Cargando…

Immunohistochemical scoring of LAG-3 in conjunction with CD8 in the tumor microenvironment predicts response to immunotherapy in hepatocellular carcinoma

INTRODUCTION: Immune checkpoint blockade (ICB) is a systemic therapeutic option for advanced hepatocellular carcinoma (HCC). However, low patient response rates necessitate the development of robust predictive biomarkers that identify individuals who will benefit from ICB. A 4-gene inflammatory sign...

Descripción completa

Detalles Bibliográficos
Autores principales: Cheung, Chun Chau Lawrence, Seah, Yong Hock Justin, Fang, Juntao, Orpilla, Nicole Hyacinth Calpatura, Lau, Mai Chan, Lim, Chun Jye, Lim, Xinru, Lee, Justina Nadia Li Wen, Lim, Jeffrey Chun Tatt, Lim, Sherlly, Cheng, Qing, Toh, Han Chong, Choo, Su Pin, Lee, Suat Ying, Lee, Joycelyn Jie Xin, Liu, Jin, Lim, Tony Kiat Hon, Tai, David, Yeong, Joe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10277502/
https://www.ncbi.nlm.nih.gov/pubmed/37342338
http://dx.doi.org/10.3389/fimmu.2023.1150985
_version_ 1785060295912194048
author Cheung, Chun Chau Lawrence
Seah, Yong Hock Justin
Fang, Juntao
Orpilla, Nicole Hyacinth Calpatura
Lau, Mai Chan
Lim, Chun Jye
Lim, Xinru
Lee, Justina Nadia Li Wen
Lim, Jeffrey Chun Tatt
Lim, Sherlly
Cheng, Qing
Toh, Han Chong
Choo, Su Pin
Lee, Suat Ying
Lee, Joycelyn Jie Xin
Liu, Jin
Lim, Tony Kiat Hon
Tai, David
Yeong, Joe
author_facet Cheung, Chun Chau Lawrence
Seah, Yong Hock Justin
Fang, Juntao
Orpilla, Nicole Hyacinth Calpatura
Lau, Mai Chan
Lim, Chun Jye
Lim, Xinru
Lee, Justina Nadia Li Wen
Lim, Jeffrey Chun Tatt
Lim, Sherlly
Cheng, Qing
Toh, Han Chong
Choo, Su Pin
Lee, Suat Ying
Lee, Joycelyn Jie Xin
Liu, Jin
Lim, Tony Kiat Hon
Tai, David
Yeong, Joe
author_sort Cheung, Chun Chau Lawrence
collection PubMed
description INTRODUCTION: Immune checkpoint blockade (ICB) is a systemic therapeutic option for advanced hepatocellular carcinoma (HCC). However, low patient response rates necessitate the development of robust predictive biomarkers that identify individuals who will benefit from ICB. A 4-gene inflammatory signature, comprising CD8, PD-L1, LAG-3, and STAT1, was recently shown to be associated with a better overall response to ICB in various cancer types. Here, we examined whether tissue protein expression of CD8, PD-L1, LAG-3, and STAT1 predicts response to ICB in HCC. METHODS: HCC samples from 191 Asian patients, comprising resection specimens from 124 patients (ICB-naïve) and pre-treatment specimens from 67 advanced HCC patients treated with ICB (ICB-treated), were analyzed for CD8, PD-L1, LAG-3, and STAT1 tissue expression using multiplex immunohistochemistry followed by statistical and survival analyses. RESULTS: Immunohistochemical and survival analyses of ICB-naïve samples showed that high LAG-3 expression was associated with shorter median progression-free survival (mPFS) and overall survival (mOS). Analysis of ICB-treated samples revealed that high proportions of LAG-3(+) and LAG-3(+)CD8(+) cells pre-treatment were most closely associated with longer mPFS and mOS. Using a log-likelihood model, adding the total LAG-3(+) cell proportion to the total CD8(+) cell proportion significantly increased the predictive values for mPFS and mOS, compared with the total CD8(+) cell proportion alone. Moreover, levels of CD8 and STAT1, but not PD-L1, were significantly correlated with better responses to ICB. After analyzing viral-related and non-viral HCC samples separately, only the LAG3(+)CD8(+) cell proportion was significantly associated with responses to ICB regardless of viral status. CONCLUSION: Immunohistochemical scoring of pre-treatment levels of LAG-3 and CD8 in the tumor microenvironment may help predict ICB benefits in HCC patients. Furthermore, immunohistochemistry-based techniques offer the advantage of being readily translatable in the clinical setting.
