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International Journal of Bioprinting Bioprinted tumor immune microenvironment

generally exhibits low immunogenicity. However, when arrangement of cells and materials, such as extrusion-based
lipopolysaccharide was used to stimulate a pro-inflammatory and inkjet bioprinting. They are designed to closely mimic
immune response, it was found that TNF-α expression was the 3D structure of actual tumors, facilitating detailed
suppressed in GelMA culture conditions when culturing studies of tumor growth, metastasis, and drug response in a
human primary peripheral blood mononuclear cells. controlled environment. However, a significant limitation
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Thus, GelMA had immune-modulatory properties and of these traditional bTME models is the exclusion of
might reduce the pro-inflammatory response. immune cells, which are crucial for accurately simulating
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Decellularized extracellular matrix (dECM) refers to the interactions within the TIME. This omission restricts
the extracellular matrix that remains after the removal the ability of these models to fully replicate the complex
of cells from a tissue or organ. Considering the role dynamics of tumor–immune system interactions and may
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of foreign cells in graft rejection, decellularization impact the evaluation of immunotherapeutic agents.
significantly attenuates the host’s immune response against In recent years, efforts have been made to include
transplants. Various decellularization methods contribute immune cells in bioprinted tumor models. These models
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to the immunogenicity of the ECM. For example, ionic not only simulate interactions between cancer and immune
detergents like sodium dodecyl sulfate (SDS) are highly cells but also broader TME. The results obtained by these
effective in removing protein antigens, especially in dense models such as cytokine profiling and drug response are
tissues, but can expose hidden antigenic sites. 75 highly consistent with real tumors. However, optimizing
culture conditions for multiple cell types remains
4.1.3. Structural complexity challenging, requiring high-resolution and accurate
For the investigation of immune–tumor interaction bioprinting method. The following section explains
using bTIME, structural complexity, particularly spatial the research on simulating TIME using bioprinting,
heterogeneity, is crucial for accurately modeling the categorized by the complexity of the models.
migration behavior of immune cells interacting with tumor
sites (Figure 2A). Reynolds et al. bioprinted melanoma 4.2.1. Bioprinting immune cells with tumor
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model in helix shape, and CD8+ T cells were shown to Bioprinting immune cells with tumor cells enable the
migrate within the matrix to the tumor site (Figure 2B). study of direct cytokine and chemokine-mediated
Morley et al. spatially defined the distributions of glioma interactions. Constructing TIME using various bioprinting
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cells, hematopoietic stem cells (HSCs), and T cells using techniques involves encapsulating immune cells, such as
bioprinting, and observed that tumor spheroids containing macrophages, and tumor cells within a bioink, provides a
HSCs recruited T cells more rapidly due to cytokine more favorable environment for immune cell culture and
diffusion. Mazzaglia et al. introduced deployable extrusion activation, 85–87 which is crucial for simulating TIME. Not
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bioprinters to create compartmentalized tumoroids with only can the tumor cytotoxicity effects be observed, but
cancer-associated fibroblasts (CAFs), embedded in an also the specific tumor-supporting effects of immune cells,
immune cell-laden collagen matrix, which facilitated the such as M2 macrophages. For example, Li et al. printed
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tracking of immune–tumor interactions and revealed a cholangiocarcinoma (bile duct cancer) cell line RBE
enhanced cellular proliferation. Flores-Torres et al. in a square structure and arranged macrophages around
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bioprinted gastric cancer patient-derived organoids and the square like a fence using extrusion-based bioprinting
tumor infiltrated lymphocytes (TILs), using an alginate, (Figure 3A). Bioprinting RBE cells and macrophages cells
gelatin, and basal membrane mix designed to present separately in this configuration could evade the contact
physical barriers, and facilitated detailed analysis of TIL inhibition during cell growth and ensure better viability
migration and activation dynamics (Figure 2C). These than direct mixing. RBE cells bioprinted with macrophages
studies collectively underscore the significance of spatial showed higher proliferation and expression in tumor-
heterogeneity in 3D bioprinting for studying immune cell related genes like epithelial cell adhesion molecule
migration and interactions within the TIME, providing (EPCAM), N-cadherin, and matrix metalloproteinase-9
valuable insights for developing effective immunotherapies. (MMP9).
4.2. Development of bioprinted tumor Heinrich et al. printed a miniature brain shape using
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immune microenvironment mouse macrophage-encapsulated GelMA leaving a cavity
In order to bioprint tumors, early studies focused on for the tumor site. Subsequently, glioblastoma (GBM) cells
creating a bTME that primarily includes cancer cells, were injected into the cavity. Thus, the bioprinting method
fibroblasts, and the ECM, along with synthetic blood vessels offered the cellular position between GBM cells and
to simulate the vascular network of the tumor. 76,81 These macrophages, enabling the study of cell–cell interactions
models typically use methods to achieve precise spatial such as migration and invasion. The expression of glioma-

Volume 10 Issue 5 (2024) 36 doi: 10.36922/ijb.3988