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


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

Publication Date: 

20 November 2019

Last Updated: 





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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Publication Type: 

Journal Article