Abstract A76: Microenginered human lymphoid tissue on chip

Abstract

Human immune responses are markedly different from those of rodents or non-human primates. A poignant example of this unmet need is the immunotherapy TGN1412 which caused an unpredicted cytokine storm in 6 patients. Immunotherapy is designed in animal models and then tested on human immune cells in the blood (the least invasive and most accessible resource). However, blood immune cells are significantly different from tissue resident immune cells i.e. immune cells in the tumor, lymph node and other areas of the body. Blood and tissues have different types and proportions of cells, mechanical forces, extracellular matrix (ECM) and resulting biological interactions. One of the reasons of the TGN1412 cytokine storm was that tissue resident immune cells are hypersensitive to the therapy.

Organ-on-chip studies of the immune system have the potential to dramatically streamline clinical trials and enable personalized medicine. To model human tissue resident immunity without relying on animal models, we are using the design principles from the human lymph node and organs-on-chip technology to reverse engineer a prototype of human lymphoid tissue on chip with human blood.

We have developed a combination of matrix and cellular components to induce formation of lymphocyte organoids in 3D culture reminiscent of organized lymphoid tissue or follicles usually found in secondary and tertiary lymphoid organs. T and B cell functions are simulated in this model as evidenced by cytokine and immunoglobulin M production in response to heat killed formalin fixed Staph aureus Cowan I (SAC), commonly used to induce a T cell-dependent antibody response. Further organoid formation correlates with increasing levels of CXCL13, a cytokine known to be important in the organization of follicles. Interestingly, the 3D lymphocyte organoids express the coinhibitory receptor CTLA-4, known to be expressed in follicular T cells. As expected of lymphoid follicles, activation by SAC causes these organoids to expand and proliferate.

We also present preliminary studies optimizing the perfusion of the lymphocyte parenchyma with microengineered channels lined with lymphatic and vascular endothelial cells to model antigen delivery and immune cell trafficking. These devices will enable near real-time assessment of secreted factors, cell trafficking and high-resolution imaging of dynamic cellular interactions that occur in the human lymph node, and hence, they should prove invaluable in studying human cancer response to anti-cancer immunotherapies in the future. As proof-of-concept, we will compare several clinically approved immunotherapies as well as TGN1412 to test the differences between the response of the engineered lymphoid tissue as compared to standard low density cultures as well as high density cultures. Our preliminary data strongly supports potential applications in understanding basic mechanistic human immunology as well as using the lymphoid tissue on chip for development of immunotherapeutics.

Citation Format: Girija Goyal, Jaclyn Long, Donald E. Ingber. Microenginered human lymphoid tissue on chip [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A76.