Interleukin-35 promotes progression of prostate cancer and inhibits anti-tumour immunity

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.

IL-35 Regulates the Function of Immune Cells in Tumor Microenvironment

“…The discovery that IL-35 can induce the angiogenesis by monocyte/macrophage which secrete this cytokine offers key insights that can guide future studies of the role of IL-35 in cancer and immunotherapeutic treatment. The expression and promoting effect of IL-35 in tumor have been described in plenty of malignant tumors, such as HCC, PDAC & PCA (19,20,29). As a result of the "cold" nature of these tumors, patients receive little benefit from conventional immunotherapy treatments, and by developing a more comprehensive understanding of the mechanisms governing the production and signaling activities of IL-35 it may be possible to develop better targeted anti-tumor treatment strategies for these patients.…”

“…IL-35 has been shown to play an essential role in development of benign and malignant tumors, including hepatocellular carcinoma (HCC), advanced breast cancer (BRCA), pancreatic ductal adenocarcinoma (PDAC), nonsmall cell lung cancer (NSCLC), and prostate carcinoma (PCA) (19,20,28,29 (19). In vivo, IL-35 has been demonstrated to promote tumor growth, progression and metastasis by enhancing the secretion of other cytokines, such as IL-6 and G-CSF (granulocyte colony stimulating factor) (30).…”

“…IL-35 has been shown to promote N2 neutrophil polarization by increasing G-CSF and IL-6 production, thereby enhancing the ability of these N2 cells to promote angiogenesis and to suppress immune responses, thereby enabling invasion of N2 cells into tumor tissue (30). MDSCs within the TME can secrete a range of immunosuppressive factors including IL-35, and in PCA model mice, high IL-35 levels were associated with increases in MDSC and Treg levels and reductions in CD4 + and CD8 + T cell frequencies within the spleen, blood, and TME, and with alterations in tumor growth, metastasis, and worse survival outcomes (19). Moreover, tumor-cell derived IL-35 was reported to promote tumor growth and angiogenesis through the enhancement of myeloid cell accumulation in the TME (92,93).…”

“…First identified by Collison et al (16), IL-35 has since been shown to be an important regulator of tumor progression owing to its ability to drive the establishment of an immunosuppressive microenvironment (15,17,18). IL-35 expression within the TME can promote primary tumor cell growth and metastatic colonization at a secondary site (19,20), signaling through a receptor composed of gp130 and IL-12Rb2 to induce downstream Ebi3 and IL-12a transcription and the activation of a classical JAK-STAT signaling pathway (15,21). STAT1 phosphorylation occurs upon IL-35 binding to gp130, whereas STAT4 phosphorylation occurs upon IL-35 binding to IL-12Rb2 (22).…”

Pathogenesis and Function of Interleukin-35 in Rheumatoid Arthritis

“…It can induce the proliferation of Tregs and inhibit the differentiation of Th17 (T Helper cell 17) cells ( Wang et al, 2014 ; Behzadi et al, 2016 ). IL-35 is closely related to the occurrence of infections, inflammation, tumors, autoimmune diseases, such as primary biliary cirrhosis, Crohn’s disease, systemic sclerosis, and RA ( Kong et al, 2016 ; Zou et al, 2017 ; Teymouri et al, 2018 ; Zhao et al, 2020 ; Zhu et al, 2020 ).…”