The 4th Joint Session between JDDW-KDDW-TDDW4(JDDW)
Thu. November 5th   14:00 - 16:15   Room 10: Portopia Hotel Waraku
JKT4-RS3
 Immune contexture of HCC: from Sorafenib to immune checkpoint inhibitors
Li-Chun Lu
National Taiwan University Hospital
Antiangiogenic agents and/or immune checkpoint inhibitors (ICIs) have been standard-of-care for advanced hepatocellular carcinoma (HCC). Recently, the interaction between the tumor microenvironment (TME) and systemic therapy response has been a major focus of research.
Sorafenib, a multikinase inhibitor with antiangiogenic properties and the first systemic therapy approved for HCC, has been demonstrated to exhibit various immunomodulatory effects. The impact of sorafenib on PD-L1 expression in the TME of advanced HCC was unclear. We analyzed the tissue slides using immunohistochemistry to semiquantitatively score the membrane PD-L1 staining in tumor cells (TCs) or tumor-infiltrating immune cells (ICs). In 23 paired HCC tissues, PD-L1 expression in ICs was increased in HCC tissues after sorafenib treatment. However, PD-L1 expression in TCs did not increase significantly after sorafenib treatment. We also demonstrated that PD-L1-expressing ICs were highly co-localized with CD68-positive tumor-infiltrating macrophages, suggesting that PD-L1-expressing macrophages play roles in HCC progression after treatment with sorafenib.
In addition, the antitumor effects of ICIs are influenced by the immune contexture of the TME. However, whether distinct immune contextures in different organ systems contribute to the variable tumor response to ICIs in HCC was unknown. We reviewed data from patients with advanced HCC who had received ICIs and had measurable diseases. The objective response to ICIs in tumors located in different organ systems was evaluated independently. Among the 75 enrolled patients, 58, 34, 19, and 18 patients had measurable hepatic tumors and lung, lymph node, and other intra-abdominal metastases, respectively, with the corresponding organ-specific objective response rates being 22.4%, 41.2%, 26.3%, and 38.9%. Among the patients who had both hepatic and extrahepatic tumors such as lung metastases, more patients had disease control in the extrahepatic tumors but progressive disease in the hepatic tumors. We demonstrated that hepatic tumors of HCC are less responsive to ICIs than extrahepatic lesions, and lung metastases respond most favorably to ICIs, suggesting that the TME influences the efficacy of ICIs. Mechanistically, we utilized orthotopic liver tumor models and found that higher percentages of macrophages, more exhausted CD8+ T cells, and higher VEGF levels in liver tumors, which could render the TME in liver more immunosuppressive and lead to a poorer ICI response than in other organ systems. Our findings provide insights that could facilitate the development of systemic therapy for advanced HCC in the future.
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