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

Autor: 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, Vincenzo Cerundolo
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Nature Communications, Vol 15, Iss 1, Pp 1-18 (2024)
Druh dokumentu: article
ISSN: 2041-1723
20318049
DOI: 10.1038/s41467-024-47424-z
Popis: 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.
Databáze: Directory of Open Access Journals
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