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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli Protein / genetics*
  • Adenomatous Polyposis Coli Protein / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Line, Tumor
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / immunology*
  • Colorectal Neoplasms / pathology
  • Colorectal Neoplasms / therapy
  • Cytotoxicity, Immunologic / genetics
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Intercellular Signaling Peptides and Proteins / immunology
  • Intestinal Neoplasms / genetics
  • Intestinal Neoplasms / immunology
  • Intestinal Neoplasms / therapy
  • Killer Cells, Natural / immunology
  • Low Density Lipoprotein Receptor-Related Protein-5 / genetics*
  • Melanoma / genetics
  • Melanoma / immunology*
  • Melanoma / pathology
  • Melanoma / therapy
  • PTEN Phosphohydrolase
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / immunology
  • STAT5 Transcription Factor / genetics
  • Signal Transduction
  • Tumor Escape / genetics*
  • beta Catenin / genetics

Substances

  • APC protein, human
  • Adenomatous Polyposis Coli Protein
  • CTNNB1 protein, human
  • DKK2 protein, human
  • Intercellular Signaling Peptides and Proteins
  • LRP5 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-5
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • STAT5 Transcription Factor
  • beta Catenin
  • PTEN Phosphohydrolase
  • PTEN protein, human