Journal
COMMUNICATIONS BIOLOGY
Volume 3, Issue 1, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s42003-020-0916-2
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Funding
- Research Council of Norway [262814, 262613, 267639, 287990]
- South-Eastern Norway Regional Health Authority [16/00528-9, 15/00779-2, 2015012, 2019090]
- Norwegian Cancer Society [189562, 181674, 197403, 5803958]
- K.G. Jebsen centre of B cell malignancies, Institute of clinical medicine, University of Oslo, Oslo, Norway [SKGJ-MED-019]
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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/beta -catenin signaling-mediated immune evasion is found in a subset of cancers including melanoma. Currently, there are no therapeutic strategies available for targeting WNT/beta -catenin signaling. Here we show that a specific small-molecule tankyrase inhibitor, G007-LK, decreases WNT/beta -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 beta -catenin in the tumor cells, anti-PD-1-stimulated infiltration of T cells into the tumor and induction of an IFN gamma- and CD8(+) T cell-mediated anti-tumor immune response. Our study uncovers a combinatorial therapeutical strategy using tankyrase inhibition to overcome beta -catenin-mediated resistance to immune checkpoint blockade in melanoma. Waaler et al. show that a tankyrase inhibitor, G007-LK, decreases WNT/beta -catenin and YAP signaling, sensitizing tumors to anti-PD-1 immune checkpoint therapy in mice. This study suggests that a combinatorial therapy using tankyrase inhibition can be used to overcome beta -catenin-mediated resistance to immune checkpoint blockade in melanoma.
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