An Immunocompetent Microphysiological System to Simultaneously Investigate Effects of Anti-Tumor Natural Killer Cells on Tumor and Cardiac Microtissues

• DOI: 10.3389/fimmu.2021.781337
• Publication Date: 2021-12-02T12:27:17Z
• Authors: Oanh T. P. Nguyen; Patrick M. Misun; Christian Lohasz; Jihyun Lee; Weijia Wang; Timm Schroeder; Andreas Hierlemann
• Keywords: Male; 0301 basic medicine; 3D microtissue; Intravital Microscopy; Immunology; Induced Pluripotent Stem Cells; Primary Cell Culture; Cell Separation; Immunotherapy, Adoptive; Proof of Concept Study; Cell Line; 03 medical and health sciences; Lab-On-A-Chip Devices; Neoplasms; Humans; Cell Culture Techniques, Three Dimensional; Myocytes, Cardiac; microphysiological system; adoptive cell therapy; RC581-607; natural killer cell; Fetal Blood; efficacy and safety assessment; Healthy Volunteers; 3. Good health; Killer Cells, Natural; Biological Assay; Female; Immunologic diseases. Allergy

Existing first-line cancer therapies often fail to cope with the heterogeneity and complexity of cancers, so that new therapeutic approaches are urgently needed. Among novel alternative therapies, adoptive cell therapy (ACT) has emerged as a promising cancer treatment in recent years. The limited clinical applications of ACT, despite its advantages over standard-of-care therapies, can be attributed to (i) time-consuming and cost-intensive procedures to screen for potent anti-tumor immune cells and the corresponding targets, (ii) difficulties to translate in-vitro and animal-derived in-vivo efficacies to clinical efficacy in humans, and (iii) the lack of systemic methods for the safety assessment of ACT. Suitable experimental models and testing platforms have the potential to accelerate the development of ACT. Immunocompetent microphysiological systems (iMPS) are microfluidic platforms that enable complex interactions of advanced tissue models with different immune cell types, bridging the gap between in-vitro and in-vivo studies. Here, we present a proof-of-concept iMPS that supports a triple culture of three-dimensional (3D) colorectal tumor microtissues, 3D cardiac microtissues, and human-derived natural killer (NK) cells in the same microfluidic network. Different aspects of tumor-NK cell interactions were characterized using this iMPS including: (i) direct interaction and NK cell-mediated tumor killing, (ii) the development of an inflammatory milieu through enrichment of soluble pro-inflammatory chemokines and cytokines, and (iii) secondary effects on healthy cardiac microtissues. We found a specific NK cell-mediated tumor-killing activity and elevated levels of tumor- and NK cell-derived chemokines and cytokines, indicating crosstalk and development of an inflammatory milieu. While viability and morphological integrity of cardiac microtissues remained mostly unaffected, we were able to detect alterations in their beating behavior, which shows the potential of iMPS for both, efficacy and early safety testing of new candidate ACTs.