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

Guoying Zhou*, Ruby Lieshout, Gilles S. van Tienderen, Valeska de Ruiter, Martin E. van Royen, Patrick P.C. Boor, Luc Magré, Jyaysi Desai, Kübra Köten, Yik Yang Kan, Zhouhong Ge, Lucia Campos Carrascosa, Cecile Geuijen, Dave Sprengers, Luc J.W. van der Laan, Monique M.A. Verstegen*, Jaap Kwekkeboom

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)649-660
Number of pages12
JournalBritish Journal of Cancer
Volume127
Issue number4
Early online date21 May 2022
DOIs
Publication statusPublished - 1 Sep 2022

Bibliographical note

Funding Information:
We would like to acknowledge André Boonstra, Gertine van Oord, and Jeffrey Oliveira from the Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center Rotterdam for supporting and performing the Lumipulse® CYFRA assay. We would also like to thank the Zon Mw Meer Kennis met Minder Dieren program grant 114024068 (M.P.P.) for sponsoring the publication costs.

Funding Information:
This study was supported by Health Holland TKI-LSH grant LSH17064 in consortium with Merus N.V. and Gastrostart research grant 2017–31.

Publisher Copyright:
© 2022, The Author(s).

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