Abstract
The development of immune checkpoint inhibitors represents a major breakthrough in cancer therapy. Nevertheless, a substantial number of patients fail to respond to checkpoint pathway blockade. Evidence for WNT/β-catenin signaling-mediated immune evasion is found in a subset of cancers including melanoma. Currently, there are no therapeutic strategies available for targeting WNT/β-catenin signaling. Here we show that a specific small-molecule tankyrase inhibitor, G007-LK, decreases WNT/β-catenin and YAP signaling in the syngeneic murine B16-F10 and Clone M-3 melanoma models and sensitizes the tumors to anti-PD-1 immune checkpoint therapy. Mechanistically, we demonstrate that the synergistic effect of tankyrase and checkpoint inhibitor treatment is dependent on loss of β-catenin in the tumor cells, anti-PD-1-stimulated infiltration of T cells into the tumor and induction of an IFNγ- and CD8+ T cell-mediated anti-tumor immune response. Our study uncovers a combinatorial therapeutical strategy using tankyrase inhibition to overcome β-catenin-mediated resistance to immune checkpoint blockade in melanoma.
Highlights
The development of immune checkpoint inhibitors represents a major breakthrough in cancer therapy
We show that the mechanistic basis for the synergy was not G007-LK-mediated enhanced release of the BATF3lineage dendritic cells (DC)-attracting chemokine C motif chemokine ligand 4 (CCL4) or increased tumor infiltration by CD8+ T cells
Efficacy of G007-LK treatment on Wingless-type mammary tumor virus integration site (WNT)/β-catenin and yes associated protein 1 (YAP) signaling in B16-F10 cells was explored in vitro and in vivo
Summary
The development of immune checkpoint inhibitors represents a major breakthrough in cancer therapy. We show that a specific small-molecule tankyrase inhibitor, G007-LK, decreases WNT/β-catenin and YAP signaling in the syngeneic murine B16-F10 and Clone M-3 melanoma models and sensitizes the tumors to anti-PD-1 immune checkpoint therapy. Our study uncovers a combinatorial therapeutical strategy using tankyrase inhibition to overcome β-catenin-mediated resistance to immune checkpoint blockade in melanoma. A recent study, using genetically engineered murine melanoma models, revealed that tumors expressing a dominant stable form of β-catenin showed negligible T-cell infiltration and were resistant to checkpoint blockade therapy[11]. In these β-catenin-positive tumors, production of C–C motif chemokine ligand 4 (CCL4) and additional chemokines was reduced. This, at least partly[12], resulted in reduced recruitment of cluster of differentiation (CD) 103+/ basic leucine zipper transcriptional factor ATF-like 3
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