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

Jo Waaler; Line Mygland; Anders Tveita; Martin Frank Strand; Nina Therese Solberg; Petter Angell Olsen; Aleksandra Aizenshtadt; Marte Fauskanger; Kaja Lund; Shoshy Alam Brinch; Max Lycke; Elisabeth Dybing; Vegard Nygaard; Sigurd Læines Bøe; Karen-Marie Heintz; Eivind Hovig; Clara Hammarström; Alexandre Corthay; Stefan Krauss

doi:10.1038/s42003-020-0916-2

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

Commun Biol. 2020 Apr 24;3(1):196. doi: 10.1038/s42003-020-0916-2.

Authors

Jo Waaler^#^{1

2}, Line Mygland^#^{3

4}, Anders Tveita^{3

5}, Martin Frank Strand⁶, Nina Therese Solberg^{3

4}, Petter Angell Olsen^{3

4}, Aleksandra Aizenshtadt⁴, Marte Fauskanger^{3

5}, Kaja Lund^{3

4}, Shoshy Alam Brinch^{3

4}, Max Lycke^{3

4}, Elisabeth Dybing^{3

4}, Vegard Nygaard⁷, Sigurd Læines Bøe⁸, Karen-Marie Heintz⁷, Eivind Hovig^{7

9}, Clara Hammarström¹⁰, Alexandre Corthay^{4

10}, Stefan Krauss^{3

4}

Affiliations

¹ Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, 0424, Oslo, Norway. [email protected].
² Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, 0317, Oslo, Norway. [email protected].
³ Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, 0424, Oslo, Norway.
⁴ Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, 0317, Oslo, Norway.
⁵ K. G. Jebsen Centre for B cell malignancies, Oslo University Hospital, P.O. Box 4950, Nydalen, 0424, Oslo, Norway.
⁶ School of Health Sciences, Kristiania University College, P.O. Box 1190, Sentrum, 0107, Oslo, Norway.
⁷ Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, P.O. Box 4953, Nydalen, 0424, Oslo, Norway.
⁸ Department of Medical Biochemistry, Oslo University Hospital, Radiumhospitalet, Ullernchausseen 70, 0379, Oslo, Norway.
⁹ Center of Bioinformatics, Department of Informatics, University of Oslo, P.O. Box 1080, Blindern, 0316, Oslo, Norway.
¹⁰ Department of Pathology, Oslo University Hospital, Rikshospitalet, P.O. box 4950, Nydalen, 0424, Oslo, Norway.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
CD8-Positive T-Lymphocytes / drug effects
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / metabolism
Cytotoxicity, Immunologic / drug effects
Drug Synergism
Enzyme Inhibitors / pharmacology*
Female
HEK293 Cells
Humans
Immune Checkpoint Inhibitors / pharmacology*
Interferon-gamma / metabolism
Lymphocytes, Tumor-Infiltrating / drug effects
Lymphocytes, Tumor-Infiltrating / immunology
Lymphocytes, Tumor-Infiltrating / metabolism
Melanoma, Experimental / drug therapy*
Melanoma, Experimental / enzymology
Melanoma, Experimental / immunology
Melanoma, Experimental / pathology
Mice, Inbred C57BL
Mice, Inbred DBA
Mice, Transgenic
Programmed Cell Death 1 Receptor / antagonists & inhibitors*
Programmed Cell Death 1 Receptor / metabolism
Skin Neoplasms / drug therapy*
Skin Neoplasms / enzymology
Skin Neoplasms / immunology
Skin Neoplasms / pathology
Sulfones / pharmacology*
Tankyrases / antagonists & inhibitors*
Tankyrases / metabolism
Triazoles / pharmacology*
Tumor Burden / drug effects
Wnt Signaling Pathway / drug effects*
YAP-Signaling Proteins
beta Catenin / genetics
beta Catenin / metabolism

Substances

Adaptor Proteins, Signal Transducing
CTNNB1 protein, mouse
Enzyme Inhibitors
G007-LK
IFNG protein, mouse
Immune Checkpoint Inhibitors
Pdcd1 protein, mouse
Programmed Cell Death 1 Receptor
Sulfones
Triazoles
YAP-Signaling Proteins
Yap1 protein, mouse
beta Catenin
Interferon-gamma
Tankyrases