Journal Article

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

Valvo, Salvatore, Townsend, Alain R, Macklin, Philip S, Dustin, Michael L, Woodcock, Victoria K, Chen, Ji-Li, André, Violaine, Bull, Joshua A, Olsen, Lars R, Fritzsche, Marco, Michaels, Yale S, Gérard, Audrey, Gileadi, Uzi, Cerundolo, Vincenzo, Kulicke, Corinna, Kong, Youxin, Pugh, Christopher W, Rijal, Pramila, Mazet, Julie M, Mead, Gracie-Jennah, Mayya, Viveka, Hadjinicolaou, Andreas V, Barnkob, Mike B, Rei, Margarida, Colin-York, Huw, Jain, Vitul, Jones, E Yvonne, Fulga, Tudor A

2024

Overview

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.

• Publisher: Nature Publishing Group UK
• Subject: Actins / Animals / Carcinoma, Renal Cell / CD8-Positive T-Lymphocytes / Cytoskeleton / Humans / Kidney Neoplasms / Semaphorin-3A - genetics