Pharmacological Wnt ligand inhibition overcomes key tumor-mediated resistance pathways to anti-PD-1 immunotherapy

Abstract

SUMMARY While immune checkpoint blockade is associated with prolonged responses in multiple cancers, most patients still do not benefit from this therapeutic strategy. The Wnt-β-catenin pathway is associated with diminished T cell infiltration; however, activating mutations are rare, implicating a role for autocrine/paracrine Wnt ligand-driven signaling in immune evasion. In this study, we show that proximal mediators of the Wnt signaling pathway are associated with anti-PD-1 resistance, and pharmacologic inhibition of Wnt ligand signaling supports anti-PD-1 efficacy by reversing dendritic cell tolerization and the recruitment of granulocytic myeloid-derived suppressor cells in autochthonous tumor models. We further demonstrate that the inhibition of Wnt signaling promotes the development of a tumor microenvironment that is more conducive to favorable responses to checkpoint blockade in cancer patients. These findings support a rationale for Wnt ligand-focused treatment approaches in future immunotherapy clinical trials and suggest a strategy for selecting those tumors more responsive to Wnt inhibition.

Development and Validation of Tumor Immunogenicity Based Gene Signature for Skin Cancer Risk Stratification

“…Our result found a positive correlation between the expression of this gene and longer survival. A recent study emphasized the function of Wnt/β catenin activation in immunotherapy resistance [ 34 ]. Therefore, we analyzed the prediction power of the signature in immunotherapy response.…”

Transcriptomic datasets of cancer patients treated with immune-checkpoint inhibitors: a systematic review

“…We have to note here two smaller studies with metastatic melanoma samples which were published under the NCBI GEO accession numbers GSE123728 [ 77 ] and GSE165745 [ 78 ] with 13 and 24 patients, respectively. Both studies administered anti-PD-1 monotherapy (pembrolizumab or nivolumab) and determined gene expression using the NanoString nCounter platform from FFPE samples.…”

Modulation of Lymphocyte Functions in the Microenvironment by Tumor Oncogenic Pathways

“…Preliminary data confirmed that treatment with WNT inhibitors were able to revert the immune suppressive conditions ( 83 , 84 ) and could also enhance response to different immunotherapeutic approaches ranging from adoptive transfer to ICPi. The tumor rejection was correlated both to changes in the tumor cells, like an upregulation of MHC class I surface expression ( 85 ) and modulation of PD-L1 expression ( 86 ) that render tumor cells more sensitive to cytotoxic T lymphocytes (CTLs) as well as to alterations in the TME, which reverted the immune suppressive conditions and allowed recruitment of effector cells ( 87 , 88 ).…”