.; Colin-York, H.; Hadjinicolaou, A. V.; Kong, Y.; Mayya, V.; Bull, J. A.; Rijal, P.; Pugh, C. W.; Townsend, A.; Olsen, L. R.; Fritzsche, M.; Fulga, T. A.; Dustin, M. L.; Jones, E. Y.; Cerundolo, V.

doi:10.1101/849083

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bioRxiv · 10.1101/849083

Semaphorin 3A induces cytoskeletal paralysis in tumor-specific CD8+ T cells

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Abstract

Semaphorin-3A (Sema3A) regulates tumor angiogenesis, but its role in modulating anti-tumor immunity is unclear. We demonstrate that Sema3A secreted within the tumor microenvironment (TME) suppresses tumor-specific CD8+ T cell function via Neuropilin-1 (NRP1), a receptor that is upregulated upon activation with T cells cognate antigen. Sema3A inhibits T cell migration, assembly of the immunological synapse, and tumor killing. It achieves these functional effects through hyper-activating the acto-myosin system in T cells leading to cellular paralysis. Finally, using a clear cell renal cell carcinoma patient cohort, we demonstrate that human tumor-specific CD8+ T cells express NRP1 and are trapped in Sema3A rich regions of tumors. Our study establishes Sema3A as a potent inhibitor of anti-tumor immunity.

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Barnkob, M. B., Michaels, Y. S., Andre, V., Macklin, P. S., Gileadi, U., Valvo, S., Rei, M., Kulicke, C., Chen, J.-L., Jain, V., Woodcock, V., Colin-York, H., Hadjinicolaou, A. V., Kong, Y., Mayya, V., Bull, J. A., Rijal, P., Pugh, C. W., Townsend, A., Olsen, L. R., Fritzsche, M., Fulga, T. A., Dustin, M. L., Jones, E. Y., Cerundolo, V.. 2019-11-20. Semaphorin 3A induces cytoskeletal paralysis in tumor-specific CD8+ T cells. https://doi.org/10.1101/849083

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