Interleukin-35 promotes progression of prostate cancer and inhibits anti-tumour immunity
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Cancer Cell International Open Access
PRIMARY RESEARCH
Interleukin‑35 promotes progression of prostate cancer and inhibits anti‑tumour immunity Jialin Zhu1†, Yan Wang2†, Dai Li3†, Haonan Zhang4, Zhi Guo4* and Xueling Yang4*
Abstract Background: Interleukin-35 (IL-35) has been reported to play an important role in the progression of cancers. The role of IL-35 in prostate cancer (PCA) is not well understood. In this study, we investigated the effects of IL-35 on PCA and its immunoregulatory effect on PCA. Methods: The protein and mRNA expression of IL-35 in PCA cells was detected by western blot and RT-PCR. The invasion and migration of cells were detected using transwell and wound‐healing assays. A CCK-8 assay was conducted to observe cell proliferation. In vivo, IL-35 plasma concentration was test by enzyme-linked immunosorbent assay. The role of IL-35 in tumour cell proliferation and angiogenesis of mice was detected by immunohistochemical stains. The mouse survival and tumour volumes were calculated, and lung metastasis rate was detected by HE staining. The modulatory effects of IL-35 on myeloid-derived inhibitory cells (MDSCs), regulatory T cells (Tregs), CD4+ T cells and CD8+ T cells from PCA mice were investigated by immunohistochemical stains and flow cytometry. Results: High levels of IL-35 significantly promoted the migration, invasion and cell proliferation of PCA cells in vitro. IL-35 was associated with tumour growth, metastasis and poor prognosis in PCA mice. Additionally, high levels of IL-35 significantly increased the proportions of MDSCs and Tregs and decreased the proportions of CD4+ and CD8+ T cells in the spleen, blood and tumour microenvironment. The IL-35 neutralizing antibody played the opposite role. Conclusions: IL-35 contributed to the progression of PCA through promoting cell proliferation and tumour angiogenesis. IL-35 might limit the anti-tumour immune response by upregulating the proportions of Tregs and MDSCs and by reducing the proportions of CD4+ and CD8+ T cells. IL-35 might serve as a novel therapeutic target for PCA. Keywords: Interleukin-35, Prostate cancer, Proliferation, Angiogenesis, Anti-tumour immunity Background Prostate cancer (PCA) is the second most common malignant tumour and the fifth leading cause of cancerassociated mortality in men worldwide [1]. Patients with
*Correspondence: [email protected]; [email protected] † Jialin Zhu, Yan Wang and Dai Li contributed equally to this work 4 Department of Interventional Therapy, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Huan Hu West Road, Tianjin 300060, China Full list of author information is available at the end of the article
localized PCA are usually treated with surgery or radiotherapy. However, 20–40% of patients receiving radical prostatectomy and 30–50% of patients receiving radiation therapy will have a recurrence that develops into metastatic d
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