The prognosis of hepatocellular carcinoma (HCC) remains poor, with only one third of patients eligible for curative treatments and very limited survival benefits with the use of sorafenib, the current standard of care for advanced disease. Recently, agents targeting the programmed death ligand 1 (PD‐L1)/programmed death receptor 1 (PD‐1) immune checkpoint were shown to display impressive antitumor activity in various solid or hematological malignancies, including HCC. PD‐L1 immunohistochemical expression is thought to represent a biomarker predictive of drug sensitivity. Here, we investigated PD‐L1 expression in a series of 217 HCCs and correlated our results with clinical and histological features and immunohistochemical markers (PD‐1, cytokeratin 19, glutamine synthetase, and β‐catenin expression). PD‐L1 expression by neoplastic cells was significantly associated with common markers of tumor aggressiveness (high serum alpha‐fetoprotein levels, P = 0.038; satellite nodules, P < 0.001; macrovascular invasion, P < 0.001; microvascular invasion, P < 0.001; poor differentiation, P < 0.001) and with the progenitor subtype of HCC (cytokeratin 19 expression, P = 0.031). High PD‐L1 expression by inflammatory cells from the tumor microenvironment also correlated with high serum alpha‐fetoprotein levels (P < 0.001), macrovascular invasion (P = 0.001), poor differentiation (P = 0.001), high PD‐1 expression (P < 0.001), and the so‐called lymphoepithelioma‐like histological subtype of HCC (P = 0.003). Conclusion: PD‐L1 expression by either neoplastic or intratumoral inflammatory cells is related to tumor aggressiveness and suggests that the response to treatments targeting the PD‐L1/PD‐1 immune checkpoint could be restricted to particular HCC variants; thus, enrichment of these tumor subtypes in future clinical trials should be considered. (Hepatology 2016;64:2038‐2046)

PD-L1 expression in perihilar and intrahepatic cholangiocarcinoma

Hepatocellular carcinoma (HCC) is the second deadliest cancer worldwide, due to its high incidence and poor prognosis. Frequent initial presentation at advanced stages along with impaired liver function limit the use of a broad therapeutic arsenal in patients with HCC. Although main HCC oncogenic drivers have been deciphered in recent years (TERT, TP53, CTNNB1 mutations, miR122 and CDKN2A silencing), therapeutic applications derived from this molecular knowledge are still limited. Given its high vascularization and immunogenicity, antiangiogenics and immune checkpoint inhibitors (ICI), respectively, are two therapeutic approaches that have shown efficacy in HCC. Depending on HCC immune profile, combinations of these therapies aim to modify the protumoral/antitumoral immune balance, and to reactivate and favor the intratumoral trafficking of cytotoxic T cells. Combination therapies involving antiangiogenics and ICI may be synergistic, because vascular endothelial growth factor A inhibition increases intratumoral infiltration and survival of cytotoxic T lymphocytes and decreases regulatory T lymphocyte recruitment, resulting in a more favorable immune microenvironment for ICI antitumoral activity. First results from clinical trials evaluating combinations of these therapies are encouraging with response rates never observed before in patients with HCC. A better understanding of the balance and interactions between protumoral and antitumoral immune cells will help to ensure the success of future therapeutic trials. Here, we present an overview of the current state of clinical development of antitumoral therapies in HCC and the biological rationale for their use. Moreover, translational studies on tumor tissue and blood, prior to and during treatment, will help to identify biomarkers and immune signatures with predictive value for both clinical outcome and response to combination therapies.