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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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Ding, S., Hsu, C., Wang, Z., Natesh, N. R., Millen, R., Negrete, M., Giroux, N., Rivera, G. O., Dohlman, A., Bose, S., et al. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2022.04.006 · Cited by 228
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“Due to space limitations, we do not touch other models which might also have preclinical potentials; conditionally reprogrammed cell lines [21,22], early passage PDX 2D cell lines [23], co-culture with fibroblast [24] and immune cells [25], and explant/organotypic culture models [26,27].”
BackgroundOrganoids and organs-on-chips: Insights into human gut-microbe interactions
Puschhof, J., Pleguezuelos‐Manzano, C., & Clevers, H. C. (2021) · Cell Host & Microbe · doi:10.1016/j.chom.2021.04.002 · Cited by 231
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Clinical applications of human organoids
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An expanded universe of cancer targets
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“Alternatively, tumor cell lines or organoids can be reconstituted with peripheral blood lymphocyte populations to identify both tumor cell intrinsic and extrinsic immune response modifiers (Dijkstra et al., 2018; Mo et al., 2019; Yuki et al., 2020).”
BackgroundPatient‐Derived Organoids Can Guide Personalized‐Therapies for Patients with Advanced Breast Cancer
Chen, P., Zhang, X., Ding, R., Yang, L., Lyu, X., Zeng, J., Lei, J. H., Wang, L., Bi, J., Shao, N., et al. (2021) · Advanced Science · doi:10.1002/advs.202101176 · Cited by 222
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Applications of organoids for cancer biology and precision medicine
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Targeting public neoantigens for cancer immunotherapy
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“Large-scale efforts such as the PDX encyclopedia (PDXE) and ProXe, as well as several organoid biobanks, provide both resources and the conceptual framework for future scaling-up and compound screens (Dijkstra et al., 2018; Gao et al., 2015; Townsend et al., 2016).”
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Review article: the future of microbiome‐based therapeutics
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Radiation-induced bystander and abscopal effects: important lessons from preclinical models
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Model of Patient-Specific Immune-Enhanced Organoids for Immunotherapy Screening: Feasibility Study
Votanopoulos, K. I., Forsythe, S. D., Sivakumar, H., Mazzocchi, A. R., Aleman, J., Miller, L. D., Levine, E. A., Triozzi, P. L., & Skardal, A. (2019) · Annals of Surgical Oncology · doi:10.1245/s10434-019-08143-8 · Cited by 179
“recently generated tumor-reactive T cells by coculturing them with PTOs from 13 mismatch repair (MMR)-deficient colon and 6 non-small-cell lung carcinoma (NSCLC) patients.(23)”
Zhou, Z., Cong, L., & Cong, X. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.762184 · Cited by 189
“Coculture of non-small-cell lung cancer and colorectal cancer organoids with autologous peripheral blood lymphocytes generates tumor-reactive T cells, and these T cells have the ability to kill tumor cells derived from the parental tumor tissue (20).”
BackgroundZhuang, J., Tan, J., Wu, C., Zhang, J., Liu, T., Fan, C., Li, J., & Zhang, Y. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa683 · Cited by 180
“Notably, human PLO models contained a few CD45+ leukocytes, which could be used to differentiate targeted delivery from non-targeted delivery (34).”
BackgroundTumor heterogeneity: preclinical models, emerging technologies, and future applications
Proietto, M., Crippa, M., Damiani, C., Pasquale, V., Sacco, E., Vanoni, M., & Gilardi, M. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1164535 · Cited by 188
“(80) successfully produced colon-rectal and non-small cell lung cancer PDOs, and later, to study immune response toward cancer and delineate a strategy to develop tailored immunotherapy, they used T-cell populations from peripheral blood to generate a co-culture with organoids; in such a manner, they were able to elic…”
Background3D Tumor Models and Their Use for the Testing of Immunotherapies
Boucherit, N., Gorvel, L., & Olive, D. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.603640 · Cited by 188
“Both matrixes are generated from murine sarcoma and therefore are compose of greatmurine antigen amounts, which can activate immune cell subtypes such as CD4 T cells (87).”
