Prognostic significance of inflammatory biomarkers in hepatocellular carcinoma following hepatic resection

Abstract

Background: Cancer-related inflammation has been correlated with cancer prognosis. This study evaluated inflammatory biomarkers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR), programmed death ligand (PD-L) 1 expression, and tumour microenvironment in relation to prognosis and clinicopathological features of patients with hepatocellular carcinoma (HCC) undergoing curative hepatic resection.

Methods: Patients who had liver resection for HCC in 2000-2011 were analysed. Univariable and multivariable analyses were conducted for overall (OS) and recurrence-free (RFS) survival. Immunohistochemical analyses of PD-L1, CD8 and CD68 expression were performed. HCC cell lines were evaluated for PD-L1 expression. A subgroup analysis was conducted to determine patient features, survival and the tumour microenvironment. Results were validated in a cohort of patients with HCC treated surgically in 2012-2016.

Results: Some 281 patients who underwent hepatic resection for HCC were included. Multivariable analysis showed that low LMR was an independent prognostic factor of OS (hazard ratio (HR) 1·59, 95 per cent c.i. 1·00 to 2·41; P = 0·045) and RFS (HR 1·47, 1·05 to 2·04; P = 0·022) after resection. Low preoperative LMR values were correlated with higher α-fetoprotein values (P < 0·001), larger tumour size (P < 0·001), and high rates of poor differentiation (P = 0·035) and liver cirrhosis (P = 0·008). LMR was significantly lower in PD-L1-positive patients than in those with PD-L1 negativity (P < 0·001). Results were confirmed in the validation cohort. PD-L1 expression was upregulated in HCC cell lines treated with interferon-γ and co-cultured with THP-1 monocyte cells.

Conclusion: LMR is an independent predictor of survival after hepatic resection in patients with HCC. Modulation of the immune checkpoint pathway in the tumour microenvironment is associated with a low LMR.

Figure 1

Immunohistochemical staining of programmed death ligand (PD‐L) 1 in a hepatocellular carcinoma specimen. Positive expression of PD‐L 1 in the membrane of hepatocellular carcinoma cells: a magnification ×100; b magnification ×200

Figure 2

Box‐and‐whisker plot of lymphocyte‐to‐monocyte ratio in patients with programmed death ligand 1 positivity and negativity. Median values, interquartile ranges and ranges are denoted by horizontal bars, boxes and error bars respectively. LMR, lymphocyte‐to‐monocyte ratio; PD‐L1, programmed death ligand 1. P < 0·001 (Mann–Whitney U test)

Figure 3

Immunohistochemical staining of CD8 and CD68 in a hepatocellular carcinoma (HCC) specimen. a Low and b high staining of CD8 in HCC specimens. c Low and d high staining of CD68 in HCC specimens. a–d Magnification ×200

Figure 4

Box‐and‐whisker plot of CD8+/CD68+ cell ratios in patients with high and low lymphocyte‐to‐monocyte ratios. Median values, interquartile ranges and ranges (excluding outliers) are denoted by horizontal bars, boxes and error bars respectively. LMR, lymphocyte‐to‐monocyte ratio. P = 0·010 (Mann–Whitney U test)

Figure 5

a,b Kaplan–Meier survival curves after resection of hepatocellular carcinoma in patients with high and low lymphocyte‐to‐monocyte ratios. a Overall and b recurrence‐free survival. LMR, lymphocyte‐to‐monocyte ratio. a,b P < 0·001 (log rank test)