format Online
Article
Text
id pubmed-10277502
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-102775022023-06-20 Immunohistochemical scoring of LAG-3 in conjunction with CD8 in the tumor microenvironment predicts response to immunotherapy in hepatocellular carcinoma Cheung, Chun Chau Lawrence Seah, Yong Hock Justin Fang, Juntao Orpilla, Nicole Hyacinth Calpatura Lau, Mai Chan Lim, Chun Jye Lim, Xinru Lee, Justina Nadia Li Wen Lim, Jeffrey Chun Tatt Lim, Sherlly Cheng, Qing Toh, Han Chong Choo, Su Pin Lee, Suat Ying Lee, Joycelyn Jie Xin Liu, Jin Lim, Tony Kiat Hon Tai, David Yeong, Joe Front Immunol Immunology INTRODUCTION: Immune checkpoint blockade (ICB) is a systemic therapeutic option for advanced hepatocellular carcinoma (HCC). However, low patient response rates necessitate the development of robust predictive biomarkers that identify individuals who will benefit from ICB. A 4-gene inflammatory signature, comprising CD8, PD-L1, LAG-3, and STAT1, was recently shown to be associated with a better overall response to ICB in various cancer types. Here, we examined whether tissue protein expression of CD8, PD-L1, LAG-3, and STAT1 predicts response to ICB in HCC. METHODS: HCC samples from 191 Asian patients, comprising resection specimens from 124 patients (ICB-naïve) and pre-treatment specimens from 67 advanced HCC patients treated with ICB (ICB-treated), were analyzed for CD8, PD-L1, LAG-3, and STAT1 tissue expression using multiplex immunohistochemistry followed by statistical and survival analyses. RESULTS: Immunohistochemical and survival analyses of ICB-naïve samples showed that high LAG-3 expression was associated with shorter median progression-free survival (mPFS) and overall survival (mOS). Analysis of ICB-treated samples revealed that high proportions of LAG-3(+) and LAG-3(+)CD8(+) cells pre-treatment were most closely associated with longer mPFS and mOS. Using a log-likelihood model, adding the total LAG-3(+) cell proportion to the total CD8(+) cell proportion significantly increased the predictive values for mPFS and mOS, compared with the total CD8(+) cell proportion alone. Moreover, levels of CD8 and STAT1, but not PD-L1, were significantly correlated with better responses to ICB. After analyzing viral-related and non-viral HCC samples separately, only the LAG3(+)CD8(+) cell proportion was significantly associated with responses to ICB regardless of viral status. CONCLUSION: Immunohistochemical scoring of pre-treatment levels of LAG-3 and CD8 in the tumor microenvironment may help predict ICB benefits in HCC patients. Furthermore, immunohistochemistry-based techniques offer the advantage of being readily translatable in the clinical setting. Frontiers Media S.A. 2023-06-05 /pmc/articles/PMC10277502/ /pubmed/37342338 http://dx.doi.org/10.3389/fimmu.2023.1150985 Text en Copyright © 2023 Cheung, Seah, Fang, Orpilla, Lau, Lim, Lim, Lee, Lim, Lim, Cheng, Toh, Choo, Lee, Lee, Liu, Lim, Tai and Yeong https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Cheung, Chun Chau Lawrence
Seah, Yong Hock Justin
Fang, Juntao
Orpilla, Nicole Hyacinth Calpatura
Lau, Mai Chan
Lim, Chun Jye
Lim, Xinru
Lee, Justina Nadia Li Wen
Lim, Jeffrey Chun Tatt
Lim, Sherlly
Cheng, Qing
Toh, Han Chong
Choo, Su Pin
Lee, Suat Ying
Lee, Joycelyn Jie Xin
Liu, Jin
Lim, Tony Kiat Hon
Tai, David
Yeong, Joe
Immunohistochemical scoring of LAG-3 in conjunction with CD8 in the tumor microenvironment predicts response to immunotherapy in hepatocellular carcinoma
title Immunohistochemical scoring of LAG-3 in conjunction with CD8 in the tumor microenvironment predicts response to immunotherapy in hepatocellular carcinoma
title_full Immunohistochemical scoring of LAG-3 in conjunction with CD8 in the tumor microenvironment predicts response to immunotherapy in hepatocellular carcinoma
