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Intrahepatic inflammatory IgA(+)PD-L1(high) monocytes in hepatocellular carcinoma development and immunotherapy

BACKGROUND: IgA neutralizes pathogens to prevent infection at mucosal sites. However, emerging evidence shows that IgA contributes to aggravating inflammation or dismantling antitumor immunity in human diseased liver. The aim of this study was to elucidate the roles of inflammation-induced intrahepa...

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Autores principales: Sung, Pil Soo, Park, Dong Jun, Roh, Pu Reun, Mun, Kyoung Do, Cho, Sung Woo, Lee, Gil Won, Jung, Eun Sun, Lee, Sung Hak, Jang, Jeong Won, Bae, Si Hyun, Choi, Jong Young, Choi, Jonghwan, Ahn, Jaegyoon, Yoon, Seung Kew
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9114848/
https://www.ncbi.nlm.nih.gov/pubmed/35577505
http://dx.doi.org/10.1136/jitc-2021-003618
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author Sung, Pil Soo
Park, Dong Jun
Roh, Pu Reun
Mun, Kyoung Do
Cho, Sung Woo
Lee, Gil Won
Jung, Eun Sun
Lee, Sung Hak
Jang, Jeong Won
Bae, Si Hyun
Choi, Jong Young
Choi, Jonghwan
Ahn, Jaegyoon
Yoon, Seung Kew
author_facet Sung, Pil Soo
Park, Dong Jun
Roh, Pu Reun
Mun, Kyoung Do
Cho, Sung Woo
Lee, Gil Won
Jung, Eun Sun
Lee, Sung Hak
Jang, Jeong Won
Bae, Si Hyun
Choi, Jong Young
Choi, Jonghwan
Ahn, Jaegyoon
Yoon, Seung Kew
author_sort Sung, Pil Soo
collection PubMed
description BACKGROUND: IgA neutralizes pathogens to prevent infection at mucosal sites. However, emerging evidence shows that IgA contributes to aggravating inflammation or dismantling antitumor immunity in human diseased liver. The aim of this study was to elucidate the roles of inflammation-induced intrahepatic inflammatory IgA(+) monocytes in the development of hepatocellular carcinoma (HCC). METHODS: Patient cohorts including steatohepatitis cohort (n=61) and HCC cohort (n=271) were established. Patients’ surgical and biopsy specimens were analyzed using immunohistochemistry. Multicolor flow cytometry was performed with a subset of patient samples. Single-cell RNA-Seq analysis was performed using Gene Expression Omnibus (GEO) datasets. Additionally, we performed in vitro differentiation of macrophages, stimulation with coated IgA, and RNA sequencing. Hepa1-6 cells and C57BL/6N mice were used to obtain HCC syngeneic mouse models. RESULTS: Serum IgA levels were associated (p<0.001) with fibrosis progression and HCC development in patients with chronic liver diseases. Additionally, immunohistochemical staining of inflamed livers or HCC revealed IgA positivity in monocytes, with a correlation between IgA(+) cell frequency and IgA serum levels. Compared with IgA(−) monocytes, intrahepatic IgA(+) monocytes expressed higher levels of programmed death-ligand 1 (PD-L1) in inflamed livers and in HCC tumor microenvironment. Single-cell RNA sequencing using NCBI GEO database indicated an upregulation in inflammation-associated genes in the monocytes of patients whose plasma cell IGHA1 expression was greater than or equal to the median value. Bulk RNA sequencing demonstrated that in vitro stimulation of M2-polarized macrophages using coated IgA complex induced PD-L1 upregulation via YAP-mediated signaling. In vivo blockade of IgA signaling decreased the number of tumor-infiltrating IgA(+)PD-L1(high) macrophages and increased the number of CD69(+)CD8(+) T cells to enhance antitumor effects in HCC mice models. CONCLUSIONS: Overall, the findings of this study showed that serum IgA levels was correlated with intrahepatic and intratumoral infiltration of inflammatory IgA(+)PD-L1(high) monocytes in chronic liver diseases and HCC, providing potential therapeutic targets.
