Abstract
The quantity of programmed cell death-ligand 1 (PD-L1) is regarded as a predicting factor of clinical response to anti-PD-1 axis immunotherapy. However, the expression of PD-L1 and its prognostic value in hepatocellular carcinoma (HCC) patients remain debated. Meanwhile, the molecular features of PD-1's other ligand, namely PD-L2, as well as its correlation with clinicopathological parameters and HCC tumor microenvironment (TME), are still poorly understood. In this study, immunohistochemistry (IHC) data from 304 HCC patients were used to determine the clinicopathological features of PD-L1 and PD-L2 and their correlation with CD8+ T cells in HCC. Moreover, fresh clinical HCC samples were used to identify the immune cell subtypes expressing PD-L1 and PD-L2. By using The Cancer Genome Atlas (TCGA) dataset, we further assessed the correlation between mutation signature, copy number variation (CNV), number of neoepitopes, immune gene expression, immune/stromal cell infiltration to the expression of PD-L1 and PD-L2. While membrane expression of PD-L2 was observed in 19.1% of tumor samples, no obvious expression of PD-L1 was detected on tumor cell membranes. High expression of PD-L2 on tumor membranes and PD-L1 in immune stroma were both significantly associated with poorer overall survival (OS) and disease-free survival (DFS) outcomes. Flow cytometry analysis and immunofluorescence showed that macrophages were the main immune cell subtype expressing both PD-L1 and PD-L2. Moreover, positive expression of PD-Ls was correlated with higher CD8+ T cells infiltration in immune stroma. CNV analysis showed a similarity between PD-L1 and PD-L2 in affecting gene expression. In addition, higher levels of PD-Ls correlated with higher expression of immune related genes, enhanced cytolytic activity, and larger proportions of immune/stromal cell infiltration. Collectively, our study reveals the impact of both PD-L1 and PD-L2 on the HCC tumor microenvironment for the first time, providing insight for new therapeutic options.
Highlights
Hepatocellular carcinoma (HCC) has recently become the second leading cause of cancer death around the world [1]
For genes with different expression patterns owing to copy number amplification, there was an overlap between programmed cell death-ligand 1 (PD-L1)-high group and programmed cell death-ligand 2 (PD-L2)-high group (43 genes, Figure 5C, lower panel). Such behavior was similar to genes that attributed their different expression pattern to copy number deletion (26 genes, Figure 5D, lower panel). These findings suggested the potential similarity between the up-regulations of PD-L1 and PD-L2 in affecting copy number variation (CNV), which leads to the differential expression of these genes
We found that there is a strong correlation between cytolytic activity and the expression of PD-Ls in HCC patients (Figure 6C), suggesting that immune response in cytolytic-high HCC samples can elicit tumor mechanisms of immune suppression regulated by PD-Ls
Summary
Hepatocellular carcinoma (HCC) has recently become the second leading cause of cancer death around the world [1]. Once diagnosed with HCC, only a small fraction of patients at early stages can benefit from curative treatments, including resection, local ablation or liver transplantation. While it has been reported that sorafenib can modestly extend the median survival of HCC patients at advanced stages [2], poor tolerance, and limited benefits due to relatively high drug resistance make the use of sorafenib a palliative care. The development of immune checkpoint inhibitors, which are capable of promoting the immune system to attack cancer cells, has experienced remarkable success [3]. Two PD1 inhibitors (Pembrolizumab and Nivolumab) and three PDL1 (Atezolizumab, Avelumab, and Durvalumab) inhibitors have been approved, with others being tested in clinical trials at this moment
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