cDC2 plasticity and acquisition of a DC3‐like phenotype mediated by IL‐6 and PGE2 in a patient‐derived colorectal cancer organoids model

• DOI: 10.1002/eji.202350891
• Publication Date: 2024-03-21T07:49:51Z
• Authors: Beatriz Subtil; Iris A. E. van de...; Jorge Cuenca‐Esca...; Anouk M. D. Becker; Mar Alvarez‐Begue; Kirti K. Iyer; Jorien Janssen; Tom van Oorschot; Dennis Poel; Mark A. J. Gorris; Koen van den Dries; Alessandra Cambi; Daniele V. F. Tau...; I. Jolanda M. de ...
• Keywords: Immunosurveillance

Abstract Metastatic colorectal cancer (CRC) is highly resistant to therapy and prone recur. The tumor‐induced local systemic immunosuppression allows cells evade immunosurveillance, facilitating their proliferation dissemination. Dendritic (DCs) are required for the detection, processing, presentation of tumor antigens, subsequently activation antigen‐specific T orchestrate an effective antitumor response. Notably, successful tumors have evolved mechanisms disrupt impair DC functions, underlining key role dysfunction in promoting growth, metastasis initiation, treatment resistance. Conventional type 2 (cDC2) prevalent been shown present high phenotypic functional plasticity response tumor‐released environmental cues. This reverberates on both development responses efficacy immunotherapies patients. Uncovering processes, mechanisms, mediators by which CRC shapes disrupts cDC2 functions crucial restoring full potential. In this study, we use our recently developed 3D DC‐tumor co‐culture system investigate how patient‐derived primary metastatic organoids modulate phenotype function. We first demonstrate that collagen‐based displays extensive interaction between organoids. Interestingly, show tumor‐corrupted shift toward a CD14+ population with defective expression maturation markers, intermediate positioned monocytes, impaired T‐cell activating abilities. aligns newly defined DC3 (CD14 + CD1c CD163 ) subset. Remarkably, comparable was found be lesions enriched peripheral blood Moreover, using EP2 EP4 receptor antagonists anti‐IL‐6 neutralizing antibody, determined observed partially mediated PGE2 IL‐6. Importantly, holds promise as platform testing therapies aimed at preventing or mitigating dysfunction. Overall, study offers novel relevant insights into (dys)function hold relevance design therapeutic approaches.