Tumor necroptosis is correlated with a favorable immune cell signature and programmed death-ligand 1 expression in cholangiocarcinoma

Abstract Necroptosis, a regulated form of necrosis, has emerged as a novel therapeutic strategy that could enhance cancer immunotherapy. However, its role in tumorigenesis is still debated because recent studies have reported both anti- and pro-tumoral effects. Here, we aimed to systematically evalu...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Thanpisit Lomphithak, Perawatt Akara-amornthum, Keigo Murakami, Masatoshi Hashimoto, Hajime Usubuchi, Erina Iwabuchi, Michiaki Unno, Zhenyu Cai, Hironobu Sasano, Siriporn Jitkaew
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bed78c056bbb47fc9e8f4e47465203de
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:bed78c056bbb47fc9e8f4e47465203de
record_format	dspace
spelling	oai:doaj.org-article:bed78c056bbb47fc9e8f4e47465203de2021-12-02T15:02:31ZTumor necroptosis is correlated with a favorable immune cell signature and programmed death-ligand 1 expression in cholangiocarcinoma10.1038/s41598-021-89977-92045-2322https://doaj.org/article/bed78c056bbb47fc9e8f4e47465203de2021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89977-9https://doaj.org/toc/2045-2322Abstract Necroptosis, a regulated form of necrosis, has emerged as a novel therapeutic strategy that could enhance cancer immunotherapy. However, its role in tumorigenesis is still debated because recent studies have reported both anti- and pro-tumoral effects. Here, we aimed to systematically evaluate the associations between tumor necroptosis (mixed lineage kinase domain-like protein, MLKL; phosphorylated MLKL, pMLKL; and receptor-interacting protein kinase 1–receptor-interacting protein kinase 3, RIPK1–RIPK3 interaction) and tumor-infiltrating immune cells (CD8+ and FOXp3+ T cells and CD163+ M2 macrophages) and tumor PD-L1 by immunohistochemistry in 88 cholangiocarcinoma (CCA) patients who had undergone surgical resection. Their associations with clinicopathological characteristics, survival data, and prognosis were evaluated. MLKL was found to be an unfavorable prognostic factor (p-value = 0.023, HR = 2.070) and was inversely correlated with a clinically favorable immune cell signature (high CD8+/high FOXp3+/low CD163+). Both pMLKL and RIPK1–RIPK3 interaction were detected in CCA primary tissues. In contrast to MLKL, pMLKL status was significantly positively correlated with a favorable immune signature (high CD8+/high FOXp3+/low CD163+) and PD-L1 expression. Patients with high pMLKL-positive staining were significantly associated with an increased abundance of CD8+ T cell intratumoral infiltration (p-value = 0.006). Patients with high pMLKL and PD-L1 expressions had a longer overall survival (OS). The results from in vitro experiments showed that necroptosis activation in an RMCCA-1 human CCA cell line selectively promoted proinflammatory cytokine and chemokine expression. Jurkat T cells stimulated with necroptotic RMCCA-1-derived conditioned medium promoted PD-L1 expression in RMCCA-1. Our findings demonstrated the differential associations of necroptosis activation (pMLKL) and MLKL with a clinically favorable immune signature and survival rates and highlighted a novel therapeutic possibility for combining a necroptosis-based therapeutic approach with immune checkpoint inhibitors for more efficient treatment of CCA patients.Thanpisit LomphithakPerawatt Akara-amornthumKeigo MurakamiMasatoshi HashimotoHajime UsubuchiErina IwabuchiMichiaki UnnoZhenyu CaiHironobu SasanoSiriporn JitkaewNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Thanpisit Lomphithak Perawatt Akara-amornthum Keigo Murakami Masatoshi Hashimoto Hajime Usubuchi Erina Iwabuchi Michiaki Unno Zhenyu Cai Hironobu Sasano Siriporn Jitkaew Tumor necroptosis is correlated with a favorable immune cell signature and programmed death-ligand 1 expression in cholangiocarcinoma
