학술논문
Semaphorin 3A causes immune suppression by inducing cytoskeletal paralysis in tumour-specific CD8+ T cells
Document Type
article
Author
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
Source
Nature Communications, Vol 15, Iss 1, Pp 1-18 (2024)
Subject
Language
English
ISSN
2041-1723
20318049
20318049
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.