Abstract
The latest advancements in oncology research are focused on autologous immune cell therapy. However, the effectiveness of this type of immunotherapy for cancer remediation is not equivalent for all patients or cancer types. This suggests the need for better preclinical screening models that more closely recapitulate in vivo tumor biology. The established method for investigating tumoricidal activity of immunotherapies has been study of two-dimensional (2D) monolayer cultures of immortalized cancer cell lines or primary tumor cells in standard tissue culture vessels. Indeed, a proven means to examine immune cell migration and invasion are 2D chemotaxis assays in permeabilized supports or Boyden chambers. Nevertheless, the more in vivo-like three-dimensional (3D) multicellular tumor spheroids are quickly becoming the favored model to examine immune cell invasion and tumor cell cytotoxicity. Accordingly, we have developed a 3D immune oncology model by combining 96-well permeable support systems and 96-well low-attachment microplates. The use of the permeable support system enables assessment of immune cell migration, which was tested in this study as chemotactic response of natural killer NK-92MI cells to human stromal-cell derived factor-1 (SDF-1α). Immune invasion was assessed by measuring NK-92MI infiltration into lung carcinoma A549 cell spheroids that were formed in low-attachment microplates. The novel pairing of the permeable support system with low-attachment microplates permitted simultaneous investigation of immune cell homing, immune invasion of tumor spheroids, and spheroid cytotoxicity. In effect, the system represents a more comprehensive and in vivo-like immune oncology model that can be utilized for high-throughput study of tumoricidal activity.
Highlights
Harnessing the power of the immune system via immunomodulatory and/or cell-based therapeutics holds great promise and is a very active area of both academic and clinical oncology research
There is a threshold effect of MHC Class-I expression in 3D spheroids of Ewing’s sarcoma tumor (ESFT) cells. This tips the balance of natural killer (NK) cell signaling toward inhibitory inputs, allowing NK evasion by ESFT spheroids [11]
Cells from a NK cell line derived from peripheral blood, NK-92MI, were placed in the apical compartments of Transwell inserts with 5.0-μm pore size, and allowed to migrate overnight toward medium containing various concentrations of SDF-1α, a CXC chemokine that signals through the CXCR4 receptor and known chemoattractant for lymphocytes [16]
Summary
Harnessing the power of the immune system via immunomodulatory and/or cell-based therapeutics holds great promise and is a very active area of both academic and clinical oncology research. Primary testing via 2D methods is often the entry point into preclinical drug screening cascades These 2D models do not accurately reflect the complexity of a three-dimensional (3D) tumor [4], a characteristic that has been cited as a contributing factor to the high attrition rate of cancer drugs [5, 6]. There is a threshold effect of MHC Class-I expression in 3D spheroids of Ewing’s sarcoma tumor (ESFT) cells This tips the balance of natural killer (NK) cell signaling toward inhibitory inputs, allowing NK evasion by ESFT spheroids [11]. Many other examples of the morphological [12] and phenotypic [13,14,15] differences between 2D and 3D experimental cell culture models have been published in the primary literature making it clear that 3D tumor models more closely resemble the in vivo tumor microenvironment
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