Tankyrase inhibition sensitizes melanoma to PD-1 immune checkpoint blockade in syngeneic mouse models.
Commun Biol
; 3(1): 196, 2020 04 24.
Article
in En
| MEDLINE
| ID: mdl-32332858
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/ß-catenin signaling-mediated immune evasion is found in a subset of cancers including melanoma. Currently, there are no therapeutic strategies available for targeting WNT/ß-catenin signaling. Here we show that a specific small-molecule tankyrase inhibitor, G007-LK, decreases WNT/ß-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 ß-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 ß-catenin-mediated resistance to immune checkpoint blockade in melanoma.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Skin Neoplasms
/
Sulfones
/
Triazoles
/
Melanoma, Experimental
/
Antineoplastic Combined Chemotherapy Protocols
/
Tankyrases
/
Enzyme Inhibitors
/
Programmed Cell Death 1 Receptor
/
Wnt Signaling Pathway
/
Immune Checkpoint Inhibitors
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
Commun Biol
Year:
2020
Type:
Article
Affiliation country:
Norway