Tankyrase inhibition sensitizes melanoma to PD-1 immune checkpoint blockade in syngeneic mouse models

• Published in: Communications biology 2020-04, Vol.3 (1), p.196-196, Article 196
• Main Authors: Waaler, Jo, Mygland, Line, Tveita, Anders, Strand, Martin Frank, Solberg, Nina Therese, Olsen, Petter Angell, Aizenshtadt, Aleksandra, Fauskanger, Marte, Lund, Kaja, Brinch, Shoshy Alam, Lycke, Max, Dybing, Elisabeth, Nygaard, Vegard, Bøe, Sigurd Læines, Heintz, Karen-Marie, Hovig, Eivind, Hammarström, Clara, Corthay, Alexandre, Krauss, Stefan
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 13/2; 13/21; 13/31; 13/51; 13/95; 14/1; 14/19; 14/63; 38/23; 38/39; 38/91; 631/67/1059/2325; 631/67/1059/602; 631/67/1813/1634; 64/60; 82/51; 82/80; Animal models; Biology; Biomedical and Life Sciences; CD8 antigen; Immune checkpoint inhibitors; Immune response (cell-mediated); Life Sciences; Lymphocytes T; Melanoma; Metastases; PD-1 protein; Tumor cells; Tumors; Wnt protein; Yes-associated protein; β-Catenin; γ-Interferon
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-020-0916-2

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. Waaler et al. show that a tankyrase inhibitor, G007-LK, decreases WNT/β-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 β-catenin-mediated resistance to immune checkpoint blockade in melanoma.