Immune checkpoint therapy in liver cancer

Abstract

Immune checkpoints include stimulatory and inhibitory checkpoint molecules. In recent years, inhibitory checkpoints, including cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed cell death ligand 1 (PD-L1), have been identified to suppress anti-tumor immune responses in solid tumors. Novel drugs targeting immune checkpoints have succeeded in cancer treatment. Specific PD-1 blockades were approved for treatment of melanoma in 2014 and for treatment of non-small-cell lung cancer in 2015 in the United States, European Union, and Japan. Preclinical and clinical studies show immune checkpoint therapy provides survival benefit for greater numbers of patients with liver cancer, including hepatocellular carcinoma and cholangiocarcinoma, two main primary liver cancers. The combination of anti-PD-1/PD-L1 with anti-CTLA-4 antibodies is being evaluated in phase 1, 2 or 3 trials, and the results suggest that an anti-PD-1 antibody combined with locoregional therapy or other molecular targeted agents is an effective treatment strategy for HCC. In addition, studies on activating co-stimulatory receptors to enhance anti-tumor immune responses have increased our understanding regarding this immunotherapy in liver cancer. Epigenetic modulations of checkpoints for improving the tumor microenvironment also expand our knowledge of potential therapeutic targets in improving the tumor microenvironment and restoring immune recognition and immunogenicity. In this review, we summarize current knowledge and recent developments in immune checkpoint-based therapies for the treatment of hepatocellular carcinoma and cholangiocarcinoma and attempt to clarify the mechanisms underlying its effects.

EGFR‐ERK pathway regulates CSN6 to contribute to PD‐L1 expression in glioblastoma

“…Recent studies have confirmed that CSN signaling is important in cell cycle control, signal transduction, transcriptional activation, DNA repair, and tumorigenesis. 11,26,27 As an important subunit of the COP9 family, CSN5 could modulate PD-L1 stabilization in breast cancer cells. 20 Structurally, CSN6 and CSN5 form a heterodimer through the MPN domain, and the dimer is topologically knotted to engage in Cullin deneddylation.…”

“…PD-1/PD-L1 checkpoint blockades have positively changed the treatment patterns for advanced non-small cell lung cancer (NSCLC), renal cancer, chronic Hodgkin's lymphoma, gastric cancer, urothelial cancer, cervical cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, and melanoma. [10][11][12][13][14] The mechanisms of PD-L1 expression in cancer cells involve multiple levels, including gene amplification, chromatin modification, transcription, and posttranscription. [15][16][17][18][19] Oncogenic RAS signaling can upregulate PD-L1 expression through a mechanism involving messenger RNA (mRNA) stability.…”

Ethanol extract of Ophiorrhiza pumila suppresses liver cancer cell proliferation and migration

“…In recent years, immunotherapy has is supposed to be an attractive treatment investigated in liver maligancy. However, resistance to immune checkpoint blockades has been observed in most cancer patients [3,4]. Therefore, it is still urgently needed to develop novel strategies for the management of liver cancer.…”

Efficacy and safety of immune checkpoint therapy in hepatocellular carcinoma: meta-analysis

“…There are currently five anti-PD-1/PD-L1 antibodies and two CTLA-4 blocking antibodies approved by the United States Food and Drug Administration (FDA). But only Nivolumab and Tremelimumab were approved to treat with HCC, with clinical trials of ICI agents currently ongoing [25] . The overall estimated ORR is only 19.8% based on the current study, which needs to be verified with multicenter randomized controlled studies and clinical trials with other endpoints (such as overall survival, OS).…”