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

Autor:	Waaler J; Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, 0424, Oslo, Norway. jo.waaler@rr-research.no.; Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, 0317, Oslo, Norway. jo.waaler@rr-research.no., Mygland L; Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, 0424, Oslo, Norway.; Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, 0317, Oslo, Norway., Tveita A; Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, 0424, Oslo, Norway.; K. G. Jebsen Centre for B cell malignancies, Oslo University Hospital, P.O. Box 4950, Nydalen, 0424, Oslo, Norway., Strand MF; School of Health Sciences, Kristiania University College, P.O. Box 1190, Sentrum, 0107, Oslo, Norway., Solberg NT; Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, 0424, Oslo, Norway.; Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, 0317, Oslo, Norway., Olsen PA; Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, 0424, Oslo, Norway.; Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, 0317, Oslo, Norway., Aizenshtadt A; Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, 0317, Oslo, Norway., Fauskanger M; Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, 0424, Oslo, Norway.; K. G. Jebsen Centre for B cell malignancies, Oslo University Hospital, P.O. Box 4950, Nydalen, 0424, Oslo, Norway., Lund K; Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, 0424, Oslo, Norway.; Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, 0317, Oslo, Norway., Brinch SA; Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, 0424, Oslo, Norway.; Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, 0317, Oslo, Norway., Lycke M; Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, 0424, Oslo, Norway.; Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, 0317, Oslo, Norway., Dybing E; Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, 0424, Oslo, Norway.; Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, 0317, Oslo, Norway., Nygaard V; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, P.O. Box 4953, Nydalen, 0424, Oslo, Norway., Bøe SL; Department of Medical Biochemistry, Oslo University Hospital, Radiumhospitalet, Ullernchausseen 70, 0379, Oslo, Norway., Heintz KM; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, P.O. Box 4953, Nydalen, 0424, Oslo, Norway., Hovig E; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, P.O. Box 4953, Nydalen, 0424, Oslo, Norway.; Center of Bioinformatics, Department of Informatics, University of Oslo, P.O. Box 1080, Blindern, 0316, Oslo, Norway., Hammarström C; Department of Pathology, Oslo University Hospital, Rikshospitalet, P.O. box 4950, Nydalen, 0424, Oslo, Norway., Corthay A; Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, 0317, Oslo, Norway.; Department of Pathology, Oslo University Hospital, Rikshospitalet, P.O. box 4950, Nydalen, 0424, Oslo, Norway., Krauss S; Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, 0424, Oslo, Norway.; Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, 0317, Oslo, Norway.
Jazyk:	angličtina
Zdroj:	Communications biology [Commun Biol] 2020 Apr 24; Vol. 3 (1), pp. 196. Date of Electronic Publication: 2020 Apr 24.
DOI:	10.1038/s42003-020-0916-2
Abstrakt:	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.
Databáze:	MEDLINE
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