Study data published in Gut suggest that targeting WNT2 secreted by cancer-associated fibroblasts (CAFs) may increase the efficacy of certain antitumor therapies. In mouse models, CAFs-secreted WNT2 was found to suppress the dendritic cell (DC)-mediated antitumor T-cell response. Targeting WNT2 restored DC differentiation and the DC-mediated antitumor response, suggesting that WNT2 may be a worthwhile target for anticancer immunotherapies.

Investigators in Shenzhen, China, performed in vivo and in vitro studies to explore the mechanism by which solid tumors appear to resist immune checkpoint inhibitor (ICI) therapies. Prior research has indicated that the immunosuppressive tumor microenvironment—of which CAFs are a key component—inhibits the efficacy of ICI. However, the pathways through which CAFs appear to mediate tumor immune evasion remain unclear.

As such, investigators designed an in vivo study in which immunocompetent C57BL/6 mice were treated with anti-WNT2 monoclonal antibody (mAb). Mice were subcutaneously injected with mEC25 or CMT93 cells to induce the growth of oesophageal and colorectal tumors, respectively.


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Following the development of tumors approximately 5 mm in diameter, mice were regularly injected with 1 of the following treatment modalities for 2 weeks: control immunoglobin G, anti-WNT2 mAb only, anti-programmed cell death protein 1 (PD-1) only, or anti-WNT2 mAb combined with PD-1. Antitumor T-cell responses were measured in resected tumor cells using flow cytometry. The impact of WNT2 on DC differentiation and activation was also analyzed in vitro using mouse bone marrow DCs.

Additionally, investigators obtained tumor sections from 47 primary cases with oesophageal squamous cell carcinoma (OSCC). Tumor sections were immunostained with markers for CAFs known to promote tumor growth. The results from the immunostaining trials were compared with outcomes from mouse studies.

In the OSCC tumor sections, investigators observed a negative correlation between active CD8+ T-cells and the presence of WNT2+ CAFs. This observed relationship suggests that WNT2-secreted CAFs may have immunosuppressive effects in the oesophageal cancer tumor environment.

During in vivo trials, treatment with anti-WNT2 mAb was found to substantially restore antitumor T-cell responses and significantly inhibit tumor growth in both oesophageal and colorectal cancer mouse models. Anti-WNT2 treatment appeared to increase the number of active DCs in both oesophageal and colorectal tumors. The combination of anti-WNT2 and anti-PD-1 was associated with more significant antitumor activity compared with either treatment alone. Treatment with anti-WNT2 mAb also appeared to improve the tumor-killing activity of CD8+ T-cells in the spleen.

Throughout in vitro models, interference with CAFs-derived WNT2 was found to restore DC differentiation and DC-mediated antitumor T-cell responses. Treatment with recombinant mouse-Wn2 protein was found to effectively suppress the differentiation of mouse DCs through the upregulation of suppressor of cytokine signaling 3 (SOCS3). Specifically, CAFs-secreted WNT2 appeared to inhibit the antitumor response through the SOCS3/p-JAK2/p-STAT3 signaling cascades. In turn, anti-WNT2 treatment was found to restore DC differentiation and the resultant antitumor T-cell response. 

Results from this study suggest that anti-WNT2 treatment may enhance the efficacy of ICI treatment, particularly with PD-1. These findings also elucidate the mechanisms and pathways through which CAFs regulate the antitumor T-cell response. Further research is necessary to better explore the treatment of oesophageal and colorectal tumors, as well as additional cancers. 

“Our findings open up a new therapeutic strategy to enhance the efficacy of PD-1/programmed death-ligand 1 immune checkpoint treatment by targeting CAFs-secreted WNT2 or other CAFs-induced immunosuppressive factors, not only in [oesophageal] and [colorectal cancer], but more broadly,” investigators wrote.

Reference

Huang T, Tan XY, Huang HS, et al. Targeting cancer-associated fibroblast-secreted WNT2 restores dendritic cell-mediated antitumour immunity Published online March 10, 2021. Gut. doi: 10.1136/gutjnl-2020-322924