Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 May 31;5(7):e1176653.
doi: 10.1080/2162402X.2016.1176653. eCollection 2016 Jul.

PD-L1 expression as a predictive biomarker for cytokine-induced killer cell immunotherapy in patients with hepatocellular carcinoma

Chang-Long Chen  1 , Qiu-Zhong Pan  2 , Jing-Jing Zhao  2 , Ying Wang  3 , Yong-Qiang Li  2 , Qi-Jing Wang  2 , Ke Pan  4 , De-Sheng Weng  4 , Shan-Shan Jiang  1 , Yan Tang  4 , Xiao-Fei Zhang  1 , Hong-Xia Zhang  1 , Zi-Qi Zhou  1 , Yi-Xin Zeng  4 , Jian-Chuan Xia  4
Affiliations

PD-L1 expression as a predictive biomarker for cytokine-induced killer cell immunotherapy in patients with hepatocellular carcinoma

Chang-Long Chen et al. Oncoimmunology. .

Abstract

Cytokine-induced killer (CIK) cell immunotherapy represents an effective treatment strategy for treating hepatocellular carcinoma (HCC). However, the therapeutic benefits of CIK cell treatment can be influenced by differences in complex immune microenvironment between patients. Herein, we investigated the relationship between PD-L1 expression and survival benefits of CIK cell immunotherapy in HCC patients. This retrospective study included 448 HCC patients: 217 cases underwent hepatectomy alone; 231 cases received hepatectomy and post-operative CIK cell transfusion. Immunohistochemistry was used to measure PD-L1 expression in tumor tissue sections from all patients. Meanwhile, flow cytometry was performed to explore the relationship between PD-L1 expression and localized inflammatory response in HCC microenvironment. We found a significantly improved prognosis in CIK treatment group compared with surgery alone group. In the CIK treatment group, higher PD-L1 expression was observed in patients who exhibited long-term survival benefit. Survival analysis showed patients with ≥5% PD-L1 expression had better overall survival (OS) and recurrence-free survival (RFS) than patients with 1-5% or <1% PD-L1 expression, particularly in the subgroup with high hepatitis B viral load. By contrast, PD-L1 expression did not show direct impact on the survival of patients in surgery alone group. Additionally, PD-L1 expression was found to be highly associated with hepatitis B viral load and the proportion of tumor-infiltrating lymphocytes in HCC patients. In conclusions, our study indicates that PD-L1 expression may reflect the presence of endogenous host immune response to tumor and serve as a biomarker for predicting survival benefits from adjuvant CIK cell immunotherapy in HCC patients.

Keywords: Adjuvant CIK immunotherapy; PD-L1; hepatocellular carcinoma; immunohistochemistry; survival benefit.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Kaplan–Meier curves of differences in survival among patients with hepatocellular carcinoma (HCC) who received adjuvant CIK cell treatment (CIK treatment group) or hepatectomy alone (surgery alone group). (A) Overall survival (OS) and (B) recurrence-free survival (RFS) curves. Significantly improved OS and PFS were observed in the CIK treatment group versus the surgery alone group.
Figure 2.
Figure 2.
Immunohistochemical analysis of PD-L1 expression in primary hepatocellular carcinoma surgical specimens. Positive staining results are reported as the percentage of tumor cells showing membranous PD-L1 expression (frequency). (A and D) PD-L1 expression was scored as <1%, (B and E) PD-L1 expression was scored as 1–5%, (C and F) PD-L1 expression was scored as ≥5%. PD-L1 staining is indicated by the presence of brown chromogen. Blue represents the hematoxylin counterstain (A–C, 100× magnification; D–F, 400× magnification).
Figure 3.
Figure 3.
Correlation of PD-L1 expression by HCC cells with the survival benefit from adjuvant CIK cell immunotherapy. Differences in levels of PD-L1 expression between patients showing a long-term versus a minimal survival benefit are shown before (A) and after (B) the propensity score weighting method was used to balance all covariates. C and D depicts the Kaplan–Meier curves for overall survival (OS) and recurrence-free survival (RFS) in the CIK cell treatment group for patients with ≥5%, 1–5% and <1 % PD-L1 expression, respectively.
Figure 4.
Figure 4.
Kaplan–Meier curves for HCC patients who received hepatectomy alone based on expression of PD-L1 on tumor cells. (A) Overall survival (OS) and (B) recurrence-free survival (RFS) curves are shown. No correlation with PD-L1 expression was observed with the OS of RFS rates of patients with HCC; p values were calculated using the log-rank test.
Figure 5.
Figure 5.
Subgroup analysis to estimate the impact of PD-L1 expression on survival benefits of additional CIK treatment according to hepatitis B viral load. (A) OS and RFS curves for patients with high hepatitis B viral load. (B) OS and RFS curves for patients with low hepatitis B viral load.
Figure 6.
Figure 6.
Association between PD-L1 expression on tumor cells and infiltration of inflammatory cells in HCC microenvironment. (A) Gating routine for the identification of tumor cells and CD45+ cells is shown. Flow cytometric analysis was performed to measure PD-L1 expression on tumor cells(gate C) and CD4+, CD8+, CD56+, and CD68+ cell subsets gating on the CD45+fraction(gate B). Significantly higher percentages of CD4+ T cells and CD8+ T cells were observed in the HCC tumor tissues with high PD-L1 expression (case 1) compared to that with low PD-L1 expression (case 2). (B) A summary of correlation analysis was shown that PD-L1 positive tumor cells in tumor tissues significantly correlated with tumor-infiltrating CD4+ and CD8+ T cells, but not associated with CD56+ NK cell and CD68+ macrophage (n = 10).
Figure 7.
Figure 7.
PD-1 expression on the autologous CIK cells. (A) The percentages of PD-1 positive cells among the populations of CIK cells. (B) The percentages of CD4+PD-1+ CIK cells. (C) The percentages of CD8+PD-1+ CIK cells. (D) The percentages of CD3−CD56+ PD-1+ and CD3+CD56+ PD-1+ CIK cells. (E) PD-1 expression on each subgroup of CIK cells in five HCC patients. These data suggested CIK cells exhibited a low PD-1 expression.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Knox JJ, Cleary SP, Dawson LA. Localized and Systemic Approaches to Treating Hepatocellular Carcinoma. J Clin Oncol 2015; 33:1835-44; PMID:25918289; http://dx.doi.org/10.1200/JCO.2014.60.1153 - DOI - PubMed
    1. Alejandro F, Josep ML, Jordi B. Hepatocellular Carcinoma. Lancet 2012; 379:1245-55; PMID:22353262; http://dx.doi.org/10.1016/S0140-6736(11)61347-0 - DOI - PubMed
    1. Jacques F, Hai-Rim S, Freddie B, David F, Colin M, Donald MP. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127:2893-917; PMID:21351269; http://dx.doi.org/10.1002/ijc.25516 - DOI - PubMed
    1. Ulahannan SV, Duffy AG, McNeel TS, Kish JK, Dickie LA, Rahma OE, McGlynn KA,. Greten TF, Altekruse SF. Earlier presentation and application of curative treatments in hepatocellular carcinoma. Hepatol 2014; 60:1637-44; PMID:24996116; http://dx.doi.org/10.1002/hep.27288 - DOI - PMC - PubMed
    1. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A et al.. Sorafenib in Advanced Hepatocellular. N Engl J Med 2008; 359:378-90; PMID:18650514; http://dx.doi.org/10.1056/NEJMoa0708857 - DOI - PubMed

Publication types