Correlation Analysis Among the Level of IL‐35, Microvessel Density, Lymphatic Vessel Density, and Prognosis in Non‐Small Cell Lung Cancer

Abstract

The aim of this study was to determine the expression of IL-35 and the lymphatic vessel density (LVD) and microvessel density (MVD) in the pathological tissues from patients with non-small cell lung cancer (NSCLC) and to analyze their correlation with other common clinical prognostic factors, as well as patients' overall survival and progression-free survival. We analyzed the pathological characteristics of 130 patients with NSCLC and determined the IL-35 expression, MVD, and LVD changes in the pathological tissues by immunohistochemistry. The results showed that IL-35 expression was significantly correlated with tumor differentiation, lymph node metastasis, T staging, LVD, and MVD (P < 0.05) but was not associated with age, sex, smoking, and other factors. Univariate analysis of risk models showed that age, lymph node metastasis, T stage, and high IL-35 expression, LVD, and MVD were significantly associated with NSCLC prognosis (P < 0.05), whereas sex, smoking, and high differentiation were not correlated with prognosis. Multivariate analysis of the proportional risk model showed that the IL-35 expression, lymph node metastasis, high LVD, and high MVD were significantly correlated with NSCLC prognosis (P < 0.05). In conclusion, IL-35, MVD, and LVD may be independent prognostic markers. In addition, IL-35 might represent a promising clinical drug target for the treatment of NSCLC.

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

“…STAT1 phosphorylation occurs upon IL-35 binding to gp130, whereas STAT4 phosphorylation occurs upon IL-35 binding to IL-12Rb2 (22). IL-35 exert immunosuppressive action through STAT1/STAT4 in T cells and STAT1 in B cells (23,24). IL-35 is a cytokine that is responsible for immune system maintenance and for this inhibition of immune responses, functioning by promoting the expansion of regulatory T cells (Tregs) and regulatory B cells (Bregs) while simultaneously suppressing effector T cells, Th1 cells, Th17 cells, and macrophages (25).…”

The Molecular Role of IL-35 in Non-Small Cell Lung Cancer

“…The study by Zhang et al showed that plasma IL-35 levels in NSCLC patients were significantly higher than those in healthy controls (55). Additionally, the overexpression of IL-35 was significantly correlated with prognostic factors such as T stage, lymph node metastasis, micro-vessel density, and tumor differentiation, and total survival time increased in patients with low expression of IL-35 (55). A recent study by Li et al showed that plasma IL-35 in the stage IV NSCLC patients was higher than that of the healthy group, and its expression levels were higher in the cachexia group than that of the non-cachexia group.…”

“…IL-35 expression is increased in the serum and tumor tissue of NSCLC patients (17) and in bronchoalveolar lavage fluid (BALF) and serum of NSCLC patients undergoing immunotherapy (54), demonstrating that this cytokine can serve as a therapeutic target for NSCLC. The study by Zhang et al showed that plasma IL-35 levels in NSCLC patients were significantly higher than those in healthy controls (55). Additionally, the overexpression of IL-35 was significantly correlated with prognostic factors such as T stage, lymph node metastasis, micro-vessel density, and tumor differentiation, and total survival time increased in patients with low expression of IL-35 (55).…”

Interleukin-35 Is Involved in Angiogenesis/Bone Remodeling Coupling Through T Helper 17/Interleukin-17 Axis

“…These findings revealed that IL-35 secretion might be influenced by immune microenvironments and a variety of stimulants. In recent years, IL-35 was found to be involved in in multiple inflammatory diseases, autoimmune diseases and cancers, including type I diabetes, hepatitis, non-small cell lung cancer (14)(15)(16). Previous study also reported that IL-35 participated in bone metabolism (17,18).…”