Inhibition of STAT3 activity re-activates anti-tumor immunity but fails to restore the immunogenicity of tumor cells in a B-cell lymphoma model

Cao, Yang; Zhou, Xiaoxi; Zhou, Mi; Xu, Danmei; Ma, Qing; Zhang, Peilin; Huang, Xiaoyuan; Li, Qinlu; Ma, Ding; Zhou, Jianfeng

doi:10.4161/cbt.29453

Cited by 3 publications

(2 citation statements)

References 39 publications

(45 reference statements)

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“…This is in agreement with an original report in mouse lymphoma cells that suggested the role of STAT3 in restricting BCL cell immunogenicity 50 . Importantly, while mutations may prevent direct effects of STAT3 inhibition on BCL cells, the increased activity of non-malignant antigen-presenting cells can be sufficient for the induction of antitumor immune responses 51 . Several small-molecule JAK inhibitors and STAT3 antisense oligonucleotides are currently in clinical trials for hematologic malignancies, including drug-resistant or relapsed BCL cells 22, 52.…”

Section: Discussionsupporting

confidence: 92%

B Cell Lymphoma Immunotherapy Using TLR9-Targeted Oligonucleotide STAT3 Inhibitors

et al. 2018

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Growing evidence links the aggressiveness of non-Hodgkin's lymphoma, especially the activated B cell-like type diffuse large B cell lymphomas (ABC-DLBCLs) to Toll-like receptor 9 (TLR9)/MyD88 and STAT3 transcription factor signaling. Here, we describe a dual-function molecule consisting of a clinically relevant TLR9 agonist (CpG7909) and a STAT3 inhibitor in the form of a high-affinity decoy oligodeoxynucleotide (dODN). The CpG-STAT3dODN blocked STAT3 DNA binding and activity, thus reducing expression of downstream target genes, such as MYC and BCL2L1, in human and mouse lymphoma cells. We further demonstrated that injections (i.v.) of CpG-STAT3dODN inhibited growth of human OCI-Ly3 lymphoma in immunodeficient mice. Moreover, systemic CpG-STAT3dODN administration induced complete regression of the syngeneic A20 lymphoma, resulting in long-term survival of immunocompetent mice. Both TLR9 stimulation and concurrent STAT3 inhibition were critical for immune-mediated therapeutic effects, since neither CpG7909 alone nor CpG7909 co-injected with unconjugated STAT3dODN extended mouse survival. The CpG-STAT3dODN induced expression of genes critical to antigen-processing/presentation and Th1 cell activation while suppressing survival signaling. These effects resulted in the generation of lymphoma cell-specific CD8/CD4-dependent T cell immunity protecting mice from tumor rechallenge. Our results suggest that CpG-STAT3dODN as a systemic/local monotherapy or in combination with PD1 blockade can provide an opportunity for treating patients with B cell NHL.

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Section: Discussionsupporting

confidence: 92%

B Cell Lymphoma Immunotherapy Using TLR9-Targeted Oligonucleotide STAT3 Inhibitors

et al. 2018

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“…For example, STAT3 is subject to phosphorylation on serine 727 (that lacks in STAT3β) by serine protein kinases, as well as, lysine acetylation and methylation by protein acetyltransferase and methyltransferases [ 16 , 42 ]. Multiple studies reported about the possible roles of Ser727 phosphorylation in both protein functions and progression of specific cancers [ 43 ].…”

Section: Post-transcriptional Modifications and Their Role In The mentioning

confidence: 99%

Structural Biology of STAT3 and Its Implications for Anticancer Therapies Development

Sgrignani

Garofalo

Matkovic

et al. 2018

IJMS

115

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Transcription factors are proteins able to bind DNA and induce the transcription of specific genes. Consequently, they play a pivotal role in multiple cellular pathways and are frequently over-expressed or dysregulated in cancer. Here, we will focus on a specific “signal transducer and activator of transcription” (STAT3) factor that is involved in several pathologies, including cancer. For long time, the mechanism by which STAT3 exerts its cellular functions has been summarized by a three steps process: (1) Protein phosphorylation by specific kinases, (2) dimerization promoted by phosphorylation, (3) activation of gene expression by the phosphorylated dimer. Consequently, most of the inhibitors reported in literature aimed at blocking phosphorylation and dimerization. However, recent observations reopened the debate and the entire functional mechanism has been revisited stimulating the scientific community to pursue new inhibition strategies. In particular, the dimerization of the unphosphorylated species has been experimentally demonstrated and specific roles proposed also for these dimers. Despite difficulties in the expression and purification of the full length STAT3, structural biology investigations allowed the determination of atomistic structures of STAT3 dimers and several protein domains. Starting from this information, computational methods have been used both to improve the understanding of the STAT3 functional mechanism and to design new inhibitors to be used as anticancer drugs. In this review, we will focus on the contribution of structural biology to understand the roles of STAT3, to design new inhibitors and to suggest new strategies of pharmacological intervention.

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(+)-Isocryptotanshinone derivatives and its simplified analogs as STAT3 signaling pathway inhibitors

Shi

Zhang

et al. 2022

Bioorganic Chemistry

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Inhibition of STAT3 activity re-activates anti-tumor immunity but fails to restore the immunogenicity of tumor cells in a B-cell lymphoma model

Cited by 3 publications

References 39 publications

B Cell Lymphoma Immunotherapy Using TLR9-Targeted Oligonucleotide STAT3 Inhibitors

B Cell Lymphoma Immunotherapy Using TLR9-Targeted Oligonucleotide STAT3 Inhibitors

Structural Biology of STAT3 and Its Implications for Anticancer Therapies Development

(+)-Isocryptotanshinone derivatives and its simplified analogs as STAT3 signaling pathway inhibitors

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