Elevated plasma interleukin-35 levels predict poor prognosis in patients with non-small cell lung cancer

Gu, Xiaobin; Tian, Tian; Zhang, Bo; Yang, Liu; Yuan, Chao; Shao, Lijuan; Guo, Yajun; Fan, Kexing

doi:10.1007/s13277-014-2887-8

Cited by 30 publications

(33 citation statements)

References 20 publications

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“…High expression of IL-35 in tumor tissues and the elevated plasma IL-35 levels have been reported in patients with solid or hematopoietic malignancy [10, 11, 36]. The increase of IL-35 in tumor could promote tumor progression as shown by our data and others [37].…”

Section: Discussionsupporting

confidence: 76%

“…Clinical evidences showed that the higher expression of p35 and EBI3 was detected in tumor tissues [9]. The elevated serum IL-35 levels correlated with poor prognosis in patients with renal cell carcinoma and non-small cell lung cancer [10, 11]. Given that a chronic inflammatory microenvironment is an essential component of all of tumors [1], it is possible that IL-35 may promote tumor development by facilitating chronic inflammation.…”

Section: Introductionmentioning

confidence: 99%

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IL-35 induces N2 phenotype of neutrophils to promote tumor growth

Zou

Qin

et al. 2017

Oncotarget

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IL-35 is an immunosuppressive cytokine and exerts regulatory effects on T cells, B cells, macrophages and dendritic cells. Neutrophils are important innate immune cells that play key roles in tumor development. The effect of IL-35 on neutrophils remains unknown. Here, we report that IL-35 can induce N2 neutrophil polarization (protumor phenotype) by increasing G-CSF and IL-6 production, and promote neutrophil infiltration into tumor microenvironment. The sustained expression of IL-35 could promote chronic inflammation to augment the proangiogenic and immunosuppressive function of neutrophils. IL-35 stimulated macrophages to secrete proinflammatory cytokines IL-1β and IL-6. IL-1β stimulated γδ T cells to produce IL-17, which in turn increased the production of G-CSF. By increasing the expression of G-CSF and IL-6, IL-35 could up-regulate the expression of MMP-9 and Bv8, and down-regulate TRAIL expression in neutrophils, thus augmenting the proangiogenic function of neutrophils. Moreover, G-CSF/IL-6 induced the enhanced activation of STAT3 and ERK pathways in neutrophils, thus increasing the expression of iNOS to suppress T cell activation. Our findings suggest that IL-35 can promote tumor progression by functioning as an up-stream cytokine to promote cancer-associated inflammation and control neutrophil polarization. Targeting IL-35 might be an important approach for designing new strategy of tumor therapy.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

IL-35 induces N2 phenotype of neutrophils to promote tumor growth

Zou

Qin

et al. 2017

Oncotarget

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“…While no significant association was identified in the present study, an insufficient number of cases may have contributed to this lack of significance. In previous studies, over-expression of IL-35 in peripheral blood has been recognized as an unfavorable prognostic factor for malignant tumors, including nasopharyngeal carcinoma, pancreatic ductal adenocarcinoma, colorectal and non-small cell lung cancer (14,21,28,29). Nevertheless, another study detected increased IL-35 expression in early stage breast cancer and non-metastatic cases (27).…”

Section: The Association Between Il-35 Expression and The Prognosis Omentioning

confidence: 98%

IL-35 expression is increased in laryngeal squamous cell carcinoma and in the peripheral blood of patients

Jiang

et al. 2017

Oncology Letters

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Abstract. has been proposed as a novel immune-suppressing cytokine. However, the function of IL-35 in malignant diseases is yet to be elucidated. The present study investigated IL-35 expression levels in laryngeal squamous cell carcinoma (LSCC) tissues and the peripheral blood of patients to explore the potential involvement of IL-35 in LSCC progression. In the present study, IL-35 expression levels in tissues and peripheral blood were analyzed by reverse transcription-quantitative polymerase chain reaction and an enzyme-linked immunosorbent assay. The association between IL-35 expression levels and clinical characteristics was also evaluated. The present results demonstrated that IL-35 expression in tumor tissues was significantly higher than in adjacent normal tissues, and a significant association between IL-35 expression levels in tissues and the tumor site was detected. Furthermore, the expression of IL-35 in the peripheral blood of patients was significantly decreased subsequent to tumor resection. No correlation between peripheral blood IL-35 expression and clinical characteristics was detected. In conclusion, the present study demonstrated that IL-35 is highly expressed in LSCC tissues and in the peripheral blood of patients with LSCC. There was a notable, significant reduction of peripheral blood IL-35 expression following surgical resection of tumors. These results may be useful for diagnostic or therapeutic purposes in patients with LSCC.

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“…7D, F The aberrant expression of IL-35 has been shown in different cancers including acute myeloid leukemia [27,28], prostate cancer [18], breast cancer [19,29], colorectal cancer [17,30], pancreatic ductal adenocarcinoma [31], gastric cancer [32], and hepatocellular carcinoma [33]. Gu et al [21]. showed that plasma IL-35 expression was elevated and was a promising potential predictor in prognosis of clinical outcome of NSCLC patients.…”

Section: Il-35 Suppressed the Function Of Cd8mentioning

confidence: 99%

“…In addition, elevated IL-35 levels are also associated with cancer progression, aggressiveness, and recurrence [17][18][19][20]. A previous study also demonstrated that IL-35 overexpression correlated with a poor prognosis in patients with NSCLC [21]. However, the role of IL-35 in NSCLC has not been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-35 Suppresses the Antitumor Activity of T Cells in Patients with Non-Small Cell Lung Cancer

Wang¹,

Zhang²,

Feng³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Interleukin (IL)-35 has immunosuppressive functions in autoimmune diseases, infectious diseases, and certain cancers. However, few studies have focused on its immunoregulatory activity in non-small cell lung cancer (NSCLC). Thus, we investigated the role of IL-35 in the pathogenesis of this disease. Methods: A total of 66 NSCLC patients and 21 healthy individuals were enrolled. IL-35 expression in peripheral blood and bronchoalveolar lavage fluid (BALF) was measured. The modulatory functions of IL-35 on purified CD4⁺ and CD8⁺ T cells from NSCLC patients were investigated in direct and indirect coculture systems with NSCLC cell lines. Results: IL-35 expression was significantly increased in BALF from the tumor site, but not in the peripheral blood of NSCLC patients. IL-35 did not affect the bioactivity including proliferation, cytokine production, cell cycle, and cellular invasion of NSCLC cells. It suppressed responses from type 1 T helper (Th1) and Th17 cells but elevated the regulatory T cell response in cultured CD4⁺ T cells from NSCLC patients, and reduced cytokine-mediated CD4⁺ T cells cytotoxicity to NSCLC cells. Moreover, IL-35 also inhibited cytotoxic gene expression in CD8⁺ T cells from NSCLC, reducing their cytolytic and noncytolytic functions. Conclusion: The results of this study suggest that IL-35 contributes to the dysfunction/exhaustion of T cells and limited antitumor immune responses in NSCLC.

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Elevated plasma interleukin-35 levels predict poor prognosis in patients with non-small cell lung cancer

Cited by 30 publications

References 20 publications

IL-35 induces N2 phenotype of neutrophils to promote tumor growth

IL-35 induces N2 phenotype of neutrophils to promote tumor growth

IL-35 expression is increased in laryngeal squamous cell carcinoma and in the peripheral blood of patients

Interleukin-35 Suppresses the Antitumor Activity of T Cells in Patients with Non-Small Cell Lung Cancer

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