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-L., 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.
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.