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.

中文翻译：

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DKK2 通过独立于 β-连环蛋白抑制细胞毒性免疫细胞激活来逃避肿瘤免疫。


免疫疗法为癌症治疗提供了新的选择，但功效因癌症类型而异。结直肠癌（CRC）在很大程度上对免疫检查点封锁具有抵抗力，这表明存在尚未表征的免疫抑制机制。在此，我们报道肠道肿瘤细胞中腺瘤性息肉病 (APC) 或黑色素瘤细胞中肿瘤抑制因子 PTEN 的缺失会上调 Dickkopf 相关蛋白 2 (DKK2) 的表达，该蛋白与其受体 LRP5 一起提供了一种非常规的机制。肿瘤免疫逃避机制。肿瘤细胞分泌的 DKK2 作用于细胞毒性淋巴细胞，通过 LRP5 阻碍 STAT5 核定位，从而抑制 STAT5 信号传导，但与 LRP6 和 Wnt-β-连环蛋白途径无关。基因或抗体介导的 DKK2 消融可激活肿瘤中的自然杀伤 (NK) 细胞和 CD8 ⁺ T 细胞，阻止肿瘤进展，并增强 PD-1 阻断的效果。因此，我们已经确定了一种以前未知的肿瘤免疫抑制机制和与结直肠癌和黑色素瘤亚型特别相关的免疫治疗靶点。