Combined inhibition of JAK1,2/Stat3‑PD‑L1 signaling pathway suppresses the immune escape of castration‑resistant prostate cancer to NK cells in hypoxia

Xu, Lanfang; Ma, Qi; Zhu, Jin; Li, Jian; Xue, Boxin; Gao, Jie; Sun, Chuanyu; Zang, Yu‐Feng; Zhou, Yibin; Yang, Dian; Shan, Yuxi

doi:10.3892/mmr.2018.8905

Cited by 36 publications

(38 citation statements)

References 52 publications

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“…As for the IL6-JAK-STAT3 signaling, studies showed it involved in tumor growth, metastasis, and the immune escaping. [23][24][25][26][27] Therefore, it may be a reason for unfavorable prognosis in low-purity group. Both IL2-STAT5 signaling and IL6-JAK-STAT3 signaling may become potential immunotherapeutic targets for low-purity gastric tumors.…”

Section: Discussionmentioning

confidence: 99%

Tumor purity as a prognosis and immunotherapy relevant feature in gastric cancer

Gong

Zhang

2020

Cancer Medicine

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Tumor microenvironment (TME) has been illustrated their clinic pathological significance in predicting outcomes and therapeutic efficacy by more and more studies. Tumor purity, which reflects the features of TME, is defined as the proportion of cancer cell in the tumor tissue. However, the current staging and prognostic prediction system in gastric cancer (GC) paid little attention to TME. Therefore, we carried out the study to explore the role of tumor purity in GC. We retrospectively collected the clinical and transcriptomic data from four public data sets (n = 1340), GSE15459 , GSE26253 , GSE62254 , and The Cancer Genome Atlas (TCGA). About 34 GC patients from Fudan University Shanghai Cancer Center (FUSCC) were assigned as an independent validation group. Tumor purity was measured by a computational method. Low tumor purity was associated with unfavorable prognosis, upregulated EMT and stemness pathways, more infiltrating of Tregs, M1 and M2 macrophages and a higher expression level of various immune checkpoints and chemokines recruiting immune suppressive cells. Our study indicates low tumor purity in GC was associated with unfavorable prognosis and immune‐evasion phenotype. Further investigations toward tumor purity in GC may contribute to prognosis prediction and the decision of therapy strategies.

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Section: Discussionmentioning

confidence: 99%

Tumor purity as a prognosis and immunotherapy relevant feature in gastric cancer

Gong

Zhang

2020

Cancer Medicine

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“…Castration-resistant prostate cancer (CRPC) cells increased the expression of PD-L1 which participated in tumor immune evasion under hypoxic conditions. Silencing STAT3 signaling can reverse the level of PD-L1 and enhance the susceptibility of CRPC cells to NK cell immunity [ 155 ].…”

Section: Stat3 Target Genes Impact Chemoresistance and Radioresistmentioning

confidence: 99%

STAT3, the Challenge for Chemotherapeutic and Radiotherapeutic Efficacy

Yang

Liu

et al. 2020

Cancers

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Chemoradiotherapy is one of the most effective and extensively used strategies for cancer treatment. Signal transducer and activator of transcription 3 (STAT3) regulates vital biological processes, such as cell proliferation and cell growth. It is constitutively activated in various cancers and limits the application of chemoradiotherapy. Accumulating evidence suggests that STAT3 regulates resistance to chemotherapy and radiotherapy and thereby impairs therapeutic efficacy by mediating its feedback loop and several target genes. The alternative splicing product STAT3β is often identified as a dominant-negative regulator, but it enhances sensitivity to chemotherapy and offers a new and challenging approach to reverse therapeutic resistance. We focus here on exploring the role of STAT3 in resistance to receptor tyrosine kinase (RTK) inhibitors and radiotherapy, outlining the potential of targeting STAT3 to overcome chemo(radio)resistance for improving clinical outcomes, and evaluating the importance of STAT3β as a potential therapeutic approach to overcomes chemo(radio)resistance. In this review, we discuss some new insights into the effect of STAT3 and its subtype STAT3β on chemoradiotherapy sensitivity, and we explore how these insights influence clinical treatment and drug development for cancer.

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“…Cytotoxicity assays. CytoTox 96 ® non-radioactive cytotoxicity assay (Promega Corporation) was used for the detection of SW480 cell killing by NK-92 cells according to the manufacturer's protocol as a previous report (15). SW480 cells were first washed with PBS, re-suspended in fresh NK-92 culture medium (fully supplemented as previously described) and seeded into 96-well plates (density, 5x10 3 cells/well).…”

Section: Methodsmentioning

confidence: 99%

NK cell‑produced IFN‑γ regulates cell growth and apoptosis of colorectal cancer by regulating IL‑15

Cui

Sun

et al. 2019

Exp Ther Med

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Globally, colorectal cancer (CC) is the third leading cause of mortality associated with cancer. Natural killer (NK) cells are a major class of cells that are responsible for eliminating tumor cells and cytokine production. NK cell-mediated production of interferon gamma (IFN-γ) has antiviral, immunoregulatory and anti-tumor properties. IL-15 is important in linking inflammation with cancer. For instance, IL-15 promotes humoral and cell-mediated immune responses to inhibit tumor growth. IL-15 inhibits colitis-associated colon carcinogenesis by inducing antitumor immunity. However, the effect of NK cell-mediated IFN-γ on IL-15 expression in CC progression remains unknown. mRNA and protein level were detected using reverse transcription-quantitative PCR and western blotting, respectively. IFN-γ concentrations were detected using ELISAs. The cytotoxicity of NK-92 cells on SW480 cells was detected using cytoTox 96 ® non-radioactive cytotoxicity assays. Cell apoptosis and cell proliferation was detected using flow cytometry and CCK-8 assays, respectively. IL-2 was used for NK-92 stimulation, IL-15 antibodies were used to neutralize IL-15 bioactivity. For the present study, 21 patients with CC and 21 healthy volunteers were enrolled at the First Affiliated Hospital of Xi'an Jiaotong University. IL-15 mRNA and protein expression were significantly lower in NK cells isolated from the CC group compared with healthy volunteer group. IL-2 enhanced the production/secretion of IFN-γ in addition to enhancing NK-92 cell-mediated killing of SW480 cells. Compared with the control group, NK-92 cells treated with IL-2 alone significantly increased cell apoptosis, BAX expression levels as well as phosphorylated (p)-Janus kinase 2 and p-STAT1 protein levels, whilst reducing cell viability and Bcl-2 protein levels in SW480 cells. These observations were not made when treated with IL-2 and polyclonal antibody (pAb) targeting IL-15. Taken together, NK cell-mediated IFN-γ served a pivotal role in CC by regulating IL-15. The effects of IL-2 induced IFN-γ were abolished by pAb IL-15 treatment. The mechanisms of action behind how IFN-γ regulates IL-2 is unclear, and is a promising area for future research.

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Combined inhibition of JAK1,2/Stat3‑PD‑L1 signaling pathway suppresses the immune escape of castration‑resistant prostate cancer to NK cells in hypoxia

Cited by 36 publications

References 52 publications

Tumor purity as a prognosis and immunotherapy relevant feature in gastric cancer

Tumor purity as a prognosis and immunotherapy relevant feature in gastric cancer

STAT3, the Challenge for Chemotherapeutic and Radiotherapeutic Efficacy

NK cell‑produced IFN‑γ regulates cell growth and apoptosis of colorectal cancer by regulating IL‑15

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