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Nat Med. 2018 Mar;24(3):262-270. doi: 10.1038/nm.4496. Epub 2018 Feb 12.

DKK2 imparts tumor immunity evasion through β-catenin-independent suppression of cytotoxic immune-cell activation.

Author information

1
Vascular Biology and Therapeutic Program and Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut, USA.
2
State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
3
State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
4
Biostatistics Department, Yale University, New Haven, Connecticut, USA.
5
Departments of Dermatology and Pathology, Yale School of Medicine, New Haven, Connecticut, USA.
6
Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA.
7
Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA.
8
Institute of Pharmacology and Toxicology, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria.
9
AbMax, Beijing, China.

Abstract

Immunotherapy offers new options for cancer treatment, but efficacy varies across cancer types. Colorectal cancers (CRCs) are largely refractory to immune-checkpoint blockade, which suggests the presence of yet uncharacterized immune-suppressive mechanisms. Here we report that the loss of adenomatosis polyposis coli (APC) in intestinal tumor cells or of the tumor suppressor PTEN in melanoma cells upregulates the expression of Dickkopf-related protein 2 (DKK2), which, together with its receptor LRP5, provides an unconventional mechanism for tumor immune evasion. DKK2 secreted by tumor cells acts on cytotoxic lymphocytes, inhibiting STAT5 signaling by impeding STAT5 nuclear localization via LRP5, but independently of LRP6 and the Wnt-β-catenin pathway. Genetic or antibody-mediated ablation of DKK2 activates natural killer (NK) cells and CD8+ T cells in tumors, impedes tumor progression, and enhances the effects of PD-1 blockade. Thus, we have identified a previously unknown tumor immune-suppressive mechanism and immunotherapeutic targets particularly relevant for CRCs and a subset of melanomas.

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