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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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In-vitro model to mimic T cell subset change in human PDAC organoid co-culture
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MethodInfluentialAddressing Key Questions in Organoid Models: Who, Where, How, and Why?
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BackgroundFacilitation of Tumor Stroma-Targeted Therapy: Model Difficulty and Co-Culture Organoid Method
Feng, Q.-S., Shan, X., Yau, V., Cai, Z., & Xie, S. (2025) · Pharmaceuticals · doi:10.3390/ph18010062 · Cited by 21
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“Recently, two different platforms have been described to allow co-culture of tumour organoids from NSCLC (non-small-cell lung cancer) [77], colorectal cancer [77], and breast cancer [78] with peripheral blood lymphocytes in order to induce and analyse tumour-specific T cell responses.”
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Organoid models in oncology: advancing precision cancer therapy and vaccine development
Xiao, Y., Li, Y., Jing, X., Weng, L., Liu, X., Liu, Q., & Chen, K. (2025) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2025.0127 · Cited by 20
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Iteration of Tumor Organoids in Drug Development: Simplification and Integration
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Progress and perspective of organoid technology in cancer-related translational medicine
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In Vitro Human Cancer Models for Biomedical Applications
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Patient-derived organoids as a model for tumor research
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Tumor Organoids as a Research Tool: How to Exploit Them
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“A side-by-side comparison of H&E staining for both colorectal and non-small cell lung patients clearly showed the similarity in terms of architecture and 3D structure between organoids and the tissue of origin [44].”
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“Exhausted T-cells, T regulatory cells, and macrophages of the M2 phenotype were also present in immune PDTO cultures [57].”
BackgroundImmunotherapy response modeling by ex-vivo organ culture for lung cancer
Kamer, I., Bab-Dinitz, E., Zadok, O., Ofek, E., Gottfried, T., Daniel‐Meshulam, I., Hout‐Siloni, G., Nun, A. B., Barshack, I., Onn, A., et al. (2021) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-020-02828-w · Cited by 15
Bioengineering methods for organoid systems
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“The biobank of cancer organoids has shifted the study of cancers to investigate the identification of predictive biomarkers and tumor pathophysiology such as mechanisms of metastasis, chemosensitivity of anti-cancer drugs, and tumor-immune cell interactions [66].”
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The Display between HPV Infection and Host Immunity in Cervical Cancer
Gu, Y., Li, T., Zhang, M., Chen, J., Shen, F., Ding, J., Zhou, G., & Hua, K. (2024) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2912426 · Cited by 14
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Organoids in Lung Cancer Management
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“’s study showed that when peripheral blood lymphocytes coculture with autologous lung cancer organoids it could expand and enrich the tumor-reactive T cells (54).”
BackgroundMethodHakuno, S. K., Michiels, E., Kuhlemaijer, E. B., Rooman, I., Hawinkels, L. J. A. C., & Slingerland, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23063147 · Cited by 15
“time in the context of colorectal cancer and non-small-cell lung cancer [83].”
BackgroundNovel Ex Vivo Models of Epithelial Ovarian Cancer: The Future of Biomarker and Therapeutic Research
Clark, J. A., Fotopoulou, C., Cunnea, P., & Krell, J. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.837233 · Cited by 17
A roadmap for translational cancer glycoimmunology at single cell resolution
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Lung cancer organoids: models for preclinical research and precision medicine
Liu, Y., Zhou, Y., & Chen, P. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1293441 · Cited by 14
“The potential immunogenicity of Matrigel, which is derived from mouse cells, has hindered certain studies on human tumor organoids in immunology (41).”
BackgroundHuman pluripotent stem cell-derived kidney organoids: Current progress and challenges
Long, H., Qian, Z.-P., Lan, Q., Xu, Y., Da, J., Yu, F., & Zha, Y. (2024) · World Journal of Stem Cells · doi:10.4252/wjsc.v16.i2.114 · Cited by 14
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“PDTO specific autologous T cells will be induced according to modified version of the protocol described in Dijk-stra et al. [28].”
Single-cell EpiChem jointly measures drug–chromatin binding and multimodal epigenome
Dong, C. F., Meng, X., Zhang, T., Guo, Z., Liu, Y., Wu, P., Chen, S., Zhou, F., Ma, Y., Xiong, H., et al. (2024) · Nature Methods · doi:10.1038/s41592-024-02360-0 · Cited by 17
“CRC organoids were established as described previously and cultured in CRC organoid medium 55 .”
