The tumor microenvironment (TME) plays a major role in the pathogenesis of multiple
cancer types, including upper-gastrointestinal (GI)
cancers that currently lack effective therapeutic options. Cancer-associated fibroblasts (CAF) are an essential component of the TME, contributing to
tumorigenesis by secreting
growth factors, modifying the extracellular matrix, supporting angiogenesis, and suppressing antitumor immune responses. Through an unbiased approach, we have established that
IL-6 mediates cross-talk between
tumor cells and CAF not only by supporting
tumor cell growth, but also by promoting fibroblast activation. As a result,
IL-6 receptor (IL6Rα) and downstream effectors offer opportunities for targeted
therapy in upper-GI
cancers.
IL-6 loss suppressed
tumorigenesis in physiologically relevant three-dimensional (3D) organotypic and 3D tumoroid models and murine models of
esophageal cancer.
Tocilizumab, an anti-IL6Rα antibody, suppressed
tumor growth in vivo in part via inhibition of STAT3 and
MEK/ERK signaling. Analysis of a pan-
cancer TCGA dataset revealed an inverse correlation between
IL-6 and IL6Rα overexpression and patient survival. Therefore, we expanded evaluation of
tocilizumab to
head and neck squamous cell carcinoma patient-derived xenografts and gastric
adenocarcinoma xenografts, demonstrating suppression of
tumor growth and altered STAT3 and ERK1/2 gene signatures. We used small-molecule inhibitors of STAT3 and MEK1/2 signaling to suppress
tumorigenesis in the 3D organotypic model of
esophageal cancer. We demonstrate that
IL6 is a major contributor to the dynamic cross-talk between
tumor cells and CAF in the TME. Our findings provide a translational rationale for inhibition of IL6Rα and downstream signaling pathways as a novel targeted
therapy in oral-upper-GI
cancers.Significance: These findings demonstrate the interaction of
esophageal cancer and cancer-associated fibroblasts through
IL-6 signaling, providing rationale for a novel therapeutic approach to target these
cancers.
Cancer Res; 78(17); 4957-70. ©2018 AACR.