The Interleukin-17 Family of Cytokines in Breast Cancer

Abstract

Breast cancer (BC) is the most common cancer in women worldwide and remains a major cause of mortality with an expected 137,000 death this year in Europe. Standard management of metastatic BC comprises hormonotherapy, chemotherapy, and targeted therapies. Cyclin dependent kinase (CDK) and mammalian target of rapamycin (mTOR) inhibitors have recently proved their efficiency in hormonal receptor expressing BC. Checkpoint proteins inhibition is being evaluated in phase 3 studies. Since inflammation is constantly present in cancers, research teams have focused their attention on the interleukin-17 (IL-17) family of proinflammatory cytokines. Preclinical experiments have reported both pro and antitumor effects depending on the conditions. In the present article, we review the accumulating evidences about the roles of IL-17 in BC and discuss whether this family of cytokines could be a new target in anticancer treatments.

Role of Matrix Metalloproteinases in Angiogenesis and Cancer

“…Chemoattractant proteins such as MCP-1, MCP-2, MCP-3, and MCP-4 are targets for MMP activity, as result the modified MCPs changing their activity from agonist to antagonist and causing inflammation. Inflammation produces immune tolerance and leads to specific micro-environment conditions, exploited by tumors to evade immune cells and enhance progression, angiogenesis and metastasis (78,171). In the inflammation process, FGF2 expression can facilitate induction of FGF-dependent angiogenesis by mononuclear phagocytes, Tlymphocytes, and mast cells.…”

Role of the Neutrophil in the Pathogenesis of Advanced Cancer and Impaired Responsiveness to Therapy

“…IL-17A produced by Th17 cells promotes neutrophil activation and recruitment indirectly via receptor-activated production of IL-8 and G-CSF by various cell types, including structural cells [130]. In this context, the targeting of IL-17A is seemingly efficacious in the experimental immunotherapy of colorectal, breast and non-small cell lung cancers in murine models [40,131,132]. Although untested in the clinical setting of cancer chemotherapy, it is noteworthy that several members of the macrolide class of antibiotics such as azithromycin, clarithromycin and erythromycin attenuate the pro-inflammatory activities of neutrophils via inhibition of the production of IL-17A and IL-8 by both immune and structural cells [133,134].…”

“…Clearly, the clinical utility of all of the aforementioned MDSC-targeted, adjunctive anti-cancer therapies (summarized in Table 4) remains to be established, with CXCR1/2 antagonists seemingly the most promising. [35,129] mAb targeting of IL-17A or its receptor Promising pre-clinical findings in colorectal, breast and non-small cell lung cancers [40,131,132] Macrolide antibiotic targeting of IL-8 and IL-17A production Uncertain [135] mAb targeting of TGFβ1 Promising, but poses the risk of dysregulated immune homeostasis [59] Administration of type I interferons to prevent N1→N2 TAN reprogramming…”

Targeting the interleukin-17 immune axis for cancer immunotherapy

“…Similarly, IL-17 ligation up-regulates NF-κB signaling in a dosedependent fashion in glioblastoma cell lines (Kehlen et al, 1999); mediates intracellular NF-κB, MAPK, and AP-1 activity in gastric cancer (Zhou et al, 2007); and promotes hepatocellular carcinoma invasion and prostate cancer epithelial to mesenchymal transition in vivo via MMP-2, MMP-7, MMP-9, and NF-κB signal transduction (Li et al, 2011a;Liu et al, 2016). Finally, IL-17 directly contributes to the proliferation of keratinocytes via the IL-17R-Act1-TRAF4-MEKK3-ERK5 circuit in skin cancer, and promotes MMP-dependent cell invasion, supports angiogenesis, inhibits TGF-β-dependent cellular apoptosis, and enhances MEK-, ERK-, JNK-, and STAT3-mediated cell proliferation in breast cancer (Fabre et al, 2018;Wu et al, 2015b). Thus, IL-17 has been implicated in the oncogenesis of many tumor types.…”