Overexpression of interleukin‐35 in intrahepatic cholangiocarcinoma is a prognostic indicator after curative resection

Zhang, Meixia; Gan, Wei; Jing, Chuyu; Zheng, Su-Su; Zhang, Juan; Shen, Hujia; Xu, Xiaowu; Lin, Jiajia; Zhang, Bo‐heng; Qiu, Shuang–Jian

doi:10.1111/cas.13535

Cited by 14 publications

(12 citation statements)

References 35 publications

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“…We found that overexpression of IL-35 in HCC was an independent risk factor for overall survival and recurrence. The GP130 and IL-12 Rβ2 receptors were also found to be expressed in HCC tissues, indicating a structural basis for the paracrine and autocrine function of IL-35, consistent with previous reports [22,30] . We further combined the expression levels of IL-35 and its receptors in HCC tissues, and found that patients with high expression of IL-35 and its receptors in tumor tissues had the worst prognosis, indicating that IL-35 expressed in HCC might activate the receptors of tumor cells through an autocrine pathway to promote the progression of liver cancer.…”

Section: Discussionsupporting

confidence: 91%

Interleukin 35 Activates Intratumor Neovascularization Via Enhanced Secretion of FGF2 in Hepatocellular Carcinoma Through The Recruitment of Neutrophils, and Blocking it Could Facilitate The Efficacy of The PD-1 Antibody

Gan

Zhang

et al. 2020

Preprint

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Background: Recently, more and more treatment strategies for Hepatocellular carcinoma (HCC) have emerged, but the therapeutic effect is still not satisfactory. This study is aimed to explore the mechanism of Interleukin 35 (IL-35) in promoting the progression of liver cancer and to explore the application value of IL-35 in the treatment of HCC.Methods: We used clinical tissue microarray (TMA) immunohistochemistry (IHC) to explore the prognostic value of IL-35 expression in patients with HCC. The effect of IL-35 on the function of HCC was explored by functional experiments including wound-healing assay, transwell, cell counting kit-8, cell adhesion assay and endothelial tube formation assay in vitro and mouse xenografts in vivo. And flow cytometry was used to study the effect of IL-35 on infiltrating immune cells in tumor. The molecular mechanism of the function of IL-35 on the progression of HCC was explored by sequencing, ELISA, WB, PCR and other technical means. Finally, through in vivo tumor animal experiments to explore the value of anti-IL-35 antibody and combined with anti-PD-1 antibody in the treatment of liver cancer.Results: High expression of IL-35 in patients with HCC were identified to be associated with poor prognosis. And we have found that IL-35 facilitated tumor progression by affecting neutrophil infiltration, angiogenesis, and CD8+ T-cell infiltration in a mouse model. Additionally, on the one hand C-C motif chemokine ligand 3 (CCL3) has been found to be a key factor mediating the recruitment of neutrophils by IL-35, on the other hand fibroblast growth factor 2 (FGF2) secreting by neutrophil when stimulated by IL-35 was also found to be the core cytokine to promote intratumoral angiogenesis. And IL-35 was also discovered to facilitated the adhesion of tumor to endothelial cells, with neutrophils further enhancing this effect in vitro and vivo. More important, anti-IL-35 antibody was found to be a valid treatment for HCC in xenograft tumor model, and it could give full play to the curative effect of 1:1＞2 when combination therapy with PD-1 antibody.Conclusion: Our data show that the expression of IL-35 in patients with HCC is an important tumor promoting factor. The application of anti-IL-35 antibody and treatment combined anti-IL-35 antibody with anti-PD-1 antibody have potential therapeutic value in the treatment of liver cancer.

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Section: Discussionsupporting

confidence: 91%

Interleukin 35 Activates Intratumor Neovascularization Via Enhanced Secretion of FGF2 in Hepatocellular Carcinoma Through The Recruitment of Neutrophils, and Blocking it Could Facilitate The Efficacy of The PD-1 Antibody

Gan

Zhang

et al. 2020

Preprint

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“…IL-35 played a pivotal role in the pathogenesis of tumor, progression, and prognosis. Tumor derived IL-35 has been demonstrated to promote tumor progression and to be a prognostic indicator in non-small cell lung cancer (20), intrahepatic cholangiocarcinoma (21), colorectal cancer (22, 23), prostate cancer (24), and breast cancer (25). However, controversy remained as to the expression profile of liver-resident and peripheral IL-35 expression in HCC patients.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-35 Dampens CD8+ T Cells Activity in Patients With Non-viral Hepatitis-Related Hepatocellular Carcinoma

et al. 2019

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Interleukin (IL)-35 is a newly identified IL-12 cytokine family member, which has been demonstrated to induce immunotolerance by suppression of CD8 + T cells function in chronic viral hepatitis. However, the role of IL-35 in modulating CD8 + T cells activity in non-viral hepatitis-related hepatocellular carcinoma (HCC) was not fully elucidated. Forty-four patients with non-viral hepatitis-related HCC and 20 healthy individuals were enrolled. Serum IL-35 concentration was measured by ELISA. CD8 + T cells were purified from peripheral bloods and liver tissues. mRNA expression of cytotoxic/inhibitory molecules in CD8 + T cells with IL-35 stimulation was semi-quantified by real-time PCR. Direct and indirect contact co-culture systems of CD8 + T cells and HCC cell lines were set up. The modulatory function of IL-35 on peripheral and liver-resident CD8 + T cells was assessed by measurement of lactate dehydrogenase release and cytokine production in the co-culture supernatants. Serum IL-35 was notably elevated in HCC patients, while effective anti-tumor therapies down-regulated IL-35 concentration. Recombinant IL-35 stimulation suppressed cytotoxicity and proinflammatory cytokine secretion of peripheral and liver-resident CD8 + T cells in direct and indirect contact co-culture systems. This process was accompanied by reduction of perforin expression and interferon-γ production, as well as programmed death-1 and cytotoxic T-lymphocyte-associated protein 4 elevation in CD8 + T cells. The current data suggested that IL-35 inhibited both cytolytic and non-cytolytic function of CD8 + T cells to non-viral hepatitis-related HCC probably via repression of perforin expression. IL-35 might be considered to be one of the therapeutic targets for patients with HCC.