description	Abstract Necroptosis, a regulated form of necrosis, has emerged as a novel therapeutic strategy that could enhance cancer immunotherapy. However, its role in tumorigenesis is still debated because recent studies have reported both anti- and pro-tumoral effects. Here, we aimed to systematically evaluate the associations between tumor necroptosis (mixed lineage kinase domain-like protein, MLKL; phosphorylated MLKL, pMLKL; and receptor-interacting protein kinase 1–receptor-interacting protein kinase 3, RIPK1–RIPK3 interaction) and tumor-infiltrating immune cells (CD8+ and FOXp3+ T cells and CD163+ M2 macrophages) and tumor PD-L1 by immunohistochemistry in 88 cholangiocarcinoma (CCA) patients who had undergone surgical resection. Their associations with clinicopathological characteristics, survival data, and prognosis were evaluated. MLKL was found to be an unfavorable prognostic factor (p-value = 0.023, HR = 2.070) and was inversely correlated with a clinically favorable immune cell signature (high CD8+/high FOXp3+/low CD163+). Both pMLKL and RIPK1–RIPK3 interaction were detected in CCA primary tissues. In contrast to MLKL, pMLKL status was significantly positively correlated with a favorable immune signature (high CD8+/high FOXp3+/low CD163+) and PD-L1 expression. Patients with high pMLKL-positive staining were significantly associated with an increased abundance of CD8+ T cell intratumoral infiltration (p-value = 0.006). Patients with high pMLKL and PD-L1 expressions had a longer overall survival (OS). The results from in vitro experiments showed that necroptosis activation in an RMCCA-1 human CCA cell line selectively promoted proinflammatory cytokine and chemokine expression. Jurkat T cells stimulated with necroptotic RMCCA-1-derived conditioned medium promoted PD-L1 expression in RMCCA-1. Our findings demonstrated the differential associations of necroptosis activation (pMLKL) and MLKL with a clinically favorable immune signature and survival rates and highlighted a novel therapeutic possibility for combining a necroptosis-based therapeutic approach with immune checkpoint inhibitors for more efficient treatment of CCA patients.
format	article
author	Thanpisit Lomphithak Perawatt Akara-amornthum Keigo Murakami Masatoshi Hashimoto Hajime Usubuchi Erina Iwabuchi Michiaki Unno Zhenyu Cai Hironobu Sasano Siriporn Jitkaew
author_facet	Thanpisit Lomphithak Perawatt Akara-amornthum Keigo Murakami Masatoshi Hashimoto Hajime Usubuchi Erina Iwabuchi Michiaki Unno Zhenyu Cai Hironobu Sasano Siriporn Jitkaew
author_sort	Thanpisit Lomphithak
title	Tumor necroptosis is correlated with a favorable immune cell signature and programmed death-ligand 1 expression in cholangiocarcinoma
title_short	Tumor necroptosis is correlated with a favorable immune cell signature and programmed death-ligand 1 expression in cholangiocarcinoma
title_full	Tumor necroptosis is correlated with a favorable immune cell signature and programmed death-ligand 1 expression in cholangiocarcinoma
title_fullStr	Tumor necroptosis is correlated with a favorable immune cell signature and programmed death-ligand 1 expression in cholangiocarcinoma
title_full_unstemmed	Tumor necroptosis is correlated with a favorable immune cell signature and programmed death-ligand 1 expression in cholangiocarcinoma
title_sort	tumor necroptosis is correlated with a favorable immune cell signature and programmed death-ligand 1 expression in cholangiocarcinoma
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/bed78c056bbb47fc9e8f4e47465203de
work_keys_str_mv	AT thanpisitlomphithak tumornecroptosisiscorrelatedwithafavorableimmunecellsignatureandprogrammeddeathligand1expressionincholangiocarcinoma AT perawattakaraamornthum tumornecroptosisiscorrelatedwithafavorableimmunecellsignatureandprogrammeddeathligand1expressionincholangiocarcinoma AT keigomurakami tumornecroptosisiscorrelatedwithafavorableimmunecellsignatureandprogrammeddeathligand1expressionincholangiocarcinoma AT masatoshihashimoto tumornecroptosisiscorrelatedwithafavorableimmunecellsignatureandprogrammeddeathligand1expressionincholangiocarcinoma AT hajimeusubuchi tumornecroptosisiscorrelatedwithafavorableimmunecellsignatureandprogrammeddeathligand1expressionincholangiocarcinoma AT erinaiwabuchi tumornecroptosisiscorrelatedwithafavorableimmunecellsignatureandprogrammeddeathligand1expressionincholangiocarcinoma AT michiakiunno tumornecroptosisiscorrelatedwithafavorableimmunecellsignatureandprogrammeddeathligand1expressionincholangiocarcinoma AT zhenyucai tumornecroptosisiscorrelatedwithafavorableimmunecellsignatureandprogrammeddeathligand1expressionincholangiocarcinoma AT hironobusasano tumornecroptosisiscorrelatedwithafavorableimmunecellsignatureandprogrammeddeathligand1expressionincholangiocarcinoma AT siripornjitkaew tumornecroptosisiscorrelatedwithafavorableimmunecellsignatureandprogrammeddeathligand1expressionincholangiocarcinoma
_version_	1718389100895010816

Tumor necroptosis is correlated with a favorable immune cell signature and programmed death-ligand 1 expression in cholangiocarcinoma

Ejemplares similares