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Generation of Tumor-Reactive T Cells by Co-culture of Peripheral Blood Lymphocytes and Tumor Organoids
Open accessAbstract
Cancer immunotherapies have shown substantial clinical activity for a subset of patients with epithelial cancers. Still, technological platforms to study cancer T-cell interactions for individual patients and understand determinants of responsiveness are presently lacking. Here, we establish and validate a platform to induce and analyze tumor-specific T cell responses to epithelial cancers in a personalized manner. We demonstrate that co-cultures of autologous tumor organoids and peripheral blood lymphocytes can be used to enrich tumor-reactive T cells from peripheral blood of patients with mismatch repair-deficient colorectal cancer and non-small-cell lung cancer. Furthermore, we demonstrate that these T cells can be used to assess the efficiency of killing of matched tumor organoids. This platform provides an unbiased strategy for the isolation of tumor-reactive T cells and provides a means by which to assess the sensitivity of tumor cells to T cell-mediated attack at the level of the individual patient.
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“In addition, ex vivo coculture systems utilizing human peripheral blood mononuclear cells or tumor-infiltrating lymphocytes cocultured with patient-derived organoids provide valuable platforms to interrogate human-specific immune responses to phage-delivered antigens or immunotherapies [111–113]”
From Phage therapy in oncology: opportunities for cancer prevention and treatment (2026) · cites this paper as [112]
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BackgroundFaithful preclinical mouse models for better translation to bedside in the field of immuno-oncology
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“deficient colorectal cancer), and had no reactivity towards organoids derived from another form of colorectal cancer (mismatch repair-proficient colorectal cancer) [94].”
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“The E:T ratio was 5:1, as previously suggested.(46) In the 8 μM co-culture system, the upper chamber was placed with lymphoma cells and the lower chamber was placed with PBMCs.”
MethodRNF31 inhibition sensitizes tumors to bystander killing by innate and adaptive immune cells
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Networking between helminths, microbes, and mammals
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“Addition of immune cells to organoid cultures 49 could then add greater realism these models.”
Neoantigen cancer vaccines: a new star on the horizon
Li, X., You, J., Hong, L., Liu, W., Guo, P., & Hao, X. (2023) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2023.0395 · Cited by 53
“It should be noted that typically, submerged Matrigel PDO can only support the growth of cancer cells; therefore, exogenous immune cells isolated from the PBMCs or TILs must be introduced to create a co-culture system that mimics the internal microenvironment of the tumor patient 190,191 .”
BackgroundYin, S., Yu, Y., Wu, N., Zhuo, M., Wang, Y., Niu, Y., Ni, Y., Hu, F., Ding, C., Liu, H., et al. (2024) · Cell stem cell · doi:10.1016/j.stem.2024.03.008 · Cited by 47
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New generation breast cancer cell lines developed from patient-derived xenografts
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“PDO offer an ex vivo approach to screen different patients’ tumors for drug sensitivity and can potentially include other cell types contained in the microenvironment [23].”
Neoantigen-Specific Adoptive Cell Therapies for Cancer: Making T-Cell Products More Personal
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“(100) have presented a proofof-concept study in which tumor-reactive T-cells from nonsmall-cell lung cancer and colon rectal cancer patients can be obtained by coculturing autologous PBLs with matched tumor epithelial organoids.”
BackgroundHuman-Derived Model Systems in Gynecological Cancer Research
Lõhmussaar, K., Boretto, M., & Clevers, H. C. (2020) · Trends in cancer · doi:10.1016/j.trecan.2020.07.007 · Cited by 47
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A suspension technique for efficient large-scale cancer organoid culturing and perturbation screens
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Everything You Always Wanted to Know About Organoid-Based Models (and Never Dared to Ask)
Hautefort, I., Poletti, M., Papp, D., & Korcsmáros, T. (2022) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2022.04.012 · Cited by 49
Give them vasculature and immune cells – how to fill the gap of organoids
Yip, S., Wang, N., & Sugimura, R. (2023) · Cells Tissues Organs · doi:10.1159/000529431 · Cited by 48
“For instance, Krijn K Dijkstra et al. analyzed tumor-speci fi c T cell responses by coculturing autologous epithelial tumor organoids with peripheral blood mononuclear cells, and this model clearly documented the process of tumor antigen-mediated CD8+ T cell proliferation [Dijkstra et al., 2018].”
