Semaphorin 3A induces cytoskeletal paralysis in tumor-specific CD8+ T cells
Semaphorin 3A induces cytoskeletal paralysis in tumor-specific CD8+ T cells
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DOI：
10.1101/849083
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发表时间：
2019-11
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通讯作者：
M. Barnkob;Y. Michaels;Violaine Andre;P. Macklin;U. Gileadi;Salvatore Valvo;Margarida Rei;Corinna A. Kulicke;Ji-Li Chen;V. Jain;V. Woodcock;Huw Colin-York;A. Hadjinicolaou;Y. Kong;V. Mayya;J. Bull;P. Rijal;C. Pugh;A. Townsend;L. Olsen;M. Fritzsche;T. Fulga;Michael Loran Dustin;E. Jones;V. Cerundolo
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作者：
M. Barnkob;Y. Michaels;Violaine Andre;P. Macklin;U. Gileadi;Salvatore Valvo;Margarida Rei;Corinna A. Kulicke;Ji-Li Chen;V. Jain;V. Woodcock;Huw Colin-York;A. Hadjinicolaou;Y. Kong;V. Mayya;J. Bull;P. Rijal;C. Pugh;A. Townsend;L. Olsen;M. Fritzsche;T. Fulga;Michael Loran Dustin;E. Jones;V. Cerundolo
信号蛋白- 3a （Sema3A）调节肿瘤血管生成，但其在调节抗肿瘤免疫中的作用尚不清楚。我们证明，Sema3A在肿瘤微环境（TME）内分泌，通过神经匹林-1 （NRP1）抑制肿瘤特异性CD8+ T细胞功能，神经匹林-1是一种被T细胞同源抗原激活后上调的受体。Sema3A抑制T细胞迁移、免疫突触组装和肿瘤杀伤。它通过过度激活T细胞中的肌动蛋白系统来实现这些功能效果，从而导致细胞瘫痪。最后，利用透明细胞肾细胞癌患者队列，我们证明了人类肿瘤特异性CD8+ T细胞表达NRP1，并被困在肿瘤的Sema3A富集区域。我们的研究证实Sema3A是一种有效的抗肿瘤免疫抑制剂。
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.