MethodOrganoids in cancer therapies: a comprehensive review
Xin-Yi, J., Yan-Ran, W., Pin-Ru, D., Shi-Yi, Q., & Jiang, H. (2025) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2025.1607488 · Cited by 17
Human reconstructed kidney models
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“Dijkstra and colleagues obtained tumor-reactive T cells from the co-culture of PDOs from CRC and non-small cell lung cancer (NSCLC) with peripheral blood lymphocytes (PBLs) (53), indicating that the co-culture system can be used to establish individualized PDO models to study immune therapy and interactions between tu…”
BackgroundInterrogation of single-cell communications on microfluidic platforms
Huang, L., Chen, Y., & Zhou, J. (2022) · Cell Reports Physical Science · doi:10.1016/j.xcrp.2022.101129 · Cited by 14
van Amerongen, R. A., Morton, L. T., Chaudhari, U., Remst, D. F. G., Hagedoorn, R. S., van den Berg, C. W., Freund, C., Falkenburg, J. H. F., & Heemskerk, M. H. M. (2023) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2023.01.005 · Cited by 14
Studying Tumor-ReacTive T Cells: A Personalized Organoid Model
Şahin, U. (2018) · Cell stem cell · doi:10.1016/j.stem.2018.08.015 · Cited by 14
Stamati, K., Redondo, P., Nyga, A., Neves, J. B., Tran, M. G. B., Emberton, M., Cheema, U., & Loizidou, M. (2020) · Journal of Tissue Engineering · doi:10.1177/2041731420920597 · Cited by 14
Modelling adult stem cells and their niche in health and disease with epithelial organoids
Szabó, L., Seubert, A. C., & Kretzschmar, K. (2022) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2022.09.006 · Cited by 14
Advances and Challenges in Drug Screening for Cancer Therapy: A Comprehensive Review
Motohashi, S., Katsuta, E., & Ban, D. (2025) · Bioengineering · doi:10.3390/bioengineering12121315 · Cited by 14
Zhu, G., Shi, X., Jiang, Y., Zhang, W., Guo, L., Pei, G., Liu, Y., Tang, D., Wang, C., & Sun, Z. (2025) · Communications Biology · doi:10.1038/s42003-025-09390-0 · Cited by 13
Regulatory grammar in human promoters uncovered by MPRA-based deep learning
Barbadilla-Martínez, L., Klaassen, N. H. M., Franceschini-Santos, V. H., Breda, J., Yücel, H., Hernández-Quiles, M., van Lieshout, T., Urzúa-Traslaviña, C. G., Boi, M. C. L., Akbarzadeh, M., et al. (2026) · Nature · doi:10.1038/s41586-025-10093-z · Cited by 33
“The CRC organoid was derived from surgical resection and was established as previously described 66,67 .”
Self-citationKumari, R., Xu, X., & Li, H. (2022) · Current Protocols · doi:10.1002/cpz1.431 · Cited by 13
“Dijkstra et al. (2018) generated PDOs from tumors with high mutational load, including mismatch repair-deficient CRC (microsatellite instability, or MSI) and NSCLC (tobacco-related cancer), and co-cultured these with autologous peripheral blood lymphocytes from the same patient in media…”
BackgroundPreclinical models for development of immune–oncology therapies
Wang, Y., Shelton, S. E., Kastrunes, G. M., Barbie, D. A., Freeman, G. J., & Marasco, W. A. (2022) · Immuno Oncology Insights · doi:10.18609/ioi.2022.41 · Cited by 14
Adoptive neoantigen-reactive T cell therapy: improvement strategies and current clinical researches
Huang, R., Bi, Z., Hu, S., Zhang, Q., Su, X., & Zhang, W. (2023) · Biomarker Research · doi:10.1186/s40364-023-00478-5 · Cited by 15
Organoids as an Enabler of Precision Immuno-Oncology
Zhao, J., Fong, A. S. W., Seow, S. V., & Toh, H. C. (2023) · Cells · doi:10.3390/cells12081165 · Cited by 13
Application of organoids in precision immunotherapy of lung cancer (Review)
Tian, H., Ren, J., Mou, R., & Jia, Y. (2023) · Oncology Letters · doi:10.3892/ol.2023.14071 · Cited by 14
“Tumor‐reactive lymphocyte enrichment, stimulation and efficacy assessments may be performed using this co‐culture method (45).”
