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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...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2023
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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 |
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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 |
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