Zeitschriftenaufsatz
|
2018
DKK2 imparts tumor immunity evasion through β-catenin-independent suppression of cytotoxic immune-cell activation
Autor:in
Xiao, Qian; Wu, Jibo; Wang, Weijia; Chen, Shiyang; Zheng, Yingxia; Yu, Xiaoqing; Meeth, Katrina; Sahraei, Mahnaz M.; Bothwell, Alfred L. M.; Chen, Lieping; Bosenberg, Marcus; chen, jianfeng; Sexl, Veronika; Sun, Le; Li, Lin; Tang, Wenwen; Wu, Dianqing
Publikationen als Autor:in / Herausgeber:in der Vetmeduni
Journal
Abstrakt
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-beta-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.
Schlagwörter
Adenomatous Polyposis Coli Proteingeneticsimmunology; CD8-Positive T-Lymphocytesimmunology; Cell Line, Tumor; Colorectal Neoplasmsgeneticsimmunologypathologytherapy; Cytotoxicity, Immunologicgenetics; Gene Expression Regulation, Neoplasticgenetics; Humans; Intercellular Signaling Peptides and Proteinsgeneticsimmunology; Intestinal Neoplasmsgeneticsimmunologytherapy; Killer Cells, Naturalimmunology; Low Density Lipoprotein Receptor-Related Protein-5genetics; Melanomageneticsimmunologypathologytherapy; PTEN Phosphohydrolase; Programmed Cell Death 1 Receptorantagonists & inhibitorsimmunology; STAT5 Transcription Factorgenetics; Signal Transduction; Tumor Escapegenetics; beta Cateningenetics
Dokumententyp
Originalarbeit
Open Access Type
Green
ISSN/eISSN
1078-8956 - 1546-170X
DOI
10.1038/nm.4496
WoS ID
PubMed ID