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

• Main Authors: Waaler, Jo, Mygland, Line, Tveita, Anders Aune, Strand, Martin Frank, Solberg, Nina, Olsen, Petter Angell, Aizenshtadt, Aleksandra, Fauskanger, Marte, Lund, Kaja, Brinch, Shoshy Alam, Lycke, Max, Dybing, Elisabeth, Nygaard, Vegard, Bøe, Sigurd, Heintz, Karen Marie, Hovig, Eivind, Hammarström, Clara Louise, Corthay, Alexandre, Krauss, Stefan
• Format: Article
• Language: English

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.