The antitumor potential of Interleukin-27 in prostate cancer

Abstract

Prostate cancer (PCa) is of increasing significance worldwide as a consequence of the population ageing. Fragile elderly patients may particularly benefit from noninvasive and well tolerable immunotherapeutic approaches. Preclinical studies have revealed that the immune-regulatory cytokine IL-27 may exert anti-tumor activities in a variety of tumor types without discernable toxicity. We, thus, investigated whether IL-27 may function as anti-tumor agent in human (h) PCa and analyzed the rationale for its clinical application.In vitro, IL-27 treatment significantly inhibited proliferation and reduced the angiogenic potential of hPCa cells by down-regulating the pro-angiogenesis-related genes fms-related tyrosine kinase (FLT)1, prostaglandin G/H synthase 1/cyclooxygenase-1 (PTGS1/COX-1) and fibroblast growth factor receptor (FGFR)3. In addition, IL-27 up-regulated the anti-angiogenesis-related genes such as CXCL10 and TIMP metallopeptidase inhibitor 3 (TIMP3). In vivo, IL-27 reduced proliferation and vascularization in association with ischemic necrosis of tumors developed after PC3 or DU145 cell injection in athymic nude mice. In patients' prostate tissues, IL-27R was expressed by normal epithelia and low grade PCa and lost by high tumor grade and stages. Nevertheless, IL-27R was expressed by CD11c+, CD4+ and CD8+ leukocytes infiltrating the tumor and draining lymph nodes.These data lead to the conclusion that i) IL-27's anti-PCa potential may be fully exploited in patients with well-differentiated, localized IL-27R positive PCa, since in this case it may act on both cancerous epithelia and the tumor microenvironment; ii) PCa patients bearing high grade and stage tumor that lack IL-27R may benefit, however, from IL-27's immune-stimulatory properties.

The biology of interleukin-27 reveals unique pro- and anti-inflammatory functions in immunity

“…In prostate tissue from patients, WSX-1 was expressed by normal epithelia and in prostate cancer the expression of WSX-1 was lost during development of the tumors. However, in early stages IL-27 reduced proliferation and vascularization and had also an immune-stimulatory effect on the tumor microenvironment which might even be beneficial for patients with late stage tumors [69].…”

Interleukin-27 augments the inhibitory effects of sorafenib on bladder cancer cells

“…Recently, IL-27 was proven to possess multifaceted anti-tumor activity in lung (15), prostate (16), pancreatic (17) and breast cancers (18). In addition, IL-27 has been reported to possess potent antiangiogenic activity (19).…”

The cross talk between cervical carcinoma cells and vascular endothelial cells mediated by IL‐27 restrains angiogenesis

“…In tumor models, IL‐27/WSX‐1 signaling plays both protumor and antitumor effects through both generation and exhaustion of cytotoxic T lymphocyte (CTL), together with suppression of DC function . In addition, several studies reported that IL‐27 secreted by tumor cells also have antiangiogenic activity .…”