SCI

6 September 2024

ZBTB46 coordinates angiogenesis and immunity to control tumor outcome

(Nature Immunology, IF: 27.7)

  • Ashraf Ul Kabir, Carisa Zeng, Madhav Subramanian, Jun Wu, Minseo Kim, Karen Krchma, Xiaoli Wang, Carmen M. Halabi, Hua Pan, Samuel A. Wickline, Daved H. Fremont, Maxim N. Artyomov & Kyunghee Choi

  • CORRESPONDENCE TO: kchoi@wustl.edu

Tumor angiogenesis and immunity show an inverse correlation in cancer progression and outcome. Here, we report that ZBTB46, a repressive transcription factor and a widely accepted marker for classical dendritic cells (DCs), controls both tumor angiogenesis and immunity. Zbtb46 was downregulated in both DCs and endothelial cells by tumor-derived factors to facilitate robust tumor growth. Zbtb46 downregulation led to a hallmark pro-tumor microenvironment (TME), including dysfunctional vasculature and immunosuppressive conditions. Analysis of human cancer data revealed a similar association of low ZBTB46 expression with an immunosuppressive TME and a worse prognosis. In contrast, enforced Zbtb46 expression led to TME changes to restrict tumor growth. Mechanistically, Zbtb46-deficient endothelial cells were highly angiogenic, and Zbtb46-deficient bone marrow progenitors upregulated Cebpb and diverted the DC program to immunosuppressive myeloid lineage output, potentially explaining the myeloid lineage skewing phenomenon in cancer. Conversely, enforced Zbtb46 expression normalized tumor vessels and, by suppressing Cebpb, skewed bone marrow precursors toward immunostimulatory myeloid lineage output, leading to an immune-hot TME. Remarkably, Zbtb46 mRNA treatment synergized with anti-PD1 immunotherapy to improve tumor management in preclinical models. These findings identify ZBTB46 as a critical factor for angiogenesis and for myeloid lineage skewing in cancer and suggest that maintaining its expression could have therapeutic benefits.

肿瘤血管生成和免疫在癌症的进展和结局中显示出相反的相关性。在这里，我们发现ZBTB46是一种抑制性转录因子，也是经典树突状细胞（DC）广泛接受的标志物，它控制着肿瘤血管生成和免疫。Zbtb46在DC和内皮细胞中均被肿瘤衍生因子下调，以促进肿瘤的稳健生长。Zbtb46下调导向标志性的促肿瘤微环境（TME），包括功能失调的血管系统和免疫抑制条件。对人类癌症数据的分析显示，低ZBTB46表达与免疫抑制性TME和更差的预后有类似的关联。相比之下，强制Zbtb46表达导致TME变化以限制肿瘤生长。从机制上讲，Zbtb46-缺陷型内皮细胞具有高度的血管生成性，并且Zbtb46缺陷型骨髓祖细胞上调了Cebpb，并将DC程序转向免疫抑制性骨髓谱系输出，这可能解释了癌症中骨髓谱系偏倚现象。相反，强制Zbtb46表达使肿瘤血管正常化，并通过抑制Cebpb使骨髓前体向免疫刺激的髓系输出偏倚，导致免疫热TME。值得注意的是，Zbtb46 mRNA治疗与抗PD1免疫疗法协同作用，改善了临床前模型中的肿瘤管理。这些发现确定ZBTB46是癌症血管生成和髓系谱系偏倚的关键因素，并表明维持其表达可能具有治疗益处。


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