DKK2 blockage-mediated immunotherapy enhances anti-angiogenic therapy of Kras mutated colorectal cancer

[Display omitted] •DKK2 blockade activated tumor infiltrating CD8+ T cells in primary human CRC tumors expressing high levels of DKK2 in an ex vivo culture system.•DKK2 blockade retarded tumor progression via activating immune effector cells and suppressing angiogenesis.•The combinational administration of the DKK2 blockade with sub-optimal anti-VEGFR showed a synergetic effect on suppressing tumor progression.•This study provided evidence for the therapeutic application of the DKK2 blockade for treating human CRC. There are limited options for targeted therapies for colorectal cancer (CRC). Anti-EGFR therapy is limited to CRC without KRAS mutations. Even worse, most of CRC are refractory to currently immune checkpoint blockade. DKK2, which is upregulated in CRC, was recently found to suppress host immune responses, and its blockage effectively impeded tumor progression in benign genetic CRC models in our previous study. Here, our recent study demonstrated that in human CRC tumor samples expressing high levels of DKK2, DKK2 blockade caused stronger activation of tumor infiltrating CD8+ T cells in ex vivo culture. Intriguingly, we observed a correlation of high DKK2 expression with increased lymph node metastasis prevalence in these CRC patients as well. Furthermore, in a mouse genetic CRC model with mutations in APC and KRAS, which more closely mimics advanced human CRC, we confirmed the tumor inhibitory effect of DKK2 blockade, which significantly retarded tumor progression and extended survival, with increased immune effector cell activation and reduced angiogenesis. Based on this, we performed a combined administration of DKK2 blockade with sub-optimal anti-VEGFR treatment and observed a synergetic effect on suppressing tumor angiogenesis and progression, as well as extending survival, better than those of every single therapy. Thus, this study provides further evidence for the potential therapeutic application of DKK2 blockade in the clinical treatment of human CRC.