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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We thank M. Orsulak for technical assistance and B. Williams (Van Andel Institute, Grand Rapids, Michigan, USA) for providing the LRP5/6 floxed mice. This work was supported by the NIH (grants GM112182 and CA214703 to D.W.), the Connecticut Bioscience Innovation Fund (to D.W.), NSFC (grant 31530094 to L.L.), the strategic priority research program of CAS (grant XDB19000000 to L.L.), and the CAS/SAFEA International Partnership Program for Creative Research Teams (to L.L. and D.W.).
D.W. received research support from Just Biotherapeutic Asia, which licensed the intellectual property from Yale University on the basis of the findings reported in this article.
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Xiao, Q., Wu, J., Wang, W. et al. DKK2 imparts tumor immunity evasion through β-catenin-independent suppression of cytotoxic immune-cell activation. Nat Med 24, 262–270 (2018) doi:10.1038/nm.4496
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