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An Engineered Tumor-on-a-Chip Device with Breast Cancer–Immune Cell Interactions for Assessing T-cell Recruitment
Open accessPublished version of a preprint
Abstract
Recruitment of immune cells to a tumor is determined by the complex interplay between cellular and noncellular components of the tumor microenvironment. Ex vivo platforms that enable identification of key components that promote immune cell recruitment to the tumor could advance the field significantly. Herein, we describe the development of a perfusable multicellular tumor-on-a-chip platform involving different cell populations. Cancer cells, monocytes, and endothelial cells were spatially confined within a gelatin hydrogel in a controlled manner by using 3D photopatterning. The migration of the encapsulated endothelial cells against a chemokine gradient created an endothelial layer around the constructs. Using this platform, we examined the effect of cancer cell–monocyte interaction on T-cell recruitment, where T cells were dispersed within the perfused media and allowed to infiltrate. The hypoxic environment in the spheroid cultures recruited more T cells compared with dispersed cancer cells. Moreover, the addition of monocytes to the cancer cells improved T-cell recruitment. The differences in T-cell recruitment were associated with differences in chemokine secretion including chemokines influencing the permeability of the endothelial barrier. This proof-of-concept study shows how integration of microfabrication, microfluidics, and 3D cell culture systems could be used for the development of tumor-on-a-chip platforms involving heterotypic cells and their application in studying recruitment of cells by the tumor-associated microenvironment. Significance: This study describes how tumor-on-chip platforms could be designed to create a heterogeneous mix of cells and noncellular components to study the effect of the tumor microenvironment on immune cell recruitment.
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“The results showed greater T cell in fi ltration when monocytes were present in the culture, and also when higher levels of hypoxia were emulated by using tumor spheroids instead of dispersed cancer cells [71].”
From 3D In Vitro Model (R)evolution: Unveiling Tumor–Stroma Interactions (2021) · cites this paper as [71]
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“T cell recruitment to tumor spheroids was shown to be increased in the presence of monocytes due to their increased chemokine expression [45].”
From Cancer-on-chip models for metastasis: importance of the tumor microenvironment (2024) · cites this paper as [45]
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Safety, activity, and immune correlates of anti–PD-1 antibody in cancer
Topalian, S. L., Hodi, F. S., Brahmer, J. R., Gettinger, S. N., Smith, D. C., McDermott, D. F., Powderly, J. D., Carvajal, R. D., Sosman, J. A., Atkins, M. B., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1200690 · Cited by 12,628
Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia
Maude, S. L., Frey, N., Shaw, P. A., Aplenc, R., Barrett, D. M., Bunin, N. J., Chew, A., Gonzalez, V. E., Zheng, Z., Lacey, S. F., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1407222 · Cited by 5,413
Tumor-Associated Macrophages: From Mechanisms to Therapy
Noy, R., & Pollard, J. W. (2014) · Immunity · doi:10.1016/j.immuni.2014.06.010 · Cited by 4,089
Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm
Biswas, S. K., & Mantovani, A. (2010) · Nature Immunology · doi:10.1038/ni.1937 · Cited by 3,840
The immune contexture in cancer prognosis and treatment
Fridman, W. H., Zitvogel, L., Sautès–Fridman, C., & Kroemer, G. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2017.101 · Cited by 2,263
Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy
Nagarsheth, N., Wicha, M. S., & Zou, W. (2017) · Nature reviews. Immunology · doi:10.1038/nri.2017.49 · Cited by 2,253
Gettinger, S. N., Horn, L., Gandhi, L., Spigel, D. R., Antonia, S. J., Rizvi, N. A., Powderly, J. D., Heist, R. S., Carvajal, R. D., Jackman, D. M., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2014.58.3708 · Cited by 1,196
Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment
Harlin, H., Meng, Y., Peterson, A. C., Zha, Y., Tretiakova, M., Slingluff, C., McKee, M., & Gajewski, T. F. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-2281 · Cited by 1,121
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Hypoxia-Inducible Factors: Master Regulators of Cancer Progression
Schito, L., & Semenza, G. L. (2016) · Trends in Cancer · doi:10.1016/j.trecan.2016.10.016 · Cited by 962
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Three-Dimensional Spheroids as In Vitro Preclinical Models for Cancer Research
Pinto, B., Henriques, A. C., Silva, P. M. A., & Bousbaa, H. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12121186 · Cited by 440
3D In Vitro Model (R)evolution: Unveiling Tumor–Stroma Interactions
Rodrigues, J., Heinrich, M. A., Teixeira, L. M., & Prakash, J. (2021) · Trends in Cancer · doi:10.1016/j.trecan.2020.10.009 · Cited by 405
“The results showed greater T cell infiltration when monocytes were present in the culture, and also when higher levels of hypoxia were emulated by using tumor spheroids instead of dispersed cancer cells [71].”
BackgroundMethodTumor microenvironment: barrier or opportunity towards effective cancer therapy
Tiwari, A., Trivedi, R., & Lin, S. (2022) · Journal of Biomedical Science · doi:10.1186/s12929-022-00866-3 · Cited by 399
Microfluidics for Drug Development: From Synthesis to Evaluation
Liu, Y., Sun, L., Zhang, H., Shang, L., & Zhao, Y. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.0c01289 · Cited by 212
Immunosuppression in tumor immune microenvironment and its optimization from CAR-T cell therapy
Liu, Z., Zhou, Z., Dang, Q., Xu, H. M., Lv, J., Li, H., & Han, X. (2022) · Theranostics · doi:10.7150/thno.76854 · Cited by 200
Metadata
- Authors
- Aung, A., Kumar, V., Theprungsirikul, J., Davey, S. K., & Varghese, S.
- Affiliations
- University of California San Diego (US)
- Duke University (US)
- Corresponding author
- Varghese, Shyni
- Venue
- Cancer Research
- Published
- 2020-01-15
- Volume
- 80
- Issue
- 2
- Pages
- 263-275
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC8545579
- OpenAlex
- W2991421324
- Cited by
- 146
- References
- 50
- Citations by year
- 2026: 12 · 2025: 21 · 2024: 27 · 2023: 22 · 2022: 28 · 2021: 22 · 2020: 14
- FWCI
- 5.63
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH NHLBI (T32 HL 105373)
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Physical Sciences › Materials Science › Biomaterials › Hydrogels: synthesis, properties, applications
- Keywords
- tumor-on-a-chip, breast cancer, T cell recruitment, tumor microenvironment, tumor-immune interactions, monocytes, endothelial cells, gelatin hydrogel, chemokines, hypoxia, tumor spheroids, endothelial permeability, tumor cell migration
- MeSH terms
- Proof of Concept Study, Breast Neoplasms, Cell Communication, Feasibility Studies, Female, Humans, Lymphocyte Activation, Monocytes, T-Lymphocytes, Cell Hypoxia, Spheroids, Cellular, Chemokines, Cell Culture Techniques, Hydrogels, Cell Line, Tumor, Lab-On-A-Chip Devices, Tumor Microenvironment, Cell Engineering, Human Umbilical Vein Endothelial Cells
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