PMID- 36761758 OWN - NLM STAT- MEDLINE DCOM- 20230213 LR - 20230327 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 14 DP - 2023 TI - Dendritic cell phenotype and function in a 3D co-culture model of patient-derived metastatic colorectal cancer organoids. PG - 1105244 LID - 10.3389/fimmu.2023.1105244 [doi] LID - 1105244 AB - Colorectal cancer (CRC) remains one of the most aggressive and lethal cancers, with metastasis accounting for most deaths. As such, there is an unmet need for improved therapies for metastatic CRC (mCRC). Currently, the research focus is shifting towards the reciprocal interactions within the tumor microenvironment (TME), which prevent tumor clearance by the immune system. Dendritic cells (DCs) play a key role in the initiation and amplification of anti-tumor immune responses and in driving the clinical success of immunotherapies. Dissecting the interactions between DCs and CRC cells may open doors to identifying key mediators in tumor progression, and possible therapeutic targets. This requires representative, robust and versatile models and tools. Currently, there is a shortage of such in vitro systems to model the CRC TME and its tumor-immune cell interactions. Here we develop and establish a dynamic organotypic 3D co-culture system to recapitulate and untangle the interactions between DCs and patient-derived mCRC tumor organoids. To our knowledge, this is the first study investigating human DCs in co-culture with tumor organoids in a 3D, organotypic setting. This system reveals how mCRC organoids modulate and shape monocyte-derived DCs (MoDCs) behavior, phenotype, and function, within a collagen matrix, using techniques such as brightfield and fluorescence microscopy, flow cytometry, and fluorescence-activated cell sorting. Our 3D co-culture model shows high viability and extensive interaction between DCs and tumor organoids, and its structure resembles patient tissue sections. Furthermore, it is possible to retrieve DCs from the co-cultures and characterize their phenotypic and functional profile. In our study, the expression of activation markers in both mature and immature DCs and their ability to activate T cells were impacted by co-culture with tumor organoids. In the future, this direct co-culture platform can be adapted and exploited to study the CRC-DC interplay in more detail, enabling novel and broader insights into CRC-driven DC (dys)function. CI - Copyright (c) 2023 Subtil, Iyer, Poel, Bakkerus, Gorris, Escalona, Dries, Cambi, Verheul, de Vries and Tauriello. FAU - Subtil, Beatriz AU - Subtil B AD - Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands. AD - Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands. FAU - Iyer, Kirti K AU - Iyer KK AD - Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands. AD - Department of Medical Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands. FAU - Poel, Dennis AU - Poel D AD - Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands. AD - Department of Medical Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands. FAU - Bakkerus, Lotte AU - Bakkerus L AD - Department of Medical Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands. FAU - Gorris, Mark A J AU - Gorris MAJ AD - Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands. AD - Oncode Institute, Nijmegen, Netherlands. FAU - Escalona, Jorge Cuenca AU - Escalona JC AD - Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands. FAU - van den Dries, Koen AU - van den Dries K AD - Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands. FAU - Cambi, Alessandra AU - Cambi A AD - Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands. FAU - Verheul, Henk M W AU - Verheul HMW AD - Department of Medical Oncology, Erasmus Medical Center, Rotterdam, Netherlands. FAU - de Vries, I Jolanda M AU - de Vries IJM AD - Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands. FAU - Tauriello, Daniele V F AU - Tauriello DVF AD - Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230125 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 SB - IM MH - Humans MH - Coculture Techniques MH - *Colonic Neoplasms/pathology MH - *Rectal Neoplasms/pathology MH - Dendritic Cells MH - Organoids MH - Phenotype MH - Tumor Microenvironment PMC - PMC9905679 OTO - NOTNLM OT - 3D co-culture OT - dendritic cell dysfunction OT - human dendritic cells OT - immunosuppression OT - metastatic colorectal cancer OT - patient-derived tumor organoids OT - tumor microenvironment COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/02/11 06:00 MHDA- 2023/02/14 06:00 PMCR- 2023/01/01 CRDT- 2023/02/10 03:12 PHST- 2022/11/22 00:00 [received] PHST- 2023/01/12 00:00 [accepted] PHST- 2023/02/10 03:12 [entrez] PHST- 2023/02/11 06:00 [pubmed] PHST- 2023/02/14 06:00 [medline] PHST- 2023/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2023.1105244 [doi] PST - epublish SO - Front Immunol. 2023 Jan 25;14:1105244. doi: 10.3389/fimmu.2023.1105244. eCollection 2023.