Gut, 2022-02, Vol.71 (2), p.333-344
2022
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- Targeting cancer-associated fibroblast-secreted WNT2 restores dendritic cell-mediated antitumour immunity
- Ist Teil von
- Gut, 2022-02, Vol.71 (2), p.333-344
- Ort / Verlag
- England
- Erscheinungsjahr
- 2022
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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). 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. 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. CAFs could suppress antitumour immunity through WNT2 secretion. Targeting WNT2 might enhance the ICI efficacy and represent a new anticancer immunotherapy.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0017-5749eISSN: 1468-3288DOI: 10.1136/gutjnl-2020-322924Titel-ID: cdi_pubmed_primary_33692094
- Format
- –
- Schlagworte
- Animals, Cancer-Associated Fibroblasts - metabolism, Carcinoma, Squamous Cell - drug therapy, Carcinoma, Squamous Cell - metabolism, Carcinoma, Squamous Cell - pathology, CD8-Positive T-Lymphocytes, Colorectal Neoplasms - drug therapy, Colorectal Neoplasms - metabolism, Colorectal Neoplasms - pathology, Dendritic Cells - physiology, Disease Models, Animal, Esophageal Neoplasms - drug therapy, Esophageal Neoplasms - metabolism, Esophageal Neoplasms - pathology, Female, Immune Checkpoint Inhibitors - therapeutic use, Mice, Mice, Inbred C57BL, Tumor Microenvironment, Wnt2 Protein - metabolism