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

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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Figure 1: DKK2 blockade reduces tumor burdens in ApcMin/+ mice.
Figure 2: DKK2 blockade impedes tumor progression in the MC38 syngeneic tumor model.
Figure 3: DKK2 blockade enhances cytotoxic immune cell activation.
Figure 4: DKK2 directly suppresses NK cell activation.
Figure 5: DKK2 impedes pSTAT5 nuclear localization.
Figure 6: LRP5 is required for DKK2-mediated inhibition of NK cell activation.

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Acknowledgements

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.).

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D.W., L.L., Q.X., J.W., W.-J.W., W.T., M.S., and J.C. designed the experiments; Q.X., J.W., W.-J.W., S.C., Y.Z., M.S., W.T., and K.M. performed the experiments; D.W., L.L., Q.X., W.-J.W., M.S., J.W., A.L.M.B., L.C., and W.T. analyzed the data; X.Y. performed statistic and bioinformatic analyses; M.B., V.S., and L.S. created and provided important reagents; D.W., L.L., Q.X., J.W., W.-J.W., and W.T. wrote the manuscript; and all authors reviewed and approved the manuscript.

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Correspondence to Lin Li or Wenwen Tang or Dianqing Wu.

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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, WJ. et al. DKK2 imparts tumor immunity evasion through β-catenin-independent suppression of cytotoxic immune-cell activation. Nat Med 24, 262–270 (2018). https://doi.org/10.1038/nm.4496

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