title_fullStr Immunohistochemical scoring of LAG-3 in conjunction with CD8 in the tumor microenvironment predicts response to immunotherapy in hepatocellular carcinoma
title_full_unstemmed Immunohistochemical scoring of LAG-3 in conjunction with CD8 in the tumor microenvironment predicts response to immunotherapy in hepatocellular carcinoma
title_short Immunohistochemical scoring of LAG-3 in conjunction with CD8 in the tumor microenvironment predicts response to immunotherapy in hepatocellular carcinoma
title_sort immunohistochemical scoring of lag-3 in conjunction with cd8 in the tumor microenvironment predicts response to immunotherapy in hepatocellular carcinoma
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10277502/
https://www.ncbi.nlm.nih.gov/pubmed/37342338
http://dx.doi.org/10.3389/fimmu.2023.1150985
work_keys_str_mv AT cheungchunchaulawrence immunohistochemicalscoringoflag3inconjunctionwithcd8inthetumormicroenvironmentpredictsresponsetoimmunotherapyinhepatocellularcarcinoma
AT seahyonghockjustin immunohistochemicalscoringoflag3inconjunctionwithcd8inthetumormicroenvironmentpredictsresponsetoimmunotherapyinhepatocellularcarcinoma
AT fangjuntao immunohistochemicalscoringoflag3inconjunctionwithcd8inthetumormicroenvironmentpredictsresponsetoimmunotherapyinhepatocellularcarcinoma
AT orpillanicolehyacinthcalpatura immunohistochemicalscoringoflag3inconjunctionwithcd8inthetumormicroenvironmentpredictsresponsetoimmunotherapyinhepatocellularcarcinoma
AT laumaichan immunohistochemicalscoringoflag3inconjunctionwithcd8inthetumormicroenvironmentpredictsresponsetoimmunotherapyinhepatocellularcarcinoma
AT limchunjye immunohistochemicalscoringoflag3inconjunctionwithcd8inthetumormicroenvironmentpredictsresponsetoimmunotherapyinhepatocellularcarcinoma
AT limxinru immunohistochemicalscoringoflag3inconjunctionwithcd8inthetumormicroenvironmentpredictsresponsetoimmunotherapyinhepatocellularcarcinoma
AT leejustinanadialiwen immunohistochemicalscoringoflag3inconjunctionwithcd8inthetumormicroenvironmentpredictsresponsetoimmunotherapyinhepatocellularcarcinoma
AT limjeffreychuntatt immunohistochemicalscoringoflag3inconjunctionwithcd8inthetumormicroenvironmentpredictsresponsetoimmunotherapyinhepatocellularcarcinoma
AT limsherlly immunohistochemicalscoringoflag3inconjunctionwithcd8inthetumormicroenvironmentpredictsresponsetoimmunotherapyinhepatocellularcarcinoma
AT chengqing immunohistochemicalscoringoflag3inconjunctionwithcd8inthetumormicroenvironmentpredictsresponsetoimmunotherapyinhepatocellularcarcinoma
AT tohhanchong immunohistochemicalscoringoflag3inconjunctionwithcd8inthetumormicroenvironmentpredictsresponsetoimmunotherapyinhepatocellularcarcinoma
AT choosupin immunohistochemicalscoringoflag3inconjunctionwithcd8inthetumormicroenvironmentpredictsresponsetoimmunotherapyinhepatocellularcarcinoma
AT leesuatying immunohistochemicalscoringoflag3inconjunctionwithcd8inthetumormicroenvironmentpredictsresponsetoimmunotherapyinhepatocellularcarcinoma
AT leejoycelynjiexin immunohistochemicalscoringoflag3inconjunctionwithcd8inthetumormicroenvironmentpredictsresponsetoimmunotherapyinhepatocellularcarcinoma
AT liujin immunohistochemicalscoringoflag3inconjunctionwithcd8inthetumormicroenvironmentpredictsresponsetoimmunotherapyinhepatocellularcarcinoma
AT limtonykiathon immunohistochemicalscoringoflag3inconjunctionwithcd8inthetumormicroenvironmentpredictsresponsetoimmunotherapyinhepatocellularcarcinoma
AT taidavid immunohistochemicalscoringoflag3inconjunctionwithcd8inthetumormicroenvironmentpredictsresponsetoimmunotherapyinhepatocellularcarcinoma
AT yeongjoe immunohistochemicalscoringoflag3inconjunctionwithcd8inthetumormicroenvironmentpredictsresponsetoimmunotherapyinhepatocellularcarcinoma