Targeting STAT3-VISTA axis to suppress tumor aggression and burden in acute myeloid leukemia
Targeting STAT3-VISTA axis to suppress tumor aggression and burden in acute myeloid leukemia
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DOI：
10.1186/s13045-023-01410-y
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Xiaolei Zhang
中科院分区：
文献类型：
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作者：
Jianshan Mo;Lin Deng;Keren Peng;Shumin Ouyang;Wen Ding;Linlin Lou;Ziyou Lin;Jianzheng Zhu;Jingwei Li;Qiyi Zhang;Pengyan Wang;Yuanzhen Wen;Xiaobing Chen;Peibin Yue;Jin-Jian Lu;Kai Zhu;Yongjiang Zheng;Yuanxiang Wang;Xiaolei Zhang
AbstractThe acute myeloid leukemia (AML) patients obtain limited benefits from current immune checkpoint blockades (ICBs), although immunotherapy have achieved encouraging success in numerous cancers. Here, we found that V-domain Ig suppressor of T cell activation (VISTA), a novel immune checkpoint, is highly expressed in primary AML cells and associated with poor prognosis of AML patients. Targeting VISTA by anti-VISTA mAb boosts T cell-mediated cytotoxicity to AML cells. Interestingly, high expression of VISTA is positively associated with hyperactive STAT3 in AML. Further evidence showed that STAT3 functions as a transcriptional regulator to modulate VISTA expression by directly binding to DNA response element of VISTA gene. We further develop a potent and selective STAT3 inhibitor W1046, which significantly suppresses AML proliferation and survival. W1046 remarkably enhances the efficacy of VISTA mAb by activating T cells via inhibition of STAT3 signaling and down-regulation of VISTA. Moreover, combination of W1046 and VISTA mAb achieves a significant anti-AML effect in vitro and in vivo. Overall, our findings confirm that VISTA is a potential target for AML therapy which transcriptionally regulated by STAT3 and provide a promising therapeutic strategy for immunotherapy of AML.
