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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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Macrophage hitchhiking nanomedicine for enhanced β-elemene delivery and tumor therapy
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“T cells generated using this process were shown to efficiently kill cancer cells, while they did not show activity against organoids originated from healthy tissue, confirming the maintenance of self-tolerance (112).”
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“43 We wondered whether an immune organoid platform containing sufficient amounts of TILs could be established in vitro by co-culturing with a small number of PBMCs in the same way.”
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“Recent reports point to (Dijkstra et al., 2018) use peripheral blood lymphocytes co-cultured with autologous lung cancer PDOs and immunotherapy to evaluate the sensitivity of tumor-like organoids to T cell lethality, the success rate of this study was only about 33%– 50%, it is hard to evaluate the feasibility of this…”
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Tumour organoids and assembloids: Patient‐derived cancer avatars for immunotherapy
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“156 Furthermore, the concept of ‘super T cells’ with exceptional abilities to sustain high levels of specific recognition and cytotoxicity towards tumour organoids is under investigation.”
BackgroundImaging 3D cell cultures with optical microscopy
Hsieh, H.-C., Han, Q., Brenes, D., Bishop, K. W., Wang, R., Wang, Y., Poudel, C., Glaser, A. K., Freedman, B., Vaughan, J. C., et al. (2025) · Nature Methods · doi:10.1038/s41592-025-02647-w · Cited by 38
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Organoids of the Female Reproductive Tract: Innovative Tools to Study Desired to Unwelcome Processes
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“This drawback of lacking the organ’s stromal, vascular and immune cells and their interplay was readily overcome by the development of various in vitro co-culturing as well as in vivo transplant modalities (Nozaki et al., 2016; Roper et al., 2017; Dijkstra et al., 2018).”
BackgroundCross-Resistance Among Sequential Cancer Therapeutics: An Emerging Issue
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“To address these issues, researchers are testing diverse co-culture systems, with a particular focus on the inclusion of immune cells [100,101].”
BackgroundDesign Approaches for Generating Organ Constructs
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“PDO are 3D cultures obtained by dissociated tumor tissue which can be co-cultured with human lymphocytes, thus allowing to investigate tumor microenvironment, anticancer immunotherapy, and other aspects including development of novel therapeutics [181,182].”
BackgroundGenomics-guided pre-clinical development of cancer therapies
Francies, H. E., McDermott, U., & Garnett, M. J. (2020) · Nature Cancer · doi:10.1038/s43018-020-0067-x · Cited by 32
Advances in Modeling the Immune Microenvironment of Colorectal Cancer
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“co-cultured organoids from dMMR CRC patients with autologous peripheral blood lymphocytes (71).”
BackgroundUse of preclinical models for malignant pleural mesothelioma
Shamseddin, M., Obacz, J., Garnett, M. J., Rintoul, R. C., Francies, H. E., & Marciniak, S. J. (2021) · Thorax · doi:10.1136/thoraxjnl-2020-216602 · Cited by 30
Intestinal multicellular organoids to study colorectal cancer
Idris, M., Alves, M. M., Hofstra, R. M. W., Mahé, M. M., & Melotte, V. (2021) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2021.188586 · Cited by 33
In-Depth Comparison of Matrigel Dissolving Methods on Proteomic Profiling of Organoids
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“Excitingly, several approaches for PDO generation have also been developed to preserve features of the TME 43,44 , including tumour-in fi ltrating lymphocytes, which represent a platform to study the impact of the different immune clusters on immunotherapy response.”
Opportunities and challenges to engineer 3D models of tumor-adaptive immune interactions
Visalakshan, R. M., Lowrey, M. K., Sousa, M. G. C., Helms, H. R., Samiea, A., Schutt, C. E., Moreau, J. M., & Bertassoni, L. E. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1162905 · Cited by 32
Combinatorial Immunotherapies for Metastatic Colorectal Cancer
Janssen, E., Subtil, B., Ortiz, F. D. L. J., Verheul, H. M. W., & Tauriello, D. V. F. (2020) · Cancers · doi:10.3390/cancers12071875 · Cited by 31
The Progress and Clinical Application of Breast Cancer Organoids
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“(36) employed the patient’s tumor-like organs to activate T lymphocytes to amplify the patient’s immune function.”
