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Targeting cancer-associated fibroblast-secreted WNT2 restores dendritic cell-mediated antitumour immunity
- Source :
- Gut
- Publication Year :
- 2021
- Publisher :
- BMJ, 2021.
-
Abstract
- ObjectiveSolid 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).DesignAnti-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.ResultsA 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.ConclusionsCAFs could suppress antitumour immunity through WNT2 secretion. Targeting WNT2 might enhance the ICI efficacy and represent a new anticancer immunotherapy.
- Subjects :
- 0301 basic medicine
oesophageal cancer
Programmed cell death
Esophageal Neoplasms
medicine.drug_class
medicine.medical_treatment
colorectal cancer
molecular carcinogenesis
CD8-Positive T-Lymphocytes
Monoclonal antibody
Wnt2 Protein
Mice
03 medical and health sciences
0302 clinical medicine
Immune system
Cancer-Associated Fibroblasts
Tumor Microenvironment
medicine
Animals
SOCS3
Immune Checkpoint Inhibitors
Gene knockdown
business.industry
Gastroenterology
Dendritic Cells
Immunotherapy
Dendritic cell
cancer immunobiology
GI cancer
Mice, Inbred C57BL
antibody targeted therapy
Disease Models, Animal
030104 developmental biology
030220 oncology & carcinogenesis
Carcinoma, Squamous Cell
Cancer research
Female
Colorectal Neoplasms
business
CD8
Subjects
Details
- ISSN :
- 14683288 and 00175749
- Volume :
- 71
- Database :
- OpenAIRE
- Journal :
- Gut
- Accession number :
- edsair.doi.dedup.....532ef1a355f34228580ff2085c3f9d7d