BackgroundFlourishing tumor organoids: History, emerging technology, and application
Yang, Q., Li, M., Yang, X., Xiao, Z., Tong, X., Tuerdi, A., Li, S., & Lei, L. (2023) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10559 · Cited by 46
Fang, Y., Zhang, M., He, Y., Li, C., Fang, H., Xu, P., Cheng, S., Zhao, Y. F., Feng, Y., Liu, Q., et al. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01626-x · Cited by 45
The Untapped Opportunity and Challenge of Immunometabolism: A New Paradigm for Drug Discovery
Mazumdar, C., Driggers, E. M., & Turka, L. A. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.11.014 · Cited by 47
Radiotherapy as a Backbone for Novel Concepts in Cancer Immunotherapy
Kabiljo, J., Harpain, F., Carotta, S., & Bergmann, M. M. (2019) · Cancers · doi:10.3390/cancers12010079 · Cited by 48
Technologies to Assess Drug Response and Heterogeneity in Patient-Derived Cancer Organoids
Skala, M. C., Deming, D. A., & Kratz, J. D. (2022) · Annual Review of Biomedical Engineering · doi:10.1146/annurev-bioeng-110220-123503 · Cited by 46
Wang, J., Chen, C., Wang, L., Xie, M., Ge, X., Wu, S., He, Y., Mou, X., Ye, C., & Sun, Y. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.872531 · Cited by 46
Gastric Organoids: Progress and Remaining Challenges
Pang, M.-J., Burclaff, J., Jin, R. U., Adkins-Threats, M., Osaki, L. H., Han, Y., Mills, J. C., Miao, Z., & Wang, Z.-N. (2021) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2021.09.005 · Cited by 43
Early-onset cancers: Biological bases and clinical implications
Mauri, G., Patelli, G., Bianchi, A. S., Abrignani, S., Bodega, B., Marsoni, S., Costanzo, V., Bachi, A., Siena, S., & Bardelli, A. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101737 · Cited by 51
“…immune-editing phenomena and to determine whether anti-cancer immune responses elicited in EO cancers are different from later-onset tumors, 143,144 and whether there is a signature in intratumoral and peripheral T cells potentially associated with immune response failures specific for…”
Backgroundvan Tienderen, G. S., Koerkamp, B. G., IJzermans, J. N. M., van der Laan, L. J. W., & Verstegen, M. M. A. (2019) · Cancers · doi:10.3390/cancers11111706 · Cited by 43
“Various studies have focused on combining organoids with the restoration of the immune-component of the TME, including co-cultures with lymphocytes [81] and stromal cells [82], and the combination with immune cells relevant for PLC could aid in the development of novel immunotherapies.”
BackgroundIn Vitro Modeling of the Tumor Microenvironment in Tumor Organoids
Devarasetty, M., Forsythe, S. D., Shelkey, E., & Söker, S. (2020) · Tissue Engineering and Regenerative Medicine · doi:10.1007/s13770-020-00258-4 · Cited by 45
Alexander, K. L., Serrano, C. A., Chakraborty, A., Nearing, M., Riquelme, A. J., Marcelo Garrido, S., Bellis, S. L., Smythies, L. E., & Smith, P. D. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.014887 · Cited by 43
“In addition to enhancing prevention surveillance, gastric tissuederived organoids might be used therapeutically, as reported in mouse(52,53) and human studies(54-56), to restore defective or injured epithelium.”
BackgroundMethodHydrogels to engineer tumor microenvironments in vitro
Fernando, K., Kwang, L. G., Lim, J. T. C., & Fong, E. L. S. (2021) · Biomaterials Science · doi:10.1039/d0bm01943g · Cited by 44
Cancer-on-a-chip for precision cancer medicine
Liu, L., Wang, H., Chen, R., Song, Y., Wei, W., Baek, D. S. H., Gillin, M., Kurabayashi, K., & Chen, W. (2025) · Lab on a Chip · doi:10.1039/d4lc01043d · Cited by 48
Yu, Y., Yang, G., Huang, H., Fu, Z., Cao, Z., Zheng, L., You, L., & Zhang, T. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-020-01787-5 · Cited by 42
“In addition, co-culture of peripheral blood lymphocytes [73] enriched the infiltration of reactive T cells in the TME of CRC and non-small cell lung cancer (NSCLC) organoids.”
BackgroundPersonalizing Oncolytic Virotherapy for Glioblastoma: In Search of Biomarkers for Response
Stavrakaki, Ε., Dirven, C. M. F., & Lamfers, M. L. M. (2021) · Cancers · doi:10.3390/cancers13040614 · Cited by 42
“With such model systems, the T cell-mediated cell killing could be evaluated for individual patients after infection with different OVs [162].”
