Engineering Microphysiological Immune System Responses on Chips

Human tumor immune microenvironment-on-a-chip models have been developed to emulate cell-type-dependent interactions, physical and chemical perturbations, and the infiltration and cytotoxicity of therapeutic antitumor lymphocytes and clinically relevant immunomodulatory agents. Intestinal inflammation-on-a-chip models recapitulating the 3D intestinal transmural interface have been developed to discover how pathophysiological factors impair the intercellular crosstalk in the epithelium-microbiome-immune axis and trigger chronic inflammatory immune responses. Combining engineered microphysiological immune system responses with high-throughput multiomics measurements at the single-cell level facilitates a systems immunology-on-a-chip approach to gain novel insights into immune disorders. Immune cells are being incorporated in tissues- and organs-on-chips modeling a variety of diseases. Tissues- and organs-on-chips are microphysiological systems (MPSs) that model the architectural and functional complexity of human tissues and organs that is lacking in conventional cell monolayer cultures. While substantial progress has been made in a variety of tissues and organs, chips recapitulating immune responses have not advanced as rapidly. This review discusses recent progress in MPSs for the investigation of immune responses. To illustrate recent developments, we focus on two cases in point: immunocompetent tumor microenvironment-on-a-chip devices that incorporate stromal and immune cell components and pathomimetic modeling of human mucosal immunity and inflammatory crosstalk. More broadly, we discuss the development of systems immunology-on-a-chip devices that integrate microfluidic engineering approaches with high-throughput omics measurements and emerging immunological applications of MPSs. Tissues- and organs-on-chips are microphysiological systems (MPSs) that model the architectural and functional complexity of human tissues and organs that is lacking in conventional cell monolayer cultures. While substantial progress has been made in a variety of tissues and organs, chips recapitulating immune responses have not advanced as rapidly. This review discusses recent progress in MPSs for the investigation of immune responses. To illustrate recent developments, we focus on two cases in point: immunocompetent tumor microenvironment-on-a-chip devices that incorporate stromal and immune cell components and pathomimetic modeling of human mucosal immunity and inflammatory crosstalk. More broadly, we discuss the development of systems immunology-on-a-chip devices that integrate microfluidic engineering approaches with high-throughput omics measurements and emerging immunological applications of MPSs. a cell-mediated immune response in which the fragment crystallizable (Fc) region of antibodies coating a target cell bind to Fc receptors on an effector cell, typically a NK cell, stimulating the release of cytotoxic factors. T cells that are harvested from patients and engineered to express a TCR or a CAR with specificity for an antigen expressed on tumor cells. a type of TCR-engineered T cell expressing a CAR comprising an extracellular tumor antigen recognition domain, an extracellular hinge region, a transmembrane domain, and an intracellular domain to potently activate signaling pathways that promote T cell activation and antitumor activity. a semisolid medium used to create 3D cell culture environments comprising type 1 collagen, the most abundant protein in the ECM. a polyanionic dextran derivative used to induce colitis in murine models. DSS can specifically disrupt the tight junction barrier in the gut. an imbalanced population of the gut microbiome in the pathological stage that compromises host–microbiome crosstalk in the gut. a photocrosslinkable hydrogel derived from collagen with tunable stiffness properties. a diffusive immune system of the gut including Peyer’s patches, mesenteric lymph nodes, and other local immune elements in the lamina propria. chronic inflammation with autoimmunity in the human GI tract that includes Crohn’s disease and ulcerative colitis. a bacterial endotoxin, a ligand of TLR4, and a component of the cell membrane of Gram-negative bacteria. human-biomimetic platforms based on microfluidics and microfabrication technologies to create a modular controllable microenvironment with physiologically relevant hydrodynamics and biomechanics for co-culturing different cell types in 3D to model the architectural and functional complexity of human tissues and organs. a whole-blood-derived mixed population of circulating immune cells including lymphocytes, monocytes, and granulocytes isolated using density-gradient separation. an optically transparent, soft, biocompatible elastomer often used in the fabrication of microfluidic devices. a therapeutic approach in which monoclonal antibodies are used to disrupt interactions between the PD-1 receptor checkpoint receptor on the surface of cytotoxic T cells and PD-L1 on the surface of tumor cells to promote antitumor responses. proteins expressed on the surface of tumor cells and other immune cells that interact with PD-1 on T cells to promote T cell exhaustion, which prevents antitumor responses. a 3D cell-modeling structure that better mimics live-cell conditions in the ECM than 2D monolayer cultures, including the presence of a hypoxic core with reduced oxygen levels.