BackgroundHuman organoids: New strategies and methods for analyzing human development and disease
Corsini, N. S., & Knoblich, J. A. (2022) · Cell · doi:10.1016/j.cell.2022.06.051 · Cited by 176
Somatic cell-derived organoids as prototypes of human epithelial tissues and diseases
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Organoids to model liver disease
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Patient-derived organoids in precision cancer medicine
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Organoid cultures for cancer modeling
Yan, H. H. N., Chan, A., Lai, F. P.-L., & Leung, S. Y. (2023) · Cell stem cell · doi:10.1016/j.stem.2023.05.012 · Cited by 176
Modulating inflammation for cancer therapy
Ritter, B., & Greten, F. R. (2019) · The Journal of Experimental Medicine · doi:10.1084/jem.20181739 · Cited by 162
“(Dijkstra et al., 2018) will prove extremely helpful in this regard.”
BackgroundT cell receptor therapeutics: immunological targeting of the intracellular cancer proteome
Klebanoff, C. A., Chandran, S. S., Baker, B. M., Quezada, S. A., & Ribas, A. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00809-z · Cited by 164
“More recently, patient-derived tumour organoids have been used to sample the repertoire of naturally processed peptides displayed on a cancer cell’s surface 175,176 .”
BackgroundImmunotherapy for Malignant Glioma: Current Status and Future Directions
Wang, H., Xu, T., Huang, Q., Jin, W., & Chen, J. (2020) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2019.12.003 · Cited by 159
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Understanding cell‐cell communication and signaling in the colorectal cancer microenvironment
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Prospective experimental treatment of colorectal cancer patients based on organoid drug responses
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Self-citationOrganoids in gastrointestinal diseases: From experimental models to clinical translation
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Towards precision oncology with patient-derived xenografts
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“…that tumour organoids can also trigger antigen-specific expansion of tumour-reactive cytotoxic T cells and antibody-dependent tumour cytotoxicity when cultured with autologous PBMCs 126 or as cohesive units incorporating en bloc the tumour epithelium and its endogenous immune repertoire 127 .”
Patient-Derived Organoids for Precision Cancer Immunotherapy
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“Cocultures of colorectal cancer and NSCLC organoids and autologous PBMCs were shown to enrich tumor reactive T cells (25).”
BackgroundModeling Human Digestive Diseases With CRISPR-Cas9–Modified Organoids
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Self-citationOrganoid based personalized medicine: from bench to bedside
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The current state and future of T-cell exhaustion research
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Cell-type-specific signaling networks in heterocellular organoids
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Exploring the human lacrimal gland using organoids and single-cell sequencing
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“Lastly, given that Sjo¨gren’s syndrome is a poorly understood autoimmune disease, co-cultures of lacrimal gland organoids with resident immune cells or autoantibodies could be explored, as previously illustrated with tumor-derived organoids (Dijkstra et al., 2018).”
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“Indeed, the co-cultures of PDOs generated from mismatch repair-deficient non-small lung carcinoma and colorectal cancer with autologous PBMC induced the expansion of CD8+ tumor-reactive T cells [148].”
BackgroundInfluentialPatient-Derived Cancer Organoids as Predictors of Treatment Response
Verduin, M., Hoeben, A., Ruysscher, D. D., & Vooijs, M. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.641980 · Cited by 140
“In this system, autologous tumor-reactive T-cells could be induced which were also shown to specifically kill tumor organoids whereas matched healthy airway organoids were unaffected (78).”
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Theranostic cells: emerging clinical applications of synthetic biology
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Challenges for immunotherapy for the treatment of platinum resistant ovarian cancer
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Cancer research using organoid technology
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“One such approach used cancer organoid co-cultures with peripheral blood mononuclear cells (PBMCs) to generate patient-specific tumour-reactive cytotoxic T cells [107, 108].”
BackgroundThe drug-induced phenotypic landscape of colorectal cancer organoids
Betge, J., Rindtorff, N., Sauer, J., Rauscher, B., Dingert, C., Gaitantzi, H., Herweck, F., Srour-Mhanna, K., Miersch, T., Valentini, E., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-30722-9 · Cited by 132
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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