Expression and prognostic significance of programmed death protein 1 and programmed death ligand-1, and cytotoxic T lymphocyte-associated molecule-4 in hepatocellular carcinoma

Hyeyoon Chang; Wonkyung Jung; Aeree Kim; Han Kyeom Kim; Wan-Bae Kim; Ji Hoon Kim; Baek-Hui Kim

doi:10.1111/apm.12703

Expression and prognostic significance of programmed death protein 1 and programmed death ligand-1, and cytotoxic T lymphocyte-associated molecule-4 in hepatocellular carcinoma

Hyeyoon Chang
, Wonkyung Jung
, Aeree Kim
, Han Kyeom Kim
, Wan-Bae Kim
, Ji Hoon Kim
, Baek-Hui Kim^*

^*Corresponding author for this work

Department of Medicine

Research output: Contribution to journal › Article › peer-review

66 Citations (Scopus)

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignancies and causes of death worldwide. In this study, we assessed the correlation between clinicopathologic factors with programmed cell death protein 1 (PD-1) and programmed cell death ligand-1 (PD-L1), and cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) expressions. Furthermore, we analyzed the prognostic significance of these proteins in a subgroup of patients. We retrospectively evaluated the PD-1, PD-L1, and CTLA-4 expressions in 294 HCC tissue microarray samples using immunohistochemistry. PD-1 and PD-L1 expressions were significant related to high CD8+ tumor-infiltrating lymphocytes (TILs) (r = 0.664, p < 0.001 and r = 0.149, p = 0.012). Only high Edmondson–Steiner grade was statistically related to high PD-1 expression. High PD-L1 expression was demonstrated as an independent poor prognostic factor for disease-free survival in addition to previous known factors, size >5 cm and serum albumin ≤3.5 g/dL in high CD8+ TILs group. We have demonstrated that the combined high expression of PD-L1 and CD8+ TIL is an important prognostic factor related to the immune checkpoint pathway in HCC and furthermore, there is a possibility that it could be used as a predictor of therapeutic response. Also, this result would be helpful in evaluating the applicable group of PD-1/PD-L1 blocking agent for HCC patients.

Original language	English
Pages (from-to)	690-698
Number of pages	9
Journal	APMIS
Volume	125
Issue number	8
DOIs	https://doi.org/10.1111/apm.12703
Publication status	Published - 2017 Aug

Bibliographical note

Funding Information:
The biospecimens for this study were provided by the Korea University Guro Hospital of National Biobank, a member of the National Biobank of Korea. The study was supported by a Korea University fund (K1503351). Specimens were obtained from formalin-fixed, paraffin-embedded tissue blocks from patients who were diagnosed as having HCC and underwent curative surgical resection at the Korea University Guro Hospital from January 2000 to December 2013. Specimens were collected and used under the approval of Institutional Review Board of Korea University Guro Hospital (KUGH14140, Seoul, Korea). All participating patients submitted written formal informed consent for research use of their specimen. Clinical data such as age, sex, metastasis, recurrence, and date of death were collected using patient's medical records.

Publisher Copyright:
© 2017 APMIS. Published by John Wiley & Sons Ltd

Keywords

Hepatocellular carcinoma
cytotoxic T lymphocyte-associated molecule-4
programmed cell death ligand-1
programmed cell death protein 1
tumor-infiltrating lymphocytes

ASJC Scopus subject areas

Microbiology (medical)
Pathology and Forensic Medicine
Immunology and Allergy

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10.1111/apm.12703

Cite this

@article{b23b6ddd58fb4204bf4c590c677cf281,

title = "Expression and prognostic significance of programmed death protein 1 and programmed death ligand-1, and cytotoxic T lymphocyte-associated molecule-4 in hepatocellular carcinoma",

abstract = "Hepatocellular carcinoma (HCC) is one of the most common malignancies and causes of death worldwide. In this study, we assessed the correlation between clinicopathologic factors with programmed cell death protein 1 (PD-1) and programmed cell death ligand-1 (PD-L1), and cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) expressions. Furthermore, we analyzed the prognostic significance of these proteins in a subgroup of patients. We retrospectively evaluated the PD-1, PD-L1, and CTLA-4 expressions in 294 HCC tissue microarray samples using immunohistochemistry. PD-1 and PD-L1 expressions were significant related to high CD8+ tumor-infiltrating lymphocytes (TILs) (r = 0.664, p < 0.001 and r = 0.149, p = 0.012). Only high Edmondson–Steiner grade was statistically related to high PD-1 expression. High PD-L1 expression was demonstrated as an independent poor prognostic factor for disease-free survival in addition to previous known factors, size >5 cm and serum albumin ≤3.5 g/dL in high CD8+ TILs group. We have demonstrated that the combined high expression of PD-L1 and CD8+ TIL is an important prognostic factor related to the immune checkpoint pathway in HCC and furthermore, there is a possibility that it could be used as a predictor of therapeutic response. Also, this result would be helpful in evaluating the applicable group of PD-1/PD-L1 blocking agent for HCC patients.",

keywords = "Hepatocellular carcinoma, cytotoxic T lymphocyte-associated molecule-4, programmed cell death ligand-1, programmed cell death protein 1, tumor-infiltrating lymphocytes",