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spelling pubmed-91148482022-06-04 Intrahepatic inflammatory IgA(+)PD-L1(high) monocytes in hepatocellular carcinoma development and immunotherapy Sung, Pil Soo Park, Dong Jun Roh, Pu Reun Mun, Kyoung Do Cho, Sung Woo Lee, Gil Won Jung, Eun Sun Lee, Sung Hak Jang, Jeong Won Bae, Si Hyun Choi, Jong Young Choi, Jonghwan Ahn, Jaegyoon Yoon, Seung Kew J Immunother Cancer Immunotherapy Biomarkers BACKGROUND: IgA neutralizes pathogens to prevent infection at mucosal sites. However, emerging evidence shows that IgA contributes to aggravating inflammation or dismantling antitumor immunity in human diseased liver. The aim of this study was to elucidate the roles of inflammation-induced intrahepatic inflammatory IgA(+) monocytes in the development of hepatocellular carcinoma (HCC). METHODS: Patient cohorts including steatohepatitis cohort (n=61) and HCC cohort (n=271) were established. Patients’ surgical and biopsy specimens were analyzed using immunohistochemistry. Multicolor flow cytometry was performed with a subset of patient samples. Single-cell RNA-Seq analysis was performed using Gene Expression Omnibus (GEO) datasets. Additionally, we performed in vitro differentiation of macrophages, stimulation with coated IgA, and RNA sequencing. Hepa1-6 cells and C57BL/6N mice were used to obtain HCC syngeneic mouse models. RESULTS: Serum IgA levels were associated (p<0.001) with fibrosis progression and HCC development in patients with chronic liver diseases. Additionally, immunohistochemical staining of inflamed livers or HCC revealed IgA positivity in monocytes, with a correlation between IgA(+) cell frequency and IgA serum levels. Compared with IgA(−) monocytes, intrahepatic IgA(+) monocytes expressed higher levels of programmed death-ligand 1 (PD-L1) in inflamed livers and in HCC tumor microenvironment. Single-cell RNA sequencing using NCBI GEO database indicated an upregulation in inflammation-associated genes in the monocytes of patients whose plasma cell IGHA1 expression was greater than or equal to the median value. Bulk RNA sequencing demonstrated that in vitro stimulation of M2-polarized macrophages using coated IgA complex induced PD-L1 upregulation via YAP-mediated signaling. In vivo blockade of IgA signaling decreased the number of tumor-infiltrating IgA(+)PD-L1(high) macrophages and increased the number of CD69(+)CD8(+) T cells to enhance antitumor effects in HCC mice models. CONCLUSIONS: Overall, the findings of this study showed that serum IgA levels was correlated with intrahepatic and intratumoral infiltration of inflammatory IgA(+)PD-L1(high) monocytes in chronic liver diseases and HCC, providing potential therapeutic targets. BMJ Publishing Group 2022-05-16 /pmc/articles/PMC9114848/ /pubmed/35577505 http://dx.doi.org/10.1136/jitc-2021-003618 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Immunotherapy Biomarkers
Sung, Pil Soo
Park, Dong Jun
Roh, Pu Reun
Mun, Kyoung Do
Cho, Sung Woo
Lee, Gil Won
Jung, Eun Sun
Lee, Sung Hak
Jang, Jeong Won
Bae, Si Hyun
Choi, Jong Young
Choi, Jonghwan
Ahn, Jaegyoon
Yoon, Seung Kew
Intrahepatic inflammatory IgA(+)PD-L1(high) monocytes in hepatocellular carcinoma development and immunotherapy
title Intrahepatic inflammatory IgA(+)PD-L1(high) monocytes in hepatocellular carcinoma development and immunotherapy
title_full Intrahepatic inflammatory IgA(+)PD-L1(high) monocytes in hepatocellular carcinoma development and immunotherapy
title_fullStr Intrahepatic inflammatory IgA(+)PD-L1(high) monocytes in hepatocellular carcinoma development and immunotherapy
title_full_unstemmed Intrahepatic inflammatory IgA(+)PD-L1(high) monocytes in hepatocellular carcinoma development and immunotherapy
title_short Intrahepatic inflammatory IgA(+)PD-L1(high) monocytes in hepatocellular carcinoma development and immunotherapy
title_sort intrahepatic inflammatory iga(+)pd-l1(high) monocytes in hepatocellular carcinoma development and immunotherapy
topic Immunotherapy Biomarkers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9114848/
https://www.ncbi.nlm.nih.gov/pubmed/35577505
http://dx.doi.org/10.1136/jitc-2021-003618
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