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

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.

A proximal-to-distal survey of healthy adult human small intestine and colon epithelium by single-cell transcriptomics

“…PC-unique expression of FZD9 supports a WNTreceptive PC role 60 (Fig. S9), with its expected ligand WNT2 61 absent in our database yet induced in intestinal inflammation and cancer [62][63][64] . Mature PCs can dedifferentiate following injury in mice [65][66][67] , and Ascl2 is required for dedifferentiation in mouse crypts 68 .…”

The Therapeutic Potential of Tackling Tumor-Induced Dendritic Cell Dysfunction in Colorectal Cancer

“…In line with this, one study in a melanoma model has shown that expansion and activation of TIDCs at the tumor site by recruiting and activating agents such as FLT3L and poly I:C, enhanced therapeutic response to immune checkpoint inhibitors (196). In addition, a recent study indicates that blocking CRCinduced WNT2 secretion by CAFs restores DC functions enhancing anti-PD-1 efficacy (197). These studies emphasize the importance of functional DCs in effective intra-tumoral DC-T cell crosstalk for immunotherapy response.…”

The Role of Long Non-Coding RNAs in the Tumor Immune Microenvironment

“…VEGF and hepatocyte growth factor (HGF) can regulate angiogenesis ( 193 , 197 ). Moreover, by cytokine production and surface molecules, CAF can regulate immunity, including macrophage recruitment, T cells immune response, and DCs anti-tumor immunity ( 198 ). LncRNAs can regulate CAF activation, tumor progression, and chemoresistance.…”