Fibroblasts drive differential response in immunotherapy via IL-6 in bioengineered 3D cancer constructs

Abstract Despite various therapeutic advancements in cancer, heterogeneity in the tumor microenvironment is a major hindrance to the overall efficacy of treatment. In this study, we focus on the most abundantly found cellular stromal components – fibroblasts – which can be tumor-promoting or tumor-suppressing based on the extent of disease progression and numerous additional factors. In the studies described herein, we evaluated their role in influencing chemotherapy as well as in immunotherapy using colorectal cancer (CRC) cell line-derived 3D tumor constructs. Our initial efforts centered on common chemotherapeutic agents utilized in CRC. However, while the presence of fibroblasts often did influence chemotherapy efficacy, a clear and consistent increase or decrease in efficacy was not obvious. We then focused subsequent studies on natural killer (NK) cell-based immunotherapy efficacy. There are numerous components and pathways involved in tumorigenesis and tumor-immune cell interactions, and the crosstalk between fibroblasts and immune cells like NK cells is still not well-defined. Fibroblasts have been documented to be a major player with respect to immune modulation and understanding this in greater detail can elucidate more options for anti-tumor immunity. Specifically, we used an extracellular matrix-based hydrogel platform to generate 3D CRC constructs to evaluate how fibroblasts affect tumor cell viability in presence and absence of NK cells. In general, fibroblasts aid the tumor cells in our models. We then identify a cytokine-based pathway (interleukin 6 [IL-6]) via which ‘activated’ fibroblasts engage with the tumor cells and show how NK cell effector function can be restored when the IL-6 pathway is blocked in a melanoma-based tumor-on-a-chip platform. Competing Interest Statement The authors have declared no competing interest.