Tumor-associated neutrophils and macrophages interaction contributes to intrahepatic cholangiocarcinoma progression by activating STAT3

Background Tumor-associated neutrophils (TANs) and macrophages (TAMs) can each influence cancer growth and metastasis, but their combined effects in intrahepatic cholangiocarcinoma (ICC) remain unclear.Methods We explored the distributions of TANs and TAMs in patient-derived ICC samples by multiplex...

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Main Authors: Jian Zhou, Jia Fan, Zhiqiang Hu, Zhengjun Zhou, Pengcheng Wang, Rongqi Sun, Haoyang Xin, Chubin Luo, Shaolai Zhou
Format: Article
Language:English
Published: BMJ Publishing Group 2021-03-01
Series:Journal for ImmunoTherapy of Cancer
Online Access:https://jitc.bmj.com/content/9/3/e001946.full
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spelling doaj-4a2a9bfd52a64b569cab213c83e461a72021-05-30T13:00:24ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262021-03-019310.1136/jitc-2020-001946Tumor-associated neutrophils and macrophages interaction contributes to intrahepatic cholangiocarcinoma progression by activating STAT3Jian Zhou0Jia Fan1Zhiqiang Hu2Zhengjun Zhou3Pengcheng Wang4Rongqi Sun5Haoyang Xin6Chubin Luo7Shaolai Zhou8Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, ChinaDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, ChinaDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, ChinaDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, ChinaDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, ChinaDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, ChinaDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, ChinaDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, ChinaDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, ChinaBackground Tumor-associated neutrophils (TANs) and macrophages (TAMs) can each influence cancer growth and metastasis, but their combined effects in intrahepatic cholangiocarcinoma (ICC) remain unclear.Methods We explored the distributions of TANs and TAMs in patient-derived ICC samples by multiplex immunofluorescent staining and tested their separate and combined effects on ICC in vitro and in vivo. We then investigated the mechanistic basis of the effects using PCR array, western blot analysis and ELISA experiments. Finally, we validated our results in a tissue microarray composed of primary tumor tissues from 359 patients with ICC.Results The spatial distributions of TANs and TAMs were correlated with each other in patient-derived ICC samples. Interaction between TANs and TAMs enhanced the proliferation and invasion abilities of ICC cells in vitro and tumor progression in a mouse xenograft model of ICC. TANs and TAMs produced higher levels of oncostatin M and interleukin-11, respectively, in co-culture than in monoculture. Both of those cytokines activated STAT3 signaling in ICC cells. Knockdown of STAT3 abolished the protumor effect of TANs and TAMs on ICC. In tumor samples from patients with ICC, increased TAN and TAM levels were correlated with elevated p-STAT3 expression. All three of those factors were independent predictors of patient outcomes.Conclusions TANs and TAMs interact to promote ICC progression by activating STAT3.https://jitc.bmj.com/content/9/3/e001946.full
collection DOAJ
language English
format Article
sources DOAJ
author Jian Zhou
Jia Fan
Zhiqiang Hu
Zhengjun Zhou
Pengcheng Wang
Rongqi Sun
Haoyang Xin
Chubin Luo
Shaolai Zhou
spellingShingle Jian Zhou
Jia Fan
Zhiqiang Hu
Zhengjun Zhou
Pengcheng Wang
Rongqi Sun
Haoyang Xin
Chubin Luo
Shaolai Zhou
Tumor-associated neutrophils and macrophages interaction contributes to intrahepatic cholangiocarcinoma progression by activating STAT3
Journal for ImmunoTherapy of Cancer
author_facet Jian Zhou
Jia Fan
Zhiqiang Hu
Zhengjun Zhou
Pengcheng Wang
Rongqi Sun
Haoyang Xin
Chubin Luo
Shaolai Zhou
author_sort Jian Zhou
title Tumor-associated neutrophils and macrophages interaction contributes to intrahepatic cholangiocarcinoma progression by activating STAT3
title_short Tumor-associated neutrophils and macrophages interaction contributes to intrahepatic cholangiocarcinoma progression by activating STAT3
title_full Tumor-associated neutrophils and macrophages interaction contributes to intrahepatic cholangiocarcinoma progression by activating STAT3
title_fullStr Tumor-associated neutrophils and macrophages interaction contributes to intrahepatic cholangiocarcinoma progression by activating STAT3
title_full_unstemmed Tumor-associated neutrophils and macrophages interaction contributes to intrahepatic cholangiocarcinoma progression by activating STAT3
title_sort tumor-associated neutrophils and macrophages interaction contributes to intrahepatic cholangiocarcinoma progression by activating stat3
publisher BMJ Publishing Group
series Journal for ImmunoTherapy of Cancer
issn 2051-1426
publishDate 2021-03-01
description Background Tumor-associated neutrophils (TANs) and macrophages (TAMs) can each influence cancer growth and metastasis, but their combined effects in intrahepatic cholangiocarcinoma (ICC) remain unclear.Methods We explored the distributions of TANs and TAMs in patient-derived ICC samples by multiplex immunofluorescent staining and tested their separate and combined effects on ICC in vitro and in vivo. We then investigated the mechanistic basis of the effects using PCR array, western blot analysis and ELISA experiments. Finally, we validated our results in a tissue microarray composed of primary tumor tissues from 359 patients with ICC.Results The spatial distributions of TANs and TAMs were correlated with each other in patient-derived ICC samples. Interaction between TANs and TAMs enhanced the proliferation and invasion abilities of ICC cells in vitro and tumor progression in a mouse xenograft model of ICC. TANs and TAMs produced higher levels of oncostatin M and interleukin-11, respectively, in co-culture than in monoculture. Both of those cytokines activated STAT3 signaling in ICC cells. Knockdown of STAT3 abolished the protumor effect of TANs and TAMs on ICC. In tumor samples from patients with ICC, increased TAN and TAM levels were correlated with elevated p-STAT3 expression. All three of those factors were independent predictors of patient outcomes.Conclusions TANs and TAMs interact to promote ICC progression by activating STAT3.
url https://jitc.bmj.com/content/9/3/e001946.full
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