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

被引：7

作者：

Barnkob, Mike B. ^{[1
,8
]}

Michaels, Yale S. ^{[2
,9
,10
]}

Andre, Violaine ^{[1
]}

Macklin, Philip S. ^{[3
]}

Valvo, Salvatore ^{[1
]}

Rei, Margarida ^{[4
]}

Kulicke, Corinna ^{[1
,11
]}

Chen, Ji-Li ^{[1
,12
]}

Jain, Vitul ^{[1
]}

Woodcock, Victoria K. ^{[5
]}

Colin-York, Huw ^{[1
]}

Hadjinicolaou, Andreas V. ^{[1
]}

Kong, Youxin ^{[1
,13
,14
]}

Mayya, Viveka ^{[5
]}

Mazet, Julie M. ^{[4
]}

Mead, Gracie-Jennah ^{[4
]}

Bull, Joshua A. ^{[4
]}

Rijal, Pramila ^{[6
]}

Pugh, Christopher W. ^{[1
]}

Townsend, Alain R. ^{[3
]}

Gerard, Audrey ^{[1
]}

Olsen, Lars R. ^{[4
]}

Fritzsche, Marco ^{[7
]}

Fulga, Tudor A. ^{[1
,4
]}

Dustin, Michael L. ^{[2
]}

Jones, E. Yvonne ^{[4
,5
]}

Cerundolo, Vincenzo

机构：

[1] Univ Oxford, MRC Weatherall Inst Mol Med, MRC Human Immunol Unit, Headley Way, Oxford OX3 9DS, England

[2] Univ Oxford, MRC Weatherall Inst Mol Med, Headley Way, Oxford OX3 9DS, England

[3] Univ Oxford, Nuffield Dept Med, Nuffield Dept Med Res Bldg, Roosevelt Dr, Oxford OX3 7FZ, England

[4] Univ Oxford, Kennedy Inst Rheumatol, Roosevelt Dr, Oxford OX3 7FY, England

[5] Univ Oxford, Wellcome Ctr Human Genet, Div Struct Biol, Roosevelt Dr, Oxford OX3 7BN, England

[6] Univ Oxford, Math Inst, Wolfson Ctr Math Biol, Radcliffe Observ Quarter, Woodstock Rd, Oxford OX2 6GG, England

[7] Tech Univ Denmark, Dept Hlth Technol, Orsteds Plads,Bldg 345C, DK-2800 Lyngby, Denmark

[8] Univ Southern Denmark, Ctr Cellular Immunotherapy Haematol Canc Odense C, Dept Clin Immunol, Odense Univ Hosp, Odense, Denmark

[9] CancerCare Manitoba, Paul Albrechtsen Res Inst, 675 McDermot Ave, Winnipeg, MB R3E 0V9, Canada

[10] Univ Manitoba, Rady Fac Hlth Sci, Dept Biochem & Med Genet, Bannatyne Ave, Winnipeg, MB R3E 3N4, Canada

[11] Univ Lisbon, Fac Med, Inst Med Mol Joao Lobo Antunes, Lisbon, Portugal

[12] Oregon Hlth & Sci Univ, Pulm & Crit Care Med, Portland, OR USA

[13] Univ Cambridge, Div Gastroenterol & Hepatol, Dept Med, Cambridge Univ Hosp, Cambridge CB2 0QQ, England

[14] Univ Cambridge, Early Canc Inst, Dept Oncol, Cambridge, England

来源：

NATURE COMMUNICATIONS | 2024年 / 15卷 / 01期

基金：

英国工程与自然科学研究理事会; 英国惠康基金; 英国医学研究理事会;

关键词：

MYOSIN-II ACTIVITY; IMMUNOLOGICAL SYNAPSE; COMPREHENSIVE ANALYSIS; STRUCTURAL BASIS; NEUROPILIN; SEMAPHORINS; RECEPTOR; BLOCKADE; GROWTH; PROLIFERATION;

D O I：

10.1038/s41467-024-47424-z

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：18

共 85 条

[1] Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation [J].