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“…The lack of significant correlation between IL-35 expression and prognosis in DLBCL patients contrasts with previous findings in other human tumors for which IL-35 expression in tumor was associated with a worse prognosis. However, whereas most studies identified IL-35 as a factor positively linked to tumor progression (10, 19, 20, 22, 24, 25), others suggested that IL-35 may play an anti-tumor role (21, 23). The impact of IL-35 in cancer most likely results from a combination of various factors involving expression of IL-35 receptor, tumor genomics, and specific features of tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

“…However, the high expression of IL-35 at sites of immune escape such as the fetal maternal interface (17) and in tolerogenic dendritic cells (18), favors a key role in immune tolerance. In addition, IL-35 expression by tumor cells or infiltrating lymphocytes has been reported in various types of human tumors including liver, pancreatic, colorectal, or breast cancer (10, 19–25). In most of these studies, IL-35 expression was associated with a worse prognosis (10, 19, 20, 22, 24, 25).…”

Section: Introductionmentioning

confidence: 99%

Evidence for IL-35 Expression in Diffuse Large B-Cell Lymphoma and Impact on the Patient's Prognosis

et al. 2019

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IL-35 is an immunosuppressive cytokine of the IL-12 family consisting of two subunits, EBV-induced gene 3 (EBI3) and p35. It has been shown to play a pro-tumor role in murine tumor models, and in various types of human cancer such as colorectal, pancreatic, or liver carcinoma, its expression has been associated with a worse clinical outcome. Here, we show by analyzing gene expression data from public databases and by immunohistochemical studies that IL-35 is overexpressed by tumor cells in diffuse-large B-cell lymphoma (DLBCL) compared to another type of mature aggressive B-cell lymphoma, Burkitt lymphoma. However, while high IL-35 expression was significantly associated with a worse overall survival in DLBCL patients treated with chemotherapy only (cyclophosphamide, doxorubicin, vincristine, prednisone, CHOP), no significant correlation between IL-35 expression levels and the patient outcome was observed in DLBCL patients treated with CHOP combined to rituximab (R-CHOP), the current conventional treatment. In addition, we found that an anti-IL-35 antibody, clone 15k8D10, used to assess IL-35 expression by immunohistochemistry in various human tissues including tumors does not recognize IL-35 heterodimer, nor its individual subunits EBI3 and p35, but cross-reacts with human IgG1, indicating that IL-35 expression in human cancers needs to be re-evaluated.

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Overexpression of interleukin‐35 in intrahepatic cholangiocarcinoma is a prognostic indicator after curative resection

Cited by 14 publications

References 35 publications

Interleukin 35 Activates Intratumor Neovascularization Via Enhanced Secretion of FGF2 in Hepatocellular Carcinoma Through The Recruitment of Neutrophils, and Blocking it Could Facilitate The Efficacy of The PD-1 Antibody

Interleukin 35 Activates Intratumor Neovascularization Via Enhanced Secretion of FGF2 in Hepatocellular Carcinoma Through The Recruitment of Neutrophils, and Blocking it Could Facilitate The Efficacy of The PD-1 Antibody

Interleukin-35 Dampens CD8+ T Cells Activity in Patients With Non-viral Hepatitis-Related Hepatocellular Carcinoma

Evidence for IL-35 Expression in Diffuse Large B-Cell Lymphoma and Impact on the Patient's Prognosis

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Overexpression of interleukin‐35 in intrahepatic cholangiocarcinoma is a prognostic indicator after curative resection

Cited by 14 publications

References 35 publications

Interleukin 35&nbsp;Activates Intratumor Neovascularization Via Enhanced Secretion of FGF2 in Hepatocellular Carcinoma Through The Recruitment of Neutrophils, and&nbsp;Blocking it Could Facilitate The Efficacy of The PD-1 Antibody

Interleukin 35&nbsp;Activates Intratumor Neovascularization Via Enhanced Secretion of FGF2 in Hepatocellular Carcinoma Through The Recruitment of Neutrophils, and&nbsp;Blocking it Could Facilitate The Efficacy of The PD-1 Antibody

Interleukin-35 Dampens CD8+ T Cells Activity in Patients With Non-viral Hepatitis-Related Hepatocellular Carcinoma

Evidence for IL-35 Expression in Diffuse Large B-Cell Lymphoma and Impact on the Patient's Prognosis

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Product

Resources

About

Interleukin 35 Activates Intratumor Neovascularization Via Enhanced Secretion of FGF2 in Hepatocellular Carcinoma Through The Recruitment of Neutrophils, and Blocking it Could Facilitate The Efficacy of The PD-1 Antibody

Interleukin 35 Activates Intratumor Neovascularization Via Enhanced Secretion of FGF2 in Hepatocellular Carcinoma Through The Recruitment of Neutrophils, and Blocking it Could Facilitate The Efficacy of The PD-1 Antibody