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International Journal of Bioprinting Bioprinted tumor immune microenvironment

future, it is essential to include other stromal cells, as tumor angiogenesis and cancer cell invasion (Figure
they aid tumor growth and create an immunosuppressive 2D). Furthermore, perfusing human epidermal growth
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environment, significantly influencing immune cell factor receptor 2 (HER2)-targeting CAR-modified CD8+
activity in vivo. T cells through the channels resulted in significant T cell
activation, infiltration, and up to 70% reduction in tumor
4.2.2. Bioprinting immune cells with tumor and volumes. This illustrates the potential of these vascularized
stromal cells models for preclinical testing and personalized medicine.
Efforts to address the lack of stromal cells in tumor
models have led to recent advancements in bioprinting. Combining 3D bioprinting with microfluidic
These developments have allowed for the creation of technology also enhances the physiological relevance of
more sophisticated models that include not only tumor these models. A bladder cancer-on-a-chip was developed
and immune cells but also stromal cells, which play an to mimic the TIME using the bladder cancer cells along
immunosuppressive role in the TME. For example, Tang with the lung fibroblast cells, human umbilical vein
et al. fabricated GBM tumor models with glioblastoma endothelial cells (HUVECs), and human leukemia
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stem cells, macrophages, and stromal cells such as monocytic cells. The study found that the bioprinted
astrocytes, and neural progenitor cells using digital light structure integrated with the microfluidic chip enhanced
processing bioprinting (DLP). The DLP method enabled cell proliferation and allowed detailed tracking of
the adjustment of stiffness by varying the exposure time, monocyte migration and cytokine concentration changes.
allowing the mimicry of the peripheral region stiffness of These examples demonstrate how vascularization and
the brain (~1 kPa). Macrophages cultured in the bioprinted perfusion system achieved through 3D bioprinting can be
model showed more immunosuppressing RNA profiles leveraged to model complex tumor–immune interactions
than 2D-cultured macrophages, including upregulation and develop effective immunotherapies. The advantages
of M2-related markers such as CD163 and IL-10. Dey and limitations of various methods introduced in this
et al. printed 3D models of breast cancer with precise review are summarized in Table 3.
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positioning using aspiration-based bioprinting (ABB), 4.2.4. Efficacy of immunotherapeutic drugs in
a technique that harnesses aspiration forces to pick and bioprinted tumor immune microenvironment
bioprint biologics in three dimensions (Figure 3C). When The evaluation of immunotherapeutic drugs using bTIME
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combined with microvalve bioprinting, ABB is uniquely models is promising but is still in preliminary phases.
capable of printing spheroids of different sizes. They Here, we discuss how bTIME models are uniquely suited
studied the effect of localization of engineered T cells and to testing immunotherapeutic drugs, such as immune
breast cancer/human dermal fibroblasts (HDF) spheroids modulators, checkpoint inhibitors, CAR-T cells, and
on immune response. They observed that closer proximity cancer vaccines.
between T cells and breast cancer/HDF spheroids slowed
tumor invasion and enhanced secretion of granzymes, bTIME models can accurately replicate the interactions
IFN-γ, and XXX (CCL2), indicating paracrine interactions between cancer cells and immune cells, including T cells
between tumors and T cells. These studies highlight the and macrophages. Therefore, they offer a sophisticated
critical role of stromal cells in creating more advanced and platform to evaluate the effectiveness of immune
accurate tumor models, which can provide deeper insights modulators and checkpoint inhibitors in a controlled
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into tumor biology and immune responses. reproducible environment. Heinrich et al. evaluated the
effects of immune modulators, such as CSF-1 inhibitor
4.2.3. Integrated bioprinted tumor immune and the signal transducer and activator of transcription 6
microenvironment with vascular system (STAT6) inhibitor, in bioprinted miniatured brains with
The creation of vascularized models is also crucial for macrophages and glioblastoma cells. The CSF-1 inhibitor
studying the interactions between immune cells and cancer BLZ945 is known to inhibit the growth of tumor cell
cells within the TIME. These models can include blood lines both in vitro and in vivo, and the same result was
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or lymphatic vessels, which are essential for mimicking observed in this bioprinted model. Notably, the STAT
physiological conditions and enabling the study of immune inhibitor AS1517499 has been shown to reduce tumor
cell migration towards cytokine-producing cancer cells. 95,96 growth and metastasis in mouse tumor models, but no
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One method involves dynamic flow-based 3D bioprinting direct effects on GBM models have been reported in in
to create a vascularized model that responds to chemo- vitro experiments. However, in glioblastoma within the
and immuno-therapies. For instance, a breast tumor AS1517499-treated bTIME, a decrease in the expression of
model demonstrated that heterotypic tumors bioprinted at SPP-1, a GBM marker related to macrophage recruitment,
predefined distances from perfused vasculature exhibited was observed.
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Volume 10 Issue 5 (2024) 39 doi: 10.36922/ijb.3988