BackgroundXing, F., Liu, Y., Huang, S., Lyu, X., Su, S. M., Chan, U. I., Wu, P., Yan, Y., Ai, N., Li, J., et al. (2021) · Theranostics · doi:10.7150/thno.59533 · Cited by 41
“Moreover, due to the lack of immune components, the PDOs system has limitations to be used for studying interactions between tumor cells and immune cells [24, 25].”
BackgroundModelling the tumor immune microenvironment for precision immunotherapy
Mackenzie, N. J., Nicholls, C., Templeton, A. R., Perera, O. M., Jeffery, P. L., Zimmermann, K., Kulasinghe, A., Kenna, T., Vela, I., Williams, E. D., et al. (2022) · Clinical & Translational Immunology · doi:10.1002/cti2.1400 · Cited by 45
“Dijkstra et al.(88) demonstrated that by culturing PDOs with PBMCs, it is possible to induce the expansion of tumor-reactive T cells.”
BackgroundInfluentialProstate organoids: emerging experimental tools for translational research
Beshiri, M. L., Agarwal, S., Yin, J. J., & Kelly, K. (2023) · Journal of Clinical Investigation · doi:10.1172/jci169616 · Cited by 40
Ravi, K., Manoharan, T. J. M., Wang, K.-C., Pockaj, B. A., & Nikkhah, M. (2023) · Biomaterials · doi:10.1016/j.biomaterials.2023.122428 · Cited by 45
Advancing cancer research through organoid technology
Zeng, G., Yu, Y., Wang, M., Liu, J., He, G., Yu, S., Yan, H., Yang, L., Li, H., & Peng, X. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05824-1 · Cited by 43
“The co-culture system involving immune cells and tumor organoids can serve as a testing platform, facilitating the study of immune components within the TME and guiding precision cancer immunotherapy [43, 44].”
BackgroundHuman-correlated genetic models identify precision therapy for liver cancer
Müller, M., May, S., Hall, H., Kendall, T. J., McGarry, L., Blukacz, L., Nuciforo, S., Γεωργακοπούλου, Α., Jamieson, T., Phinichkusolchit, N., et al. (2025) · Nature · doi:10.1038/s41586-025-08585-z · Cited by 40
“Future research in HCCOs needs to overcome the reduced complexity in cell culture, a general issue in organoid culture 40 , and address options for co-culture with cells shaping the tumour microenvironment 41 .”
CRISPR screen in mechanism and target discovery for cancer immunotherapy
Liu, D., Zhao, X., Tang, A., Xu, X., Liu, S., Zha, L., Ma, W., Zheng, J., & Shi, M. (2020) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2020.188378 · Cited by 44
The application of patient-derived organoid in the research of lung cancer
Li, Y., Gao, X., Ni, C., Zhao, B. T., & Cheng, X. (2023) · Cellular Oncology · doi:10.1007/s13402-023-00771-3 · Cited by 41
Tumor-derived systems as novel biomedical tools—turning the enemy into an ally
Desai, N., Katare, P., Makwana, V., Salave, S., Vora, L. K., & Giri, J. (2023) · Biomaterials Research · doi:10.1186/s40824-023-00445-z · Cited by 45
Zhao, H., Chang, Y., Hu, Y., Mu, L., Huang, K., Li, Q., Li, X., Tao, D., & Qin, J. (2019) · International Journal of Oncology · doi:10.3892/ijo.2019.4683 · Cited by 41
“In general, sphere formation assays can be applied to enrich cancer cells with limited or unlimited self-renewal capacity for primary tumor cells and cell lines (38); on the other hand, organoid culture has been utilized in a range of cancer studies including drug testing, disease modeling, and co-culture models of ca…”
BackgroundRingquist, R., Ghoshal, D., Jain, R., & Roy, K. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.114003 · Cited by 39
Cattaneo, C. M., Battaglia, T., Urbanus, J. H. M., Moravec, Ž., Voogd, R., de Groot, R., Hartemink, K. J., Haanen, J. B. A. G., Voest, E. E., Schumacher, T. N., et al. (2023) · Nature Biotechnology · doi:10.1038/s41587-022-01547-0 · Cited by 45
Self-citationLung cancer organoids, a promising model still with long way to go
Ma, H., Zhu, Y.-J., Zhou, R., Yu, Y., Xiao, Z., & Zhang, H.-B. (2022) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2022.103610 · Cited by 41
Modeling glioblastoma complexity with organoids for personalized treatments
Pawlowski, K. D., Duffy, J. T., Babak, M. V., & Balyasnikova, I. V. (2023) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2023.01.002 · Cited by 42
Organoids: opportunities and challenges of cancer therapy
Jiang, X., Oyang, L., Qiu, P., Liu, Q., Xu, X., Wu, N., Tan, S., Yang, W., Han, Y., Lin, J., et al. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1232528 · Cited by 41
“Additionally, researchers have co-cultured lymphocytes with tumor organoids to generate tumor-reactive T cells, which holds great potential for the immunotherapy of tumors (Dijkstra et al., 2018).”