BackgroundMethodPPARγ induces PD-L1 expression in MSS+ colorectal cancer cells
Gutting, T., Hauber, V., Pahl, J. H. W., Klapproth, K., Wu, W., Dobrota, I., Herweck, F., Reichling, J., Helm, L., Schroeder, T., et al. (2021) · OncoImmunology · doi:10.1080/2162402x.2021.1906500 · Cited by 30
“Reconstitution of these “avatars” with autologous or allogenic immune cells shall identify novel drugable targets to avoid lack of response, prevent resistance, relieve anergy and empower the full antitumor potential of innate and adaptive immunity.(6,7) In this highly individualized contact-dependent co-culture model…”
BackgroundTumor models to assess immune response and tumor-microbiome interactions in colorectal cancer
Yuan, C., Zhao, X., Wangmo, D., Alshareef, D., Gates, T. J., & Subramanian, S. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107981 · Cited by 29
“Although tumor organoids do not innately contain immune cells, they still allow for studying immune responses and developing different targeted therapies, such as T cell-based therapies and immunotherapy using drug sensitivity/resistance screening tests, selection of tumor-reactive T cells (Dijkstra et al., 2018).”
BackgroundLin, Y.-N., Schmidt, M. O., Sharif, G. M., Vietsch, E. E., Kiliti, A. J., Barefoot, M. E., Riegel, A. T., & Wellstein, A. (2022) · OncoImmunology · doi:10.1080/2162402x.2022.2027136 · Cited by 31
Carter, M. E., Hartkopf, A. D., Wagner, A., Volmer, L. L., Brucker, S. Y., Berchtold, S., Lauer, U. M., & Koch, A. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.826302 · Cited by 31
“(Dijkstra et al., 2018) successfully incorporated autologous peripheral blood monocytes derived from patient blood samples into the corresponding colon and lung cancer organoid setup.”
BackgroundMethodHuman Kidney Organoids and Tubuloids as Models of Complex Kidney Disease
Nunez-Nescolarde, A. B., Nikolic‐Paterson, D. J., & Combes, A. N. (2022) · American Journal Of Pathology · doi:10.1016/j.ajpath.2022.01.009 · Cited by 32
3D Cell Models in Radiobiology: Improving the Predictive Value of In Vitro Research
Antonelli, F. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241310620 · Cited by 34
Intestinal Epithelial Organoids as Tools to Study Epigenetics in Gut Health and Disease
Kraiczy, J., & Zilbauer, M. (2019) · Stem Cells International · doi:10.1155/2019/7242415 · Cited by 32
“The latter option will further benefit from recent advances which have allowed coculture of IEOs with other cell types such as lymphocytes and mesenchyme [85, 86].”
BackgroundKey aspects for conception and construction of co-culture models of tumor-stroma interactions
Mason, J. E., & Öhlund, D. (2023) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2023.1150764 · Cited by 30
“Organoid co-culture models of the TME have also been used to explore immunotherapy approaches via direct tumor organoidT-cell co-culture systems and also investigate the phenomenon of immune evasion (Sharma et al., 2017; Dijkstra et al., 2018; Cattaneo et al., 2020).”
Li, P., Huang, M., Ma, Y., Zhang, Y., & Shi, C. (2024) · Cancer Cell International · doi:10.1186/s12935-024-03628-3 · Cited by 32
In vitro biomimetic models for respiratory diseases: progress in lung organoids and lung-on-a-chip
Zhang, X., Liu, H., Cheng, H., Cui, Y., Junli, W., Yao, Q., Wang, P., Hu, Y., & Wang, Y. (2025) · Stem Cell Research & Therapy · doi:10.1186/s13287-025-04500-5 · Cited by 31
“Voest et al. [90] developed an immune organoid platform enabling co-culture of patient-derived T cells with tumor organoids, effectively modeling tumor-immune interactions to assess tumor susceptibility to T cell-mediated cytotoxicity and immune evasion mechanisms.”
