Tumour-derived Interleukin 35 promotes pancreatic ductal adenocarcinoma cell extravasation and metastasis by inducing ICAM1 expression

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.

CAR T Therapy Targeting ICAM-1 Eliminates Advanced Human Thyroid Tumors

“…This correlation was also experimentally validated in our study across multiple thyroid cancer cell lines. Moreover, ICAM-1-targeting therapy has potential applications in the treatments of other malignancies, including pancreatic ductal adenocarcinoma (17), breast cancer (16), multiple myeloma (37), and gastric tumors (18), where ICAM-1 surface expression is also significantly elevated compared to normal tissues. Along with thyroid carcinoma, TCGA studies indicated that overall patient survival was shorter when levels of ICAM-1 mRNA were upregulated in glioblastoma multiforme, renal clear cell carcinoma, renal papillary cell carcinoma, and hepatocellular carcinoma (Supplementary Fig.…”

“…Under non-inflammatory conditions, ICAM-1 expression is constitutively low and faintly detectable on endothelial cells. Increased ICAM-1 expression levels have been observed in multiple myeloma (15) and across many disparate carcinomas including breast (16), pancreas (17), and gastric (18) tumors, and are correlated with tumor progression and metastatic capability (19). Moreover, clinical trials support the safety and tolerability of targeting ICAM-1 using monoclonal antibodies (20–24).…”

Interleukin 35 ameliorates myocardial ischemia‐reperfusion injury by activating the gp130‐STAT3 axis

“…Briefly, cells were plated in 6‐well culture plates and cultured in Claycomb medium (JRH Biosciences, USA) supplemented with 10% fetal bovine serum (Gibco, USA), 2 mM L‐glutamine (Gibco, USA), and 1% antibiotics (penicillin and streptomycin). Cells were cultured in serum‐free conditions for 12 hours, followed by exposure to H 2 O 2 (Sigma‐Aldrich, St. Louis, MO) alone or together with mouse IL‐35 (100 ng mL −1 , R&D Systems, Minneapolis, MN) for the detection of apoptosis and STAT activation . In the experiment concerning gp130 and IL‐12Rβ2 neutralizing antibody (R&D systems, Minneapolis, MN), cardiac muscle cell line (HL‐1) cells were prepared according to the same protocol.…”

“…IL‐35 inhibits MAPK‐AP1‐mediated VCAM‐1 expression via gp130 and IL‐12Rβ2 receptors in LPS‐treated endothelial cells (ECs) . Furthermore, IL‐35 promotes ICAM‐1 overexpression in tumor cells through a gp130‐STAT1 signaling pathway while inducing CCL5 expression through the STAT1‐STAT4 heterodimer, which requires both the gp130 and IL‐12Rβ2 receptor chains . Meanwhile, it has been reported that gp130 was also expressed on cardiomyocytes and activation of gp130‐STAT3 pathway promoted cardiomyocyte survival and played a crucial cardioprotective role in MIRI .…”

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

“…showed that overexpression of IL-35 inhibited cell growth and increased apoptosis sensitivity of different human cancer cell lines. In contrast, most studies have demonstrated that IL-35 is an autocrine growth factor [13], which promotes tumor growth through different mechanisms, including enhancement of proliferation and loss of control of tumor cell growth, inhibition of apoptosis, and promotion of angiogenesis, extravasation, and metastasis [13,15,35,36]. To the best of our knowledge, the current in vitro results provided the first data about on the influence of IL-35 to bioactivity of NSCLC cell lines.…”