BackgroundMascolo, D. D., Varesano, S., Benelli, R., Mollica, H., Salis, A., Zocchi, M. R., Decuzzi, P., & Poggi, A. D. (2019) · Cancers · doi:10.3390/cancers12010104 · Cited by 39
“On the other hand, 3D culture systems, including spheroids and organoids, have been validated as preclinical models to overcome these inconveniences by the present authors and others [44,45,56,57].”
BackgroundMethodIncorporating Tumor-Associated Macrophages into Engineered Models of Glioma
Akins, E. A., Aghi, M. K., & Kumar, S. (2020) · iScience · doi:10.1016/j.isci.2020.101770 · Cited by 43
Becker, L., Janssen, N., Layland, S. L., Mürdter, T. E., Nies, A. T., Schenke‐Layland, K., & Marzi, J. (2021) · Cancers · doi:10.3390/cancers13225682 · Cited by 44
Ao, Z., Wu, Z., Cai, H., Hu, L., Li, X., Kaurich, C., Chang, J., Gu, M., Liang Cheng, C., Lü, X., et al. (2022) · Advanced Science · doi:10.1002/advs.202201478 · Cited by 40
Metadata
- Authors
- Dijkstra, K. K., Cattaneo, C. M., Weeber, F., Chalabi, M., van de Haar, J., Fanchi, L. F., Slagter, M., van der Velden, D. L., Kaing, S., Kelderman, S., van Rooij, N., van Leerdam, M. E., Depla, A., Smit, E. F., Hartemink, K. J., de Groot, R., Wolkers, M. C., Sachs, N., Snaebjornsson, P., Monkhorst, K., Haanen, J., Clevers, H., Schumacher, T. N., & Voest, E. E.
- Affiliations
- The Netherlands Cancer Institute (NL)
- Slotervaartziekenhuis (NL)
- Sanquin (NL)
- University Medical Center Utrecht (NL)
- Corresponding author
- Voest, Emile E.
- ORCID
- Dijkstra, Krijn K.
- Cattaneo, Chiara M.
- Weeber, Fleur
- Chalabi, Myriam
- van de Haar, Joris
- Fanchi, Lorenzo F.
- Slagter, Maarten
- van Rooij, Nienke
- van Leerdam, Monique E.
- Smit, Egbert F.
- Hartemink, Koen J.
- de Groot, Rosa
- Wolkers, Monika C.
- Sachs, Norman
- Monkhorst, Kim
- Haanen, John
- Clevers, Hans
- Schumacher, Ton N.
- Voest, Emile E.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-09
- Volume
- 174
- Issue
- 6
- Pages
- 1586-1598.e12
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6558289
- OpenAlex
- W2885650843
- Cited by
- 1,135
- References
- 47
- Citations by year
- 2026: 172 · 2025: 175 · 2024: 143 · 2023: 154 · 2022: 144 · 2021: 168 · 2020: 106 · 2019: 62 · 2018: 10
- FWCI
- 37.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Pure Amsterdam UMC (submittedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- NWO Gravitation Program (NWO (2012-2022)
- KWF (HUBR2014-7006)
- KWF Queen Wilhelmina (NKI 2013-6122)
- ERC AdG SENSIT
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- tumor-reactive T cells, tumor organoids, peripheral blood lymphocytes, co-culture, personalized cancer immunotherapy, non-small cell lung cancer, epithelial cancers, T cell-mediated killing
- MeSH terms
- Aged, Carcinoma, Non-Small-Cell Lung, Female, Humans, Interferon-gamma, Leukocytes, Mononuclear, Lung Neoplasms, Lymphocyte Activation, Male, Middle Aged, T-Lymphocytes, Tumor Cells, Cultured, Colorectal Neoplasms, Coculture Techniques, Cell Culture Techniques, In Vitro Techniques
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