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International Journal of Bioprinting Bioprinted tumor immune microenvironment

Table 1. Comparison of immune cell activity in normal and cancer conditions.
Cell type Normal activity Cancer-associated activity
CTLs Directly kill infected cells and pathogens by Directly kill cancer cells by releasing perforin and granzymes to
releasing perforin and granzymes to induce induce apoptosis ; secrete cytokines (IFN-γ, TNF-α) to recruit
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apoptosis; secrete cytokines (IFN-γ, TNF-α) to and activate other immune cells, aiding in anti-tumor responses 24
recruit and activate other immune cells 32
DCs Capture and present antigens to T cells, activating Present tumor antigens to T cells, activating them and initiating
them; maintain immune surveillance 33 anti-tumor immune responses ; impaired by tumor-secreted
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immunosuppressive cytokines, reducing effectiveness in T cell
activatio 4
n3
Macrophages Phagocytose pathogens and dead cells; secrete M1 macrophages exhibit anti-tumor activity; tumors induce
cytokines to regulate immune responses; promote M2 phenotype, supporting tumor growth and metastasis ; M2
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tissue repair and remodeling 35 macrophages express PD-L1, leading to T cell exhaustion 31
NK cells Directly kill infected or stressed cells by releasing Directly kill tumor cells by releasing cytotoxic granules (perforin,
cytotoxic granules (perforin, granzymes); secrete granzymes); secrete cytokines (IFN-γ), enhancing anti-tumor
cytokines (IFN-γ) to modulate the activity of other immune response 27
immune cells 36
Abbreviations: CTLs, cytotoxic T lymphocytes; DCs, dendritic cells; IFN-γ, Interferon gamma; PD-L1, programmed death-ligand 1; TNF-α,
tumor necrosis factor alpha.

affect the consistency of responses, but this variability studies. iPSC-derived NK cells often require careful
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also provides a comprehensive understanding of human differentiation protocols. Thus, depending on the research
immune responses. 40 objective, both different cell-derived immune cells should
Stem cell-derived immune cells offer a renewable and be selected.
scalable source for research and therapeutic applications. 4.1.2. Bioinks
Immune cells derived from iPSCs can differentiate into ECM provides a physical scaffold that not only supports
various types, such as iPSC-NK or iPSC-T cells, exhibiting but also influences the behavior of tumor cells. Changes in
functional properties similar to their primary counterparts, the composition and organization of the ECM can promote
including cytotoxicity, cytokine production, and target cancer cell motility and invasiveness. 51–53 Components
recognition. 41,42 These cells can be genetically modified to like collagen, fibronectin, and laminins interact with cell
enhance specific functions or to express CARs for targeted surface receptors on cancer cells (e.g., integrins), activating
therapies. 43,44
pathways that promote tumor growth and metastasis.
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Cell line-derived immune cells, such as Jurkat (T The ECM can act as a barrier, and its composition and
cells), NK-92 (NK cells), and THP-1 (monocytes/ density can dictate the extent and effectiveness of immune
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macrophages), provide consistent and reproducible cell infiltration. A denser and more crosslinked ECM can
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models for in vitro studies. The stem cell-derived and hinder the mobility of T cells and NK cells. ECM secretes
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cell line-derived immune cells should be selected or presents chemokines and cytokines that attract immune
distinguishably in the bTIME model. For example, when cells to the tumor site, essential for initiating an immune
using NK cells, NK-92 or iPSC-derived NK cells can response. Certain ECM components promote an
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be used. NK-92 cells, which do not express killer cell immunosuppressive environment by supporting cell types
immunoglobulin-like receptors (KIRs), are advantageous such as regulatory T cells and myeloid-derived suppressor
for attacking cancer cells because they remain active even cells, which can inhibit effector immune cells. 57
when cancer cells have low MHC class I expression, which
normally inhibits NK cell activity. However, due to their When selecting bioinks for encapsulating immune cells
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cancerous origin, they require irradiation prior to use, and and cancer cells, it is essential to consider both physical
their lack of CD16 expression limits their effectiveness properties of the hydrogels and their interactions with
in antibody-dependent cellular cytotoxicity (ADCC)- the immune system. The following sections describe the
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mediated cancer models. Conversely, iPSC-derived NK characteristics and immune responses associated with
cells offer a renewable and scalable source, with the ability various hydrogels, including alginate, gelatin, hyaluronic
to be genetically engineered to enhance specific functions, acid (HA), collagen, chitosan, and gelatin methacryloyl
making them ideal for personalized immune response (GelMA) (Table 2).

Volume 10 Issue 5 (2024) 34 doi: 10.36922/ijb.3988