Development of IL-6 inhibitors for targeting CAF-immune cell crosstalk in the tumor microenvironment

Abstract

Cancer associated fibroblast (CAFs) and tumor associated macrophages (TAMs) are major players and comprise a significant majority of the cell population in the tumor microenvironment (TME). In the TME, they interact to build a niche supportive for cancer progression and therapeutic resistance. Such crosstalk is mediated by various signaling molecules such as the cytokine IL-6. Overexpression of IL-6 and its related signaling molecules is a common feature observed in numerous types of cancers and also known to be related to resistance and tumor aggressiveness. In this thesis, through IL-6 ELISA screening, a hit compound, NDT-SOR that markedly inhibits IL-6 secretion from YD-10B oral cancer cell CM activated fibroblasts, was discovered and characterized. After the confirmation that the reduction of IL-6 secretion showing dose dependent, significant increase in the expression level of several signaling genes including Stat3, Chuk, and Rela were identified using a CAF substitute model. Western blot analysis of human CAF showed that, cancer CM induced increases in p65 phosphorylation and STAT3 expression. Furthermore, treatment with NDT-SOR reduced p65 and STAT3 phosphorylation. In a co-culture system, NDT-SOR reduce the degree of monocytes adhesion, implicating this hit compound as a modulator of TAM-CAF crosstalk.