Abstract

Interleukin 35 (IL-35) is a novel member of the IL-12 family, consisting of an EBV-induced gene 3 (EBI3) subunit and a P35 subunit. IL-35 is an immune-suppressive cytokine mainly produced by regulatory T cells. However, the role of IL-35 in cancer metastasis and progression is not well understood. Here we demonstrate that IL-35 is overexpressed in human pancreatic ductal adenocarcinoma (PDAC) tissues, and that IL-35 overexpression is associated with poor prognosis in PDAC patients. IL-35 has critical roles in PDAC cell extravasation and metastasis by facilitating the adhesion to endothelial cells and transendothelial extravasation. Mechanistically, IL-35 promotes ICAM1 overexpression through a GP130-STAT1 signalling pathway, which facilitates endothelial adhesion and transendothelial migration via an ICAM1–fibrinogen–ICAM1 bridge. In an orthotopic xenograft model, IL-35 promotes spontaneous pancreatic cancer metastasis in an ICAM1-dependent manner. Together, our results indicate additional functions of IL-35 in promoting PDAC metastasis through mediating ICAM1 expression.

Highlights

  • Interleukin 35 (IL-35) is a novel member of the IL-12 family, consisting of an EBV-induced gene 3 (EBI3) subunit and a P35 subunit

  • EBI3 and P35 were frequently co-expressed in the cytoplasm of the five types of tumour tissue but they were rarely expressed in the adjacent normal tissues and the adjacent pre-neoplastic lesions (Fig. 1a and Supplementary Fig. 2)

  • The results revealed that IL-35 significantly facilitated pancreatic ductal adenocarcinoma (PDAC) adhesion to lymphatic endothelial monolayers, as it did in the human umbilical vein endothelial cells (HUVECs) adhesion assays (Supplementary Fig. 8)

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Summary

Introduction

Interleukin 35 (IL-35) is a novel member of the IL-12 family, consisting of an EBV-induced gene 3 (EBI3) subunit and a P35 subunit. Understanding the mechanisms that regulate PDAC metastasis are critical to improving PDAC treatment Both of the major theories of cancer metastasis—the seed and soil hypothesis and the mechanical trapping theory—view tumour cell adhesion to the endothelia as one of the key steps in the metastatic process[5,6]. Interleukin 35 (IL-35) is a recently identified member of the IL-12 family of cytokines, which are primarily expressed by regulatory T cells (Tregs), such as natural Tregs and inducible Tregs[9,10]. It shares components with IL-12 and IL-27, IL-35 has distinctly different immunological functions. We identified a crucial role of IL-35 in the extravasation and metastasis processes in human pancreatic ductal carcinoma

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