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

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

doi:10.1038/s41467-024-47424-z

ImmunologybioRxivNov 20, 2019

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

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

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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