Based on the known impact of the Wnt/β-catenin pathway on immune exclusion and suppression, despite an absence of mutations in the key genes, DeVito et al. investigated the role of Wnt ligands, receptors, and other regulators. Transcriptional analysis revealed an association between upregulated signaling activity and non-responsiveness to ICB in clinical samples. In multiple syngeneic and autochthonous murine models, pharmacological inhibition of signaling components enhanced anti-PD-1 therapy, leading to improved efficacy and survival, linked to a more CD8+ T cell-supportive TME (lower suppressive Tregs, PMN-MDSCs, and kynurenine).
Contributed by Ed Fritsch
ABSTRACT: 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.
Author Info: (1) Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Duke Cancer Institute, Durham, NC 27710, USA. (2) Department of Medicine, Division of Medi
Author Info: (1) Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Duke Cancer Institute, Durham, NC 27710, USA. (2) Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Duke Cancer Institute, Durham, NC 27710, USA. (3) Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Duke Cancer Institute, Durham, NC 27710, USA. (4) Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Duke Cancer Institute, Durham, NC 27710, USA. (5) Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Duke Cancer Institute, Durham, NC 27710, USA. (6) Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Duke Cancer Institute, Durham, NC 27710, USA. (7) Department of Surgery, Division of Surgical Oncology, Duke University Medical Center, Duke Cancer Institute, Durham, NC 27710, USA. (8) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. (9) Experimental Drug Development Centre (EDDC), A(_)STAR, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore. (10) Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Duke Cancer Institute, Durham, NC 27710, USA. (11) Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Duke Cancer Institute, Durham, NC 27710, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27708, USA. Electronic address: brent.hanks@duke.edu.
