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

Immunotherapy offers new cancer treatment options, but efficacy varies across cancer types. Colorectal cancers (CRCs) are largely refractory to immune checkpoint blockade, suggesting the presence of yet-to-be characterized immune suppressive mechanisms. Here we report that APC-loss in intestinal tumor cells or PTEN-loss in melanoma cells upregulates the expression of dickkopf-2 (DKK2), which, together with its receptor LRP5, constitutes 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) and CD8(+) cells in tumors, impedes tumor progression, and cooperates with 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.