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

doi:10.1038/s41416-022-01839-x

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 journal › Article › Academic › peer-review

49 Citations (Scopus)

127 Downloads (Pure)

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 language	English
Pages (from-to)	649-660
Number of pages	12
Journal	British Journal of Cancer
Volume	127
Issue number	4
Early online date	21 May 2022
DOIs	https://doi.org/10.1038/s41416-022-01839-x
Publication status	Published - 1 Sept 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).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41416-022-01839-xLicence: CC BY

Modelling immune cytotoxicity for cholangiocarcinoma with tumour-derived organoids and effector T cellsFinal published version, 2.68 MBLicence: CC BY

Cite this

Zhou, G., Lieshout, R., van Tienderen, G. S., de Ruiter, V., van Royen, M. E., Boor, P. P. C., Magré, L., Desai, J., Köten, K., Kan, Y. Y., Ge, Z., Campos Carrascosa, L., Geuijen, C., Sprengers, D., van der Laan, L. J. W., Verstegen, M. M. A., & Kwekkeboom, J. (2022). Modelling immune cytotoxicity for cholangiocarcinoma with tumour-derived organoids and effector T cells. British Journal of Cancer, 127(4), 649-660. https://doi.org/10.1038/s41416-022-01839-x

@article{ff7205ea851c4c52af5e7b7ea9523b03,

title = "Modelling immune cytotoxicity for cholangiocarcinoma with tumour-derived organoids and effector T cells",

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.",

author = "Guoying Zhou and Ruby Lieshout and \{van Tienderen\}, \{Gilles S.\} and \{de Ruiter\}, Valeska and \{van Royen\}, \{Martin E.\} and Boor, \{Patrick P.C.\} and Luc Magr{\'e} and Jyaysi Desai and K{\"u}bra K{\"o}ten and Kan, \{Yik Yang\} and Zhouhong Ge and \{Campos Carrascosa\}, Lucia and Cecile Geuijen and Dave Sprengers and \{van der Laan\}, \{Luc J.W.\} and Verstegen, \{Monique M.A.\} and Jaap Kwekkeboom",

note = "Funding Information: We would like to acknowledge Andr{\'e} 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{\textregistered} 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: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = sep,

day = "1",

doi = "10.1038/s41416-022-01839-x",

language = "English",

volume = "127",

pages = "649--660",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Springer Nature",

number = "4",

}

Zhou, G, Lieshout, R, van Tienderen, GS, de Ruiter, V, van Royen, ME, Boor, PPC, Magré, L , Desai, J, Köten, K, Kan, YY, Ge, Z, Campos Carrascosa, L, Geuijen, C, Sprengers, D , van der Laan, LJW , Verstegen, MMA & Kwekkeboom, J 2022, 'Modelling immune cytotoxicity for cholangiocarcinoma with tumour-derived organoids and effector T cells', British Journal of Cancer, vol. 127, no. 4, pp. 649-660. https://doi.org/10.1038/s41416-022-01839-x

TY - JOUR

T1 - Modelling immune cytotoxicity for cholangiocarcinoma with tumour-derived organoids and effector T cells

AU - Zhou, Guoying

AU - Lieshout, Ruby

AU - van Tienderen, Gilles S.

AU - de Ruiter, Valeska

AU - van Royen, Martin E.

AU - Boor, Patrick P.C.

AU - Magré, Luc

AU - Desai, Jyaysi

AU - Köten, Kübra

AU - Kan, Yik Yang

AU - Ge, Zhouhong

AU - Campos Carrascosa, Lucia

AU - Geuijen, Cecile

AU - Sprengers, Dave

AU - van der Laan, Luc J.W.

AU - Verstegen, Monique M.A.

AU - Kwekkeboom, Jaap

N1 - 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).

PY - 2022/9/1

Y1 - 2022/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85130226597&partnerID=8YFLogxK

U2 - 10.1038/s41416-022-01839-x

DO - 10.1038/s41416-022-01839-x

M3 - Article

C2 - 35597867

AN - SCOPUS:85130226597

SN - 0007-0920

VL - 127

SP - 649

EP - 660

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 4

ER -

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

Abstract

Bibliographical note

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this