Lymphocyte-derived interleukin-17A adds another brick in the wall of inflammation-induced breast carcinogenesis

Abstract

We have previously reported that a subset of breast tumors are infiltrated with IL-17A-producing tumor-associated lymphocytes and that IL-17A cytokine is principally associated with estrogen receptor negative (ER-) and triple negative, basal-like tumors. We established that IL-17A producing lymphocytes induced cancer cell proliferation, chemoresistance, and invasion, indicating that IL-17A is a potential therapeutic target for breast malignancies.

Keywords: ERK kinases; IL-17A; breast cancer; chemoresistance; monoclonal antibodies; tumor infiltrating lymphocytes.

Figures

Figure 1. Protumor activities of the inflammatory cytokine IL-17A in breast cancer. Interleukin-17A from the tumor microenvironment binds IL-17R on the surface of breast tumor cells and activates oncogenic ERK and NF-κB pathways, thereby leading to increased proliferation, survival and resistance to chemotherapeutics, and invasiveness. IL-17A also binds IL-17R present on fibroblasts and activates NF-κB and STAT3 pathways leading to production of IL-6 and G-CSF. IL-6, in combination with TGFβ, further activates Th17 cells leading to a chronic inflammatory state and amplification of IL-17A signaling. G-CSF participates to the recruitment of myeloid-derived suppressor cells (MDSCs) that release VEGF leading to tumor angiogenesis and also possess potent immunosuppressive activity further supporting tumor growth. ERK, extracellular signal-regulated kinase; G-CSF, granulocyte-colony stimulating factor; nuclear factor kappa B (NFκB); STAT3, signal transducer and activator-3; TGF, transforming growth factor-β; VEGF, vascular endothelial growth factor.