author = "Hyeyoon Chang and Wonkyung Jung and Aeree Kim and Kim, \{Han Kyeom\} and Wan-Bae Kim and Kim, \{Ji Hoon\} and Baek-Hui Kim",

note = "Funding Information: The biospecimens for this study were provided by the Korea University Guro Hospital of National Biobank, a member of the National Biobank of Korea. The study was supported by a Korea University fund (K1503351). Specimens were obtained from formalin-fixed, paraffin-embedded tissue blocks from patients who were diagnosed as having HCC and underwent curative surgical resection at the Korea University Guro Hospital from January 2000 to December 2013. Specimens were collected and used under the approval of Institutional Review Board of Korea University Guro Hospital (KUGH14140, Seoul, Korea). All participating patients submitted written formal informed consent for research use of their specimen. Clinical data such as age, sex, metastasis, recurrence, and date of death were collected using patient's medical records. Publisher Copyright: {\textcopyright} 2017 APMIS. Published by John Wiley \& Sons Ltd",

year = "2017",

month = aug,

doi = "10.1111/apm.12703",

language = "English",

volume = "125",

pages = "690--698",

journal = "APMIS",

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T1 - Expression and prognostic significance of programmed death protein 1 and programmed death ligand-1, and cytotoxic T lymphocyte-associated molecule-4 in hepatocellular carcinoma

AU - Chang, Hyeyoon

AU - Jung, Wonkyung

AU - Kim, Aeree

AU - Kim, Han Kyeom

AU - Kim, Wan-Bae

AU - Kim, Ji Hoon

AU - Kim, Baek-Hui

N1 - Funding Information: The biospecimens for this study were provided by the Korea University Guro Hospital of National Biobank, a member of the National Biobank of Korea. The study was supported by a Korea University fund (K1503351). Specimens were obtained from formalin-fixed, paraffin-embedded tissue blocks from patients who were diagnosed as having HCC and underwent curative surgical resection at the Korea University Guro Hospital from January 2000 to December 2013. Specimens were collected and used under the approval of Institutional Review Board of Korea University Guro Hospital (KUGH14140, Seoul, Korea). All participating patients submitted written formal informed consent for research use of their specimen. Clinical data such as age, sex, metastasis, recurrence, and date of death were collected using patient's medical records. Publisher Copyright: © 2017 APMIS. Published by John Wiley & Sons Ltd

PY - 2017/8

Y1 - 2017/8

N2 - Hepatocellular carcinoma (HCC) is one of the most common malignancies and causes of death worldwide. In this study, we assessed the correlation between clinicopathologic factors with programmed cell death protein 1 (PD-1) and programmed cell death ligand-1 (PD-L1), and cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) expressions. Furthermore, we analyzed the prognostic significance of these proteins in a subgroup of patients. We retrospectively evaluated the PD-1, PD-L1, and CTLA-4 expressions in 294 HCC tissue microarray samples using immunohistochemistry. PD-1 and PD-L1 expressions were significant related to high CD8+ tumor-infiltrating lymphocytes (TILs) (r = 0.664, p < 0.001 and r = 0.149, p = 0.012). Only high Edmondson–Steiner grade was statistically related to high PD-1 expression. High PD-L1 expression was demonstrated as an independent poor prognostic factor for disease-free survival in addition to previous known factors, size >5 cm and serum albumin ≤3.5 g/dL in high CD8+ TILs group. We have demonstrated that the combined high expression of PD-L1 and CD8+ TIL is an important prognostic factor related to the immune checkpoint pathway in HCC and furthermore, there is a possibility that it could be used as a predictor of therapeutic response. Also, this result would be helpful in evaluating the applicable group of PD-1/PD-L1 blocking agent for HCC patients.

AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies and causes of death worldwide. In this study, we assessed the correlation between clinicopathologic factors with programmed cell death protein 1 (PD-1) and programmed cell death ligand-1 (PD-L1), and cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) expressions. Furthermore, we analyzed the prognostic significance of these proteins in a subgroup of patients. We retrospectively evaluated the PD-1, PD-L1, and CTLA-4 expressions in 294 HCC tissue microarray samples using immunohistochemistry. PD-1 and PD-L1 expressions were significant related to high CD8+ tumor-infiltrating lymphocytes (TILs) (r = 0.664, p < 0.001 and r = 0.149, p = 0.012). Only high Edmondson–Steiner grade was statistically related to high PD-1 expression. High PD-L1 expression was demonstrated as an independent poor prognostic factor for disease-free survival in addition to previous known factors, size >5 cm and serum albumin ≤3.5 g/dL in high CD8+ TILs group. We have demonstrated that the combined high expression of PD-L1 and CD8+ TIL is an important prognostic factor related to the immune checkpoint pathway in HCC and furthermore, there is a possibility that it could be used as a predictor of therapeutic response. Also, this result would be helpful in evaluating the applicable group of PD-1/PD-L1 blocking agent for HCC patients.

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KW - cytotoxic T lymphocyte-associated molecule-4

KW - programmed cell death ligand-1

KW - programmed cell death protein 1

KW - tumor-infiltrating lymphocytes

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SN - 0903-4641

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ER -

Expression and prognostic significance of programmed death protein 1 and programmed death ligand-1, and cytotoxic T lymphocyte-associated molecule-4 in hepatocellular carcinoma

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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