Targeting cancer-associated fibroblast-secreted WNT2 restores dendritic cell-mediated antitumour immunity

Huang, Tu-Xiong1,2,3; Tan, Xiang-Yu1,2; Huang, Hui-Si1,2; Li, Yu-Ting1,2; Liu, Bei-Lei4; Liu, Kai-Sheng3; Chen, Xinchun1,2; Chen, Zhe5; Guan, Xin-Yuan4; Zou, Chang3; Fu, Li1,2

2021-03-01

10.1136/gutjnl-2020-322924

GUT   影响因子和分区

0017-5749

1468-3288

Objective Solid tumours respond poorly to immune checkpoint inhibitor (ICI) therapies. One major therapeutic obstacle is the immunosuppressive tumour microenvironment (TME). Cancer-associated fibroblasts (CAFs) are a key component of the TME and negatively regulate antitumour T-cell response. Here, we aimed to uncover the mechanism underlying CAFs-mediated tumour immune evasion and to develop novel therapeutic strategies targeting CAFs for enhancing ICI efficacy in oesophageal squamous cell carcinoma (OSCC) and colorectal cancer (CRC). Design Anti-WNT2 monoclonal antibody (mAb) was used to treat immunocompetent C57BL/6 mice bearing subcutaneously grafted mEC25 or CMT93 alone or combined with anti-programmed cell death protein 1 (PD-1), and the antitumour efficiency and immune response were assessed. CAFs-induced suppression of dendritic cell (DC)-differentiation and DC-mediated antitumour immunity were analysed by interfering with CAFs-derived WNT2, either by anti-WNT2 mAb or with short hairpin RNA-mediated knockdown. The molecular mechanism underlying CAFs-induced DC suppression was further explored by RNA-sequencing and western blot analyses. Results A negative correlation between WNT2(+) CAFs and active CD8(+) T cells was detected in primary OSCC tumours. Anti-WNT2 mAb significantly restored antitumour T-cell responses within tumours and enhanced the efficacy of anti-PD-1 by increasing active DC in both mouse OSCC and CRC syngeneic tumour models. Directly interfering with CAFs-derived WNT2 restored DC differentiation and DC-mediated antitumour T-cell responses. Mechanistic analyses further demonstrated that CAFs-secreted WNT2 suppresses the DC-mediated antitumour T-cell response via the SOCS3/p-JAK2/p-STAT3 signalling cascades. Conclusions CAFs could suppress antitumour immunity through WNT2 secretion. Targeting WNT2 might enhance the ICI efficacy and represent a new anticancer immunotherapy.

antibody targeted therapy cancer immunobiology colorectal cancer molecular carcinogenesis oesophageal cancer

SCI

英语

其他

National Key R&D Programme of China[2017YFA0503900] ; National Natural Science Foundation of China[81372583,81772957] ; Science and Technology Programme of Guangdong Province in China[2019B030301009] ; Industry and Information Technology Foundation of Shenzhen[20180309100135860] ; Shenzhen Basic Research Programme[JCYJ20200109113810154]

Gastroenterology & Hepatology

Gastroenterology & Hepatology

WOS:000728865400001

BMJ PUBLISHING GROUP

CLINICAL MEDICINE

Web of Science

1.Shenzhen Univ, Hlth Sci Ctr, Guangdong Prov Key Lab Reg Immun & Dis, Dept Pharmacol, Shenzhen, Peoples R China
2.Shenzhen Univ, Hlth Sci Ctr, Int Canc Ctr, Shenzhen, Peoples R China
3.Southern Univ Sci & Technol, Jinan Univ, Shenzhen Peoples Hosp, Clin Med Coll 2,Affiliated Hosp 1, Shenzhen, Peoples R China
4.Univ Hong Kong, Dept Clin Oncol, Hong Kong, Peoples R China
5.Zhejiang Chinese Med Univ, Affiliated Hosp 1, Key Lab Digest Pathophysiol Zhejiang Prov, Hangzhou, Peoples R China

Huang, Tu-Xiong,Tan, Xiang-Yu,Huang, Hui-Si,et al. Targeting cancer-associated fibroblast-secreted WNT2 restores dendritic cell-mediated antitumour immunity[J]. GUT,2021.

Huang, Tu-Xiong.,Tan, Xiang-Yu.,Huang, Hui-Si.,Li, Yu-Ting.,Liu, Bei-Lei.,...&Fu, Li.(2021).Targeting cancer-associated fibroblast-secreted WNT2 restores dendritic cell-mediated antitumour immunity.GUT.

Huang, Tu-Xiong,et al."Targeting cancer-associated fibroblast-secreted WNT2 restores dendritic cell-mediated antitumour immunity".GUT (2021).