Modelling immune cytotoxicity for cholangiocarcinoma with tumour-derived organoids and effector T cells

• DOI: 10.1038/s41416-022-01839-x
• Publication Date: 2022-05-21T05:03:48Z
• Authors: Guoying Zhou; Ruby Lieshout; Gilles S. van Tie...; Valeska de Ruiter; Martin E. van Royen; Patrick P. C. Boor; Luc Magré; Jyaysi Desai; Kübra Köten; Yik Yang Kan; Zhouhong Ge; Lucia Campos Carr...; Cecile Geuijen; Dave Sprengers; Luc J. W. van der...; Monique M. A. Ver...; Jaap Kwekkeboom
• Keywords: Cholangiocarcinoma; Organoids; 0301 basic medicine; 0303 health sciences; 03 medical and health sciences; Bile Ducts, Intrahepatic; SDG 3 - Good Health and Well-being; Bile Duct Neoplasms; T-Lymphocytes; Leukocytes, Mononuclear; Humans; Article; 3. Good health

Abstract Background Immunotherapy with immune checkpoint inhibitors (ICIs) is being explored to improve cholangiocarcinoma (CCA) therapy. However, it remains difficult to predict which ICI will be effective for individual patients. Therefore, the aim of this study is to develop a co-culture method with patient-derived CCA organoids and immune cells, which could represent anti-cancer immunity in vitro.

Methods CCA organoids were co-cultured with peripheral blood mononuclear cells or T cells. Flow cytometry, time-lapse confocal imaging for apoptosis, and quantification of cytokeratin 19 fragment (CYFRA) release were applied to analyse organoid and immune cell behaviour. CCA organoids were also cultured in immune cell-conditioned media to analyse the effect of soluble factors.

Results The co-culture system demonstrated an effective anti-tumour organoid immune response by a decrease in live organoid cells and an increase in apoptosis and CYFRA release. Interpatient heterogeneity was observed. The cytotoxic effects could be mediated by direct cell–cell contact and by release of soluble factors, although soluble factors only decreased viability in one organoid line.

Conclusions In this proof-of-concept study, a novel CCA organoid and immune cell co-culture method was established. This can be the first step towards personalised immunotherapy for CCA by predicting which ICIs are most effective for individual patients.