Semaphorin 3A causes immune suppression by inducing cytoskeletal paralysis in tumour-specific CD8+ T cells

Mike B. Barnkob (), Yale S. Michaels, Violaine André, Philip S. Macklin, Uzi Gileadi, Salvatore Valvo, Margarida Rei, Corinna Kulicke, Ji-Li Chen, Vitul Jain, Victoria K. Woodcock, Huw Colin-York, Andreas V. Hadjinicolaou, Youxin Kong, Viveka Mayya, Julie M. Mazet, Gracie-Jennah Mead, Joshua A. Bull, Pramila Rijal, Christopher W. Pugh, Alain R. Townsend, Audrey Gérard, Lars R. Olsen, Marco Fritzsche, Tudor A. Fulga, Michael L. Dustin, E. Yvonne Jones () and Vincenzo Cerundolo
Additional contact information
Mike B. Barnkob: University of Oxford
Yale S. Michaels: University of Oxford
Violaine André: University of Oxford
Philip S. Macklin: Nuffield Department of Medicine Research Building
Uzi Gileadi: University of Oxford
Salvatore Valvo: University of Oxford
Margarida Rei: University of Oxford
Corinna Kulicke: University of Oxford
Ji-Li Chen: University of Oxford
Vitul Jain: University of Oxford
Victoria K. Woodcock: University of Oxford
Huw Colin-York: University of Oxford
Andreas V. Hadjinicolaou: University of Oxford
Youxin Kong: University of Oxford
Viveka Mayya: University of Oxford
Julie M. Mazet: University of Oxford
Gracie-Jennah Mead: University of Oxford
Joshua A. Bull: Radcliffe Observatory Quarter
Pramila Rijal: University of Oxford
Christopher W. Pugh: Nuffield Department of Medicine Research Building
Alain R. Townsend: University of Oxford
Audrey Gérard: University of Oxford
Lars R. Olsen: Ørsteds Plads
Marco Fritzsche: University of Oxford
Tudor A. Fulga: University of Oxford
Michael L. Dustin: University of Oxford
E. Yvonne Jones: University of Oxford
Vincenzo Cerundolo: University of Oxford

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Semaphorin-3A (SEMA3A) functions as a chemorepulsive signal during development and can affect T cells by altering their filamentous actin (F-actin) cytoskeleton. The exact extent of these effects on tumour-specific T cells are not completely understood. Here we demonstrate that Neuropilin-1 (NRP1) and Plexin-A1 and Plexin-A4 are upregulated on stimulated CD8+ T cells, allowing tumour-derived SEMA3A to inhibit T cell migration and assembly of the immunological synapse. Deletion of NRP1 in both CD4+ and CD8+ T cells enhance CD8+ T-cell infiltration into tumours and restricted tumour growth in animal models. Conversely, over-expression of SEMA3A inhibit CD8+ T-cell infiltration. We further show that SEMA3A affects CD8+ T cell F-actin, leading to inhibition of immune synapse formation and motility. Examining a clear cell renal cell carcinoma patient cohort, we find that SEMA3A expression is associated with reduced survival, and that T-cells appear trapped in SEMA3A rich regions. Our study establishes SEMA3A as an inhibitor of effector CD8+ T cell tumour infiltration, suggesting that blocking NRP1 could improve T cell function in tumours.

Date: 2024
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DOI: 10.1038/s41467-024-47424-z

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