Abstract LB-220: A microfluidic model for real-time monitoring of tumor-lymphocyte interactions

Abstract

Abstract The emergence of immune checkpoint inhibitors and the promise of increased patient survival reinforces the potential for targeting the tumor microenvironment as a drug development strategy. The tumor microenvironment consists of a heterogeneous composition of cancer cells, vascular cells, fibroblasts, and immune cells that are regulated by both intrinsic and extrinsic chemical and physical stimuli. Within this microenvironment, aberrant blood vessel formation and extra cellular matrix (ECM) restructuring lead to increased interstitial fluid flow and shear stress that stimulate differential gene expression, reorganization of tumor cell structure, and suppression of local cytotoxic T-cell activity. Elevated levels of fluid pressure and shear stress have also been demonstrated to alter cell sensitivity and response to therapeutic agents. Traditional static 2D in vitro models fail to adequately address tumor-immune cell interactions and flow mediated change in sensitivity, contributing to inaccurate predictions of in vivo therapeutic response. The development of 3D microfluidic systems have greatly enhanced the ability to model components of the tumor microenvironment, such as fluid flow, and capture the dynamics of tumor and immune cell responses to emerging therapeutic compounds. Here, we have developed a medium throughput microfluidic device which is constructed using bioinert materials that are also compatible with real-time confocal imaging, to model the effects of therapeutic treatment on tumor viability. In addition to exposing tumors to a dynamic flow environment, this model system enables the introduction of flowing lymphocytes, permitting tracking of tumor-lymphocyte interactions in real-time. As a test case, we demonstrate the ex vivo binding and cytotoxic activity of MC38-derived tumor infiltrating lymphocytes (TILs) on tumor fragments. These results highlight the power of a dynamic microfluidic flow system to model the tumor-lymphocyte microenvironment and the potential of this system to more accurately evaluate novel therapeutic agents. Citation Format: Nathan Moore, Daniel Doty, Jose Santos, Louis B. Kratchman, Stephanie Angione, Vienna Mott, Mark Zielstroff, Hongmin Chen, Alla Gimbel, Jeffrey Borenstein. A microfluidic model for real-time monitoring of tumor-lymphocyte interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-220. doi:10.1158/1538-7445.AM2017-LB-220