Targeting STAT3-VISTA axis to suppress tumor aggression and burden in acute myeloid leukemia

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.

Novel artemisinin derivative P31 inhibits VEGF-induced corneal neovascularization through AKT and ERK1/2 pathways

“…After permeating, the cells were washed twice and dyed with EdU reaction solution to indicate proliferation. A fluorescence microscope was used to capture the image [ 27 ].…”

cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment

“…Therefore, H. Pylori infection and cAMP signaling may cooperatively promote gastric carcinogenesis. Since STAT3 is a potent oncogene in various types of cancer [ 164 ], the PKA-DARPP32-STAT3 axis may contribute to tumorigenesis at sites other than the stomach.…”

Combinatorial blockade for cancer immunotherapy: targeting emerging immune checkpoint receptors

“…A similar expression pattern of VISTA is seen in human peripheral blood monocytic cells. VISTA gene expression is positively regulated by the transcription factors P53, HIF1-α, and STAT3 ( 81 – 83 ). However, whether VISTA exerts any impact on the functions of HIF1-α and STAT3 remains unknown.…”

“…In human cancer tissues, VISTA expression was mostly enriched in tumor-infiltrating myeloid cells and T cells ( 75 , 85 ). In addition to immune cells, VISTA expression was detected in mesothelioma ( 86 ), gastric cancer ( 87 ), and AML ( 83 , 88 , 89 ). VISTA expression has been associated with resistance to immunotherapy and poor patient survival in many cancers, including prostate cancer, lymphoma, bladder cancer, melanoma, breast cancer, and AML ( 88 , 90 – 95 ),…”