TLR2 activation promotes tumour growth and associates with patient survival and chemotherapy response in pancreatic ductal adenocarcinoma

被引：10

作者：

Lundy, Joanne ^{[1
,2
]}

Gearing, Linden J. ^{[1
,2
]}

Gao, Hugh ^{[3
]}

West, Alison C. ^{[1
,2
]}

McLeod, Louise ^{[1
,2
]}

Deswaerte, Virginie ^{[1
,2
]}

Yu, Liang ^{[1
,2
]}

Porazinski, Sean ^{[4
,5
]}

Pajic, Marina ^{[4
,5
]}

Hertzog, Paul J. ^{[1
,2
]}

Croagh, Daniel ^{[1
,3
]}

Jenkins, Brendan J. ^{[1
,2
]}

机构：

[1] Hudson Inst Med Res, Ctr Innate Immun & Infect Dis, Clayton, Vic, Australia

[2] Monash Univ, Dept Mol & Translat Sci, Fac Med Nursing & Hlth Sci, Clayton, Vic, Australia

[3] Monash Univ, Sch Clin Sci Monash Hlth, Dept Surg, Clayton, Vic, Australia

[4] Kinghorn Canc Ctr, Garvan Inst Med Res, Darlinghurst, NSW, Australia

[5] Univ New South Wales, St Vincents Clin Sch, Fac Med, Darlinghurst, NSW, Australia

来源：

ONCOGENE | 2021年 / 40卷 / 41期

基金：

澳大利亚国家健康与医学研究理事会;

关键词：

TOLL-LIKE RECEPTORS; STELLATE CELLS; DIFFERENTIAL EXPRESSION; CANCER; IMMUNOTHERAPY; INFLAMMATION; GEMCITABINE; CARCINOMA; CARCINOGENESIS; IDENTIFICATION;

D O I：

10.1038/s41388-021-01992-2

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis, and is plagued by a paucity of targeted treatment options and tumour resistance to chemotherapeutics. The causal link between chronic inflammation and PDAC suggests that molecular regulators of the immune system promote disease pathogenesis and/or therapeutic resistance, yet their identity is unclear. Here, we couple endoscopic ultrasound-guided fine-needle aspiration, which captures tumour biopsies from all stages, with whole transcriptome profiling of PDAC patient primary tumours to reveal enrichment of the innate immune Toll-like receptor 2 (TLR2) molecular pathway. Augmented TLR2 expression associated with a 4-gene "TLR2 activation" signature, and was prognostic for survival and predictive for gemcitabine-based chemoresistance. Furthermore, antibody-mediated anti-TLR2 therapy suppressed the growth of human PDAC tumour xenografts, independent of a functional immune system. Our results support TLR2-based therapeutic targeting for precision medicine in PDAC, with further clinical utility that TLR2 activation is prognostic and predictive for chemoresponsiveness.

引用

页码：6007 / 6022

页数：16

共 77 条

[31]

Lanki Mira A, 2018, Tumour Biol, V40, p1010428318801188, DOI 10.1177/1010428318801188

[32] High toll-like receptor (TLR) 9 expression is associated with better prognosis in surgically treated pancreatic cancer patients [J].