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Review
. 2023 Jul 24:13:1193762.
doi: 10.3389/fonc.2023.1193762. eCollection 2023.

Combined radiotherapy and immune checkpoint inhibition for the treatment of advanced hepatocellular carcinoma

Alexander H Shannon  1 , Ashish Manne  2 , Dayssy A Diaz Pardo  3 , Timothy M Pawlik  1
Affiliations
Review

Combined radiotherapy and immune checkpoint inhibition for the treatment of advanced hepatocellular carcinoma

Alexander H Shannon et al. Front Oncol. .

Abstract

Hepatocellular Carcinoma (HCC) is one of the most common cancers and a leading cause of cancer related death worldwide. Until recently, systemic therapy for advanced HCC, defined as Barcelona Clinic Liver Cancer (BCLC) stage B or C, was limited and ineffective in terms of long-term survival. However, over the past decade, immune check point inhibitors (ICI) combinations have emerged as a potential therapeutic option for patients with nonresectable disease. ICI modulate the tumor microenvironment to prevent progression of the tumor. Radiotherapy is a crucial tool in treating unresectable HCC and may enhance the efficacy of ICI by manipulating the tumor microenvironment and decreasing tumor resistance to certain therapies. We herein review developments in the field of ICI combined with radiotherapy for the treatment of HCC, as well as look at challenges associated with these treatment modalities, and review future directions of combination therapy.

Keywords: combination therapy; hepatocellular carcinoma; immune checkpoint inhibitors; radiotherapy; stereotactic body radiotherapy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
PRISMA Flow Diagram.
Figure 2
Figure 2
Mechanism of the abscopal effect. Radiotherapy (RT) can lead to immunogenic cell death and the release of tumor antigens by irradiated tumor cells. These neoantigens are taken up by antigen-presenting cells (APCs), such as dendritic cells (DCs) and phagocytic cells. The APCs interact with tumor antigens and then migrate to the lymph nodes where they present antigens to T cells, a process that is mediated by the MHC pathway and other co-stimulatory signals, such as CD80 and CD28. After activation by multiple signals, T cells, especially the CD8+ T cells, are activated and begin to propagate. As a result, activated effector T cells exit the lymph nodes and home to tumors, including primary tumors and non-irradiated tumor metastases, to exert their effect of killing tumor cells. However, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) competitively combines with CD80/86 and inhibits the activation of T cells. Following T cell activation, programmed cell death 1 (PD-1) receptors that are expressed on the T cell surface bind primarily to programmed death-ligand 1 (PD-L1) and inhibit immune responses. The administration of immune checkpoint blockades of CTLA-1, PD-1, and PD-L1 can enhance the anti-tumor immunity of RT (92).
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