BackgroundMethodInfluentialOta, H., Tanabe, K., Saeki, Y., Takemoto, Y., Chikuie, E., Tanaka, Y., Sakamoto, N., & Ohdan, H. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e23520 · Cited by 13
“Furthermore, they demonstrated that T cells show tumor-specific injury by coculturing the T cells with cancer organoids [20].”
BackgroundZhu, L., Cheng, C., Liu, S., Yang, L., Han, P., Cui, T., & Zhang, Y. (2023) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2023.1343177 · Cited by 15
Li, J., Liu, J., Xia, W., Yang, H., Sha, W., & Chen, H. H. (2024) · Technology in Cancer Research & Treatment · doi:10.1177/15330338231221856 · Cited by 13
“Dijkstra et al 87 established a protocol for the isolation of tumor-reactive T cells.”
BackgroundAnalysis of organoid and immune cell co-cultures by machine learning-empowered image cytometry
Stüve, P., Nerb, B., Harrer, S., Wuttke, M., Feuerer, M., Junger, H. H. G., Eggenhofer, E., Lungu, B., Laslau, S., & Ritter, U. (2024) · Frontiers in Medicine · doi:10.3389/fmed.2023.1274482 · Cited by 15
Progress, application and challenges of liver organoids
Sang, C., Lin, J., Ji, S., & Gao, Q. (2024) · Clinical Cancer Bulletin · doi:10.1007/s44272-024-00012-0 · Cited by 14
“In the reductionist culture system, organoids can be co-cultured with immune cells from the peripheral blood of the same patient [130].”
Establishing mesothelioma patient-derived organoid models from malignant pleural effusions
Hocking, A. J., Mortimer, L. A., Farrall, A. L., Russell, P. A., & Klebe, S. (2024) · Lung Cancer · doi:10.1016/j.lungcan.2024.107542 · Cited by 13
Liao, C., Engelberts, P. J., Ioan‐Facsinay, A., Klip, J. E., Schmidt, T., Ruijtenbeek, R., & Danen, E. H. J. (2024) · Communications Biology · doi:10.1038/s42003-024-06682-9 · Cited by 13
“A weak sign of activation was also observed in tumor cell-T-cell co-cultures in absence of bsAbs, in line with an earlier observation 30 .”
Qu, B., Mu, Q., Bi, H., Chen, Y., Wang, Q., Ma, X., & Lu, L. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1433111 · Cited by 13
Tumor organoids improve mutation detection of pancreatic ductal adenocarcinoma
Farshadi, E. A., Wang, W., Mohammad, F., van der Oost, E., Doukas, M., van Eijck, C. H. J., van de Werken, H. J. G., & Katsikis, P. D. (2024) · Scientific Reports · doi:10.1038/s41598-024-75888-y · Cited by 13
“They do not only facilitate the identification of somatic mutations and tumor-specific neoantigens but also serve as an in vitro platform to test the immunogenicity of these neoantigens in a co-culture system 41 .”
BackgroundRevilla, S. A., Frederiks, C. L., Preković, S., Mocholí, E., Kranenburg, O., & Coffer, P. J. (2025) · iScience · doi:10.1016/j.isci.2025.111827 · Cited by 13
“11,30 35 Despite extensive research focused on studying the behavior of tumor-reactive T cells through co-culture with tumor-organoids, investigation of Treg cell-TME dynamics in vitro remains limited.”
Tumor organoids in cancer medicine: from model systems to natural compound screening
Cong, R., Lu, C., Li, X., Xu, Z., Wang, Y., & Sun, S. (2025) · Pharmaceutical Biology · doi:10.1080/13880209.2025.2458149 · Cited by 16
“This method, preferred for improved oxygenation, has been applied to various cancers, addressing the issues of cell-cell communication through coculture with native stromal cells (Dijkstra et al. 2018; Tsai et al. 2018; Zhou, Wu, et al. 2023).”