Engineering strategies to capture the biological and biophysical tumor microenvironment in vitro
Tan, M. L., Lu, L., & Fischbach, C. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.113852 · Cited by 31
Three-Dimensional in Vitro Models: A Promising Tool To Scale-Up Breast Cancer Research
Azimian, V., Rafiee, L., Sheikholeslam, M., Shariati, L., Vaseghi, G., Savoji, H., & Javanmard, S. H. (2022) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.2c00277 · Cited by 31
Toward reproducible tumor organoid culture: focusing on primary liver cancer
Guo, L., Li, C., & Gong, W. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1290504 · Cited by 34
Zhao, H., Lin, N., Ho, V. W. S., Liu, K., Chen, X., Wu, H., Chiu, P. K., Huang, L. Y., Dantes, Z., Wong, K., et al. (2025) · Advanced Science · doi:10.1002/advs.202414558 · Cited by 35
Single Cell Sequencing and Kidney Organoids Generated from Pluripotent Stem Cells
Wu, H., & Humphreys, B. D. (2020) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.07470619 · Cited by 31
“(37) showed that coculture of autologous tumor organoids and PBMCs can enrich tumor-reactive T cells from patients with colorectal cancer and lung cancer.”
BackgroundCurrent methods in translational cancer research
Lee, M. W., Miljanic, M., Triplett, T., Ramírez, C., Aung, K. L., Eckhardt, S., & Capasso, A. (2020) · Cancer and Metastasis Reviews · doi:10.1007/s10555-020-09931-5 · Cited by 32
Engineered models of tumor metastasis with immune cell contributions
Graney, P. L., Tavakol, D. N., Chramiec, A. G., Ronaldson-Bouchard, K., & Vunjak‐Novakovic, G. (2021) · iScience · doi:10.1016/j.isci.2021.102179 · Cited by 30
Itoh, T., Kawai, Y., Yasui, Y., Iriguchi, S., Minagawa, A., Ishii, T., Miyoshi, H., Taketo, M. M., Kawada, K., Obama, K., et al. (2021) · Communications Biology · doi:10.1038/s42003-021-02195-x · Cited by 30
The Hippo Signaling Pathway: The Trader of Tumor Microenvironment
Yang, D., Zhang, N., Li, M., Hong, T., Meng, W., & Ouyang, T. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.772134 · Cited by 30
“In tumor immunology, T cells are essential for both immune escape and antitumor immunity (53, 54).”
BackgroundMetabolic Studies in Organoids: Current Applications, Opportunities and Challenges
Richiardone, E., den Bossche, V. V., & Corbet, C. (2022) · Organoids · doi:10.3390/organoids1010008 · Cited by 29
Zou, J., Wang, S., Chai, N., Yue, H., Ye, P., Guo, P., Li, F., Wei, B., Ma, G., Wei, W., et al. (2022) · Journal of Nanobiotechnology · doi:10.1186/s12951-022-01431-8 · Cited by 28
Protocol for ex vivo culture of patient-derived tumor fragments
Roelofsen, L. M., Voabil, P., de Bruijn, M. J. W., Herzig, P., Zippelius, A., Schumacher, T. N., & Thommen, D. S. (2023) · STAR Protocols · doi:10.1016/j.xpro.2023.102282 · Cited by 29
Self-citationRecent advances and challenges in colorectal cancer: From molecular research to treatment
Qi, G., Zhao, R., Gao, C., Ma, Z., Wang, S., & Xu, J. (2025) · World Journal of Gastroenterology · doi:10.3748/wjg.v31.i21.106964 · Cited by 40
“Dijkstra et al [179] demonstrated that co-culturing autologous tumor organoids with peripheral blood lymphocytes can enrich tumor-reactive T cells from the blood of MMR-deficient CRC patients.”
Deciphering Organoids: High-Dimensional Analysis of Biomimetic Cultures
Qin, X., & Tape, C. J. (2020) · Trends in biotechnology · doi:10.1016/j.tibtech.2020.10.013 · Cited by 27
Miyabayashi, K., Nakagawa, H., & Koike, K. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.682872 · Cited by 28
Strategies for developing complex multi-component in vitro tumor models: Highlights in glioblastoma
DePalma, T. J., Sivakumar, H., & Skardal, A. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.114067 · Cited by 30
Colorectal Cancer Stem Cells: An Overview of Evolving Methods and Concepts
Angelis, M. L. D., Francescangeli, F., Zeuner, A., & Baiocchi, M. (2021) · Cancers · doi:10.3390/cancers13235910 · Cited by 30
Immuno-reactive cancer organoid model to assess effects of the microbiome on cancer immunotherapy
Shelkey, E., Oommen, D., Stirling, E. R., Soto‐Pantoja, D. R., Cook, K. L., Lu, Y., Votanopoulos, K. I., & Söker, S. (2022) · Scientific Reports · doi:10.1038/s41598-022-13930-7 · Cited by 29
Incorporating Immune Cells into Organoid Models: Essential for Studying Human Disease
Bogoslowski, A., An, M., & Penninger, J. M. (2023) · Organoids · doi:10.3390/organoids2030011 · Cited by 31
“In addition, cancer-derived cell lines may acquire considerable genetic mutations as a result of long-term maintenance and passages in vitro [83].”
