한빛사논문
- 조회302
Ashraf Ul Kabir 1, Carisa Zeng 1, Madhav Subramanian 1, Jun Wu 1, Minseo Kim 1, Karen Krchma 1, Xiaoli Wang 1, Carmen M. Halabi 2, Hua Pan 3, Samuel A. Wickline 4, Daved H. Fremont 1, Maxim N. Artyomov 1 & Kyunghee Choi 1,*
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
2Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
3Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
4Health Heart Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
*Corresponding author: correspondence to Kyunghee Choi
Abstract
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.
논문정보
- Research article
- 2024년 08월 (BRIC 등록일 2024-08-14)
- 국외 연구진
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