A multidisciplinary study using in vivo tumor models and microfluidic cell-on-chip approach to explore the cross-talk between cancer and immune cells
Open accessAbstract
A full elucidation of events occurring inside the cancer microenvironment is fundamental for the optimization of more effective therapies. In the present study, the cross-talk between cancer and immune cells was examined by employing mice deficient (KO) in interferon regulatory factor (IRF)-8, a transcription factor essential for induction of competent immune responses. The in vivo results showed that IRF-8 KO mice were highly permissive to B16.F10 melanoma growth and metastasis due to failure of their immune cells to exert proper immunosurveillance. These events were found to be dependent on soluble factors released by cells of the immune system capable of shaping the malignant phenotype of melanoma cells. An on-chip model was then generated to further explore the reciprocal interactions between the B16.F10 and immune cells. B16.F10 and immune cells were co-cultured in a microfluidic device composed of three culturing chambers suitably inter-connected by an array of microchannels; mutual interactions were then followed using time-lapse microscopy. It was observed that WT immune cells migrated through the microchannels towards the B16.F10 cells, establishing tight interactions that in turn limited tumor spread. In contrast, IRF-8 KO immune cells poorly interacted with the melanoma cells, resulting in a more invasive behavior of the B16.F10 cells. These results suggest that IRF-8 expression plays a key role in the cross-talk between melanoma and immune cells, and under-score the value of cell-on-chip approaches as useful in vitro tools to reconstruct complex in vivo microenvironments on a microscale level to explore cell interactions such as those occurring within a cancer immunoenvironment.
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Immune-deficient IRF-8 knockout mice develop more tumors with less immune cell infiltration than wild-type animals.
“These studies first showed that immune-deficient interferon regulatory factor-8 (IRF-8) knockout mice develop more tumors with less immune cell infiltration than wild type animals[50], and subsequently used a microfluidic assay to investigate the underlying mechanism in greater detail.”
From Microfluidics: A New Tool for Modeling Cancer–Immune Interactions (2016) · cites this paper as [50]
The melanoma-growth section reports faster tumor growth and more lung metastatic foci in IRF-8 knockout mice, but does not establish that they developed more primary tumors. The immune-cell infiltration section reports fewer infiltrating T cells and dendritic cells in knockout tumors, while myeloid-derived suppressor cell infiltration was higher; the unqualified claim of less immune-cell infiltration misses that exception. (LLM, conf=0.85)
Experimental — accuracy not yet measuredImmune spleen cells lacking IRF-8 do not migrate toward cancer cells or interact with them as efficiently as wild-type immune cells.
“Specifically, they showed that immune spleen cells lacking IRF-8 do not migrate towards cancer cells, nor interact with them as efficiently as wild type immune cells[48–50], suggesting a mechanism to explain why IRF-8 knock-out cells fail to exert proper immune-surveillance leading to a heavier metastatic burden.”
From Microfluidics: A New Tool for Modeling Cancer–Immune Interactions (2016) · cites this paper as [50]
Only a limited number of recent studies have employed microfluidics to investigate immune-cancer cell interactions.
“To the best of our knowledge, only a limited number of recent studies have employed microfluidics to investigate immune-cancer cell interactions[18, 48–52], possibly because microfluidic models are not yet widely available to cancer researchers.”
From Microfluidics: A New Tool for Modeling Cancer–Immune Interactions (2016) · cites this paper as [50]
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- Authors
- Mattei, F., Schiavoni, G., De Ninno, A., Lucarini, V., Sestili, P., Sistigu, A., Fragale, A., Sanchez, M., Spada, M., Gerardino, A., Belardelli, F., Businaro, L., & Gabriele, L.
- Affiliations
- Istituto Superiore di Sanità (IT)
- National Research Council (IT)
- Corresponding author
- Mattei, Fabrizio
- ORCID
- Venue
- Journal of Immunotoxicology
- Publisher
- Informa UK Limited
- Published
- 2014-03-06
- Volume
- 11
- Issue
- 4
- Pages
- 337-346
- ISSN
- 1547-6901 (ISSN-L)
- 1547-691X
- OpenAlex
- W2087204483
- Cited by
- 57
- References
- 25
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 1 · 2023: 3 · 2022: 6 · 2021: 4 · 2020: 7 · 2019: 4 · 2018: 7 · 2017: 5 · 2016: 8 · 2015: 2 · 2014: 3
- FWCI
- 2.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Immunotoxicology (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Funders
- Associazione Italiana per la Ricerca sul Cancro
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- IRF8, B16F10 melanoma, melanoma metastasis, tumor microenvironment, immune surveillance, microfluidic co-culture, leukocyte migration, tumor invasion, tumor surveillance
- MeSH terms
- Interferon Regulatory Factor-8, Animals, Cell Communication, Cell Movement, Humans, Immunologic Surveillance, Mice, Inbred C57BL, Neoplasm Metastasis, Neoplasms, Experimental, CD4-Positive T-Lymphocytes, Mice, Knockout, Microfluidic Analytical Techniques, Interferon Regulatory Factors, Mice, Tumor Microenvironment
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