BackgroundSAA suppresses α-PD-1 induced anti-tumor immunity by driving TH2 polarization in lung adenocarcinoma
Wang, X., Wen, S., Du, X., Zhang, Y., Yang, X., Zou, R., Feng, B., Fu, X., Jiang, F., Zhou, G., et al. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-06198-w · Cited by 28
“[45, 46], and the fresh medium without ROCK inhibitor was changed every 48 h. Organoids should be split when con fl uent or when their diameter exceeds 300 μ m. Established organoids can be passaged every 15 – 25 days at a 1:2 – 1:4 ratio.”
Patient-derived organoids: a promising tool for breast cancer research
Shi, Y., Guan, Z., Cai, G., Nie, Y., Zhang, C., Luo, W., & Liu, J. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1350935 · Cited by 29
Morice, P., Coquan, E., Weiswald, L., Lambert, B., Vaur, D., & Poulain, L. (2021) · British Journal of Cancer · doi:10.1038/s41416-021-01295-z · Cited by 29
Tumor organoids for cancer research and personalized medicine
Yang, H., Wang, Y., Wang, P., Zhang, N., & Wang, P. (2021) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2021.0335 · Cited by 29
Application of Organoid Models in Prostate Cancer Research
Zhou, L., Zhang, C., Zhang, Y., & Shi, C. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.736431 · Cited by 29
Okamura, K., Nagayama, S., Tate, T., Chan, T., Kiyotani, K., & Nakamura, Y. (2022) · Journal of Translational Medicine · doi:10.1186/s12967-022-03444-1 · Cited by 27
“1 week after the co-culture, lymphocytes were collected, counted, and replated at the concentration of 105 cells/ well with fresh tumor cells [24].”
BackgroundThe Multi-Dimensional Biomarker Landscape in Cancer Immunotherapy
Lee, J. Y., Kannan, B., Lim, B. Y., Li, Z., Lim, A. H., Loh, J. W., Ko, T. K., Ng, C. C. Y., & Chan, J. Y. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23147839 · Cited by 29
“Assays using tumor organoid models [178], humanized mouse models [179], and ex vivo tumor fragment platforms [180] may provide a dynamic means to simulate the host-tumor ecosystem and forecast real-life responses.”
BackgroundMethodAdvanced lung organoids and lung-on-a-chip for cancer research and drug evaluation: a review
Zhu, L., Zhang, J., Guo, Q., Kuang, J., Li, D., Wu, M., Mo, Y., Zhang, T., Gao, X., & Tan, J. (2023) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2023.1299033 · Cited by 28
Crosstalk of T cells within the ovarian cancer microenvironment
Chap, B. S., Rayroux, N., Grimm, A. J., Ghisoni, E., & Laniti, D. D. (2024) · Trends in cancer · doi:10.1016/j.trecan.2024.09.001 · Cited by 33
Subclonal immune evasion in non-small cell lung cancer
Dijkstra, K. K., Vendramin, R., Karagianni, D., Witsen, M., Gálvez‐Cancino, F., Hill, M. S., Foster, K. A., Barbè, V., Angelova, M., Hynds, R. E., et al. (2025) · Cancer Cell · doi:10.1016/j.ccell.2025.06.012 · Cited by 34
Self-citationTumor organoids in immunotherapy: from disease modeling to translational research
Si, Q., Tao, S., Wu, J., Ma, J., Li, Z. Y., Feng, X., Song, J., Kong, T., & Zhou, Z. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2025-011733 · Cited by 30
“52 By inhibiting certain signaling pathways, such as the prostaglandin E2 pathway, or affecting the expression of certain key molecules, such as inhibiting ubiquitin protein ligase E3 component n-recognin 5, and exploring their effects on organoid growth, researchers can reveal the potential role…”
Influential
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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