1. Targeting STAT3-VISTA axis to suppress tumor aggression and burden in acute myeloid leukemia
- Author
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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, and Xiaolei Zhang
- Subjects
AML ,VISTA ,STAT3 inhibitor ,Immunotherapy ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract The 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.
- Published
- 2023
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