PMID- 38509863 OWN - NLM STAT- Publisher LR - 20240321 IS - 1521-4141 (Electronic) IS - 0014-2980 (Linking) DP - 2024 Mar 21 TI - cDC2 plasticity and acquisition of a DC3-like phenotype mediated by IL-6 and PGE2 in a patient-derived colorectal cancer organoids model. PG - e2350891 LID - 10.1002/eji.202350891 [doi] AB - Metastatic colorectal cancer (CRC) is highly resistant to therapy and prone to recur. The tumor-induced local and systemic immunosuppression allows cancer cells to evade immunosurveillance, facilitating their proliferation and dissemination. Dendritic cells (DCs) are required for the detection, processing, and presentation of tumor antigens, and subsequently for the activation of antigen-specific T cells to orchestrate an effective antitumor response. Notably, successful tumors have evolved mechanisms to disrupt and impair DC functions, underlining the key role of tumor-induced DC dysfunction in promoting tumor growth, metastasis initiation, and treatment resistance. Conventional DC type 2 (cDC2) are highly prevalent in tumors and have been shown to present high phenotypic and functional plasticity in response to tumor-released environmental cues. This plasticity reverberates on both the development of antitumor responses and on the efficacy of immunotherapies in cancer patients. Uncovering the processes, mechanisms, and mediators by which CRC shapes and disrupts cDC2 functions is crucial to restoring their full antitumor potential. In this study, we use our recently developed 3D DC-tumor co-culture system to investigate how patient-derived primary and metastatic CRC organoids modulate cDC2 phenotype and function. We first demonstrate that our collagen-based system displays extensive interaction between cDC2 and tumor organoids. Interestingly, we show that tumor-corrupted cDC2 shift toward a CD14+ population with defective expression of maturation markers, an intermediate phenotype positioned between cDC2 and monocytes, and impaired T-cell activating abilities. This phenotype aligns with the newly defined DC3 (CD14(+) CD1c(+) CD163(+)) subset. Remarkably, a comparable population was found to be present in tumor lesions and enriched in the peripheral blood of metastatic CRC patients. Moreover, using EP2 and EP4 receptor antagonists and an anti-IL-6 neutralizing antibody, we determined that the observed phenotype shift is partially mediated by PGE2 and IL-6. Importantly, our system holds promise as a platform for testing therapies aimed at preventing or mitigating tumor-induced DC dysfunction. Overall, our study offers novel and relevant insights into cDC2 (dys)function in CRC that hold relevance for the design of therapeutic approaches. CI - (c) 2024 The Authors. European Journal of Immunology published by Wiley-VCH GmbH. FAU - Subtil, Beatriz AU - Subtil B AD - Department of Medical BioSciences (MBS), Radboud University Medical Center, Nijmegen, the Netherlands. FAU - van der Hoorn, Iris A E AU - van der Hoorn IAE AUID- ORCID: 0009-0008-8644-0678 AD - Department of Medical BioSciences (MBS), Radboud University Medical Center, Nijmegen, the Netherlands. AD - Department of Pulmonary Diseases, Radboud University Medical Center, Nijmegen, the Netherlands. FAU - Cuenca-Escalona, Jorge AU - Cuenca-Escalona J AUID- ORCID: 0000-0002-4915-1518 AD - Department of Medical BioSciences (MBS), Radboud University Medical Center, Nijmegen, the Netherlands. FAU - Becker, Anouk M D AU - Becker AMD AD - Department of Medical BioSciences (MBS), Radboud University Medical Center, Nijmegen, the Netherlands. FAU - Alvarez-Begue, Mar AU - Alvarez-Begue M AD - Department of Medical BioSciences (MBS), Radboud University Medical Center, Nijmegen, the Netherlands. FAU - Iyer, Kirti K AU - Iyer KK AD - Department of Medical BioSciences (MBS), Radboud University Medical Center, Nijmegen, the Netherlands. AD - Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands. FAU - Janssen, Jorien AU - Janssen J AUID- ORCID: 0000-0001-9190-9911 AD - Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands. FAU - van Oorschot, Tom AU - van Oorschot T AD - Department of Medical BioSciences (MBS), Radboud University Medical Center, Nijmegen, the Netherlands. FAU - Poel, Dennis AU - Poel D AUID- ORCID: 0000-0002-4395-2824 AD - Department of Medical BioSciences (MBS), Radboud University Medical Center, Nijmegen, the Netherlands. AD - Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands. FAU - Gorris, Mark A J AU - Gorris MAJ AUID- ORCID: 0000-0003-3621-226X AD - Department of Medical BioSciences (MBS), Radboud University Medical Center, Nijmegen, the Netherlands. FAU - van den Dries, Koen AU - van den Dries K AD - Department of Medical BioSciences (MBS), Radboud University Medical Center, Nijmegen, the Netherlands. FAU - Cambi, Alessandra AU - Cambi A AD - Department of Medical BioSciences (MBS), Radboud University Medical Center, Nijmegen, the Netherlands. FAU - Tauriello, Daniele V F AU - Tauriello DVF AUID- ORCID: 0000-0003-1522-3496 AD - Department of Medical BioSciences (MBS), Radboud University Medical Center, Nijmegen, the Netherlands. AD - Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, the Netherlands. FAU - de Vries, I Jolanda M AU - de Vries IJM AD - Department of Medical BioSciences (MBS), Radboud University Medical Center, Nijmegen, the Netherlands. LA - eng GR - Radboudumc/ GR - 91719371/the Netherlands Organisation for Scientific Research/ GR - LSHM22042_SGF/IHSeed/ GR - JO RUMC/ GR - LSHM18056-SGF/Health Holland/ PT - Journal Article DEP - 20240321 PL - Germany TA - Eur J Immunol JT - European journal of immunology JID - 1273201 SB - IM OTO - NOTNLM OT - 3D model OT - CD14+ cDC2 OT - Colorectal cancer OT - Conventional dendritic cells type 2 OT - DC3 OT - Dendritic cell dysfunction OT - IL-6 OT - Immunosuppression OT - Metastasis OT - PGE2 OT - Patient-derived organoids OT - Tumor microenvironment EDAT- 2024/03/21 06:43 MHDA- 2024/03/21 06:43 CRDT- 2024/03/21 03:54 PHST- 2024/03/06 00:00 [revised] PHST- 2023/11/10 00:00 [received] PHST- 2024/03/08 00:00 [accepted] PHST- 2024/03/21 06:43 [medline] PHST- 2024/03/21 06:43 [pubmed] PHST- 2024/03/21 03:54 [entrez] AID - 10.1002/eji.202350891 [doi] PST - aheadofprint SO - Eur J Immunol. 2024 Mar 21:e2350891. doi: 10.1002/eji.202350891.