Furbo, S., Urbano, P. C. M., Raskov, H., Troelsen, J. T., Fiehn, A. K., & Gögenür, I. (2022) · Cancers · doi:10.3390/cancers14041069 · Cited by 13
Application of colloidal photonic crystals in study of organoids
Huang, K., Li, Q., Xue, Y., Wang, Q., Chen, Z., & Gu, Z. (2023) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2023.115075 · Cited by 13
Reflection of neuroblastoma intratumor heterogeneity in the new OHC‐NB1 disease model
Thole-Kliesch, T. M., Toedling, J., Sprüssel, A., Pfeil, S., Savelyeva, L., Capper, D., Messerschmidt, C., Beule, D., Groeneveld‐Krentz, S., Eckert, C., et al. (2019) · International Journal of Cancer · doi:10.1002/ijc.32572 · Cited by 13
Liver Buds and Liver Organoids: New Tools for Liver Development, Disease and Medical Application
Zeng, F., Zhang, Y., Han, X., Weng, J., & Gao, Y. (2019) · Stem Cell Reviews and Reports · doi:10.1007/s12015-019-09909-z · Cited by 13
Organoids as Complex In Vitro Models for Studying Radiation-Induced Cell Recruitment
Hacker, B. C., & Rafat, M. (2020) · Cellular and Molecular Bioengineering · doi:10.1007/s12195-020-00625-0 · Cited by 15
Organoid Cultures for the Study of Mammary Biology and Breast Cancer: The Promise and ChallengesPreprint
Muthuswamy, S. K., & Brugge, J. S. (2023) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a041661 · Cited by 13
Neoantigen-driven personalized tumor therapy: An update from discovery to clinical application
Xie, N., Shen, G., Huang, C., & Zhu, H. (2025) · Chinese Medical Journal · doi:10.1097/cm9.0000000000003708 · Cited by 13
“[243] While further refinements are needed to fully recapitulate the tumor stroma, including bone marrow and stromal elements, these organoid models provide a promising in vitro platform for neoantigen presentation and T-cell recognition.”
Human Liver Organoid Models for Assessment of Drug Toxicity at the Preclinical Stage
Karabicici, M., Akbari, S., Ertem, Ö., Gümüştekin, M., & Erdal, E. (2023) · Endocrine Metabolic & Immune Disorders - Drug Targets · doi:10.2174/1871530323666230411100121 · Cited by 12
Three-dimensional bioprinting of in vitro tumor organoid and organ-on-a-chip models
Anderson, S. R., Stagner, E., Sivakumar, H., & Skardal, A. (2023) · MRS Bulletin · doi:10.1557/s43577-023-00559-8 · Cited by 12
Organoids in gastrointestinal diseases: from bench to clinic
Wang, Q., Guo, F., Zhang, Q., Hu, T., Jin, Y., Yang, Y., & Ma, Y. (2024) · MedComm · doi:10.1002/mco2.574 · Cited by 13
“For instance, coculture of epithelial organoids with immune cells can be used to construct immune microenvironments or conduct immunotherapy testing 44–46 ; coculture with endothelial cells for vascularization investigation 47,48 ; coculture with neural cells to study the paracrine signaling…”
BackgroundCock, L. D., Palubeckaitė, I., Bersani, F., Faehling, T., Pasquali, S., Umbaugh, S., Meister, M. T., Danks, M. R., Manasterski, P. J., MIALLOT, R., et al. (2025) · Neoplasia · doi:10.1016/j.neo.2025.101171 · Cited by 12
“In fact, co-culturing of immune cells with tumoroids to explore tumor ecosystem biology or investigate novel immunomodulating therapeutics has already been successfully implemented in epithelial cancer research [40 – 42].”
Tumor organoids to study gastroesophageal cancer: a primer
Jin, R. U., & Mills, J. C. (2020) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjaa035 · Cited by 13
“The genomic and transcriptomic natures of each of these could be determined, and key variations could be altered by genetic manipulations to determine which genes are most critical for each phenotype (Driehuis and Clevers, 2017 ).”
BackgroundT Cell Aging in Patients with Colorectal Cancer—What Do We Know So Far?
Thoma, O., Neurath, M. F., & Waldner, M. J. (2021) · Cancers · doi:10.3390/cancers13246227 · Cited by 12
“This knowledge can be useful for immunotherapy, or even for individualized therapy, where tumor-reactive T cells could be generated by co-culturing them with patient-derived tumor organoids [78].”
Background
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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