Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 28, 2019; 25(20): 2416-2429
Published online May 28, 2019. doi: 10.3748/wjg.v25.i20.2416
Optimizing radiotherapy with immune checkpoint blockade in hepatocellular carcinoma
Changhoon Choi, Gyu Sang Yoo, Won Kyung Cho, Hee Chul Park
Changhoon Choi, Gyu Sang Yoo, Won Kyung Cho, Department of Radiation Oncology, Samsung Medical Center, Seoul 06351, South Korea
Hee Chul Park, Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea
Author contributions: All authors equally contributed to this paper in the conception and design of the study; literature review and analysis; drafting, critical revision, and editing; and final approval of the final version.
Conflict-of-interest statement: No potential conflicts of interest. No financial support.
Open-Access: This is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Hee Chul Park, MD, PhD, Full Professor, Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, South Korea.
Telephone: +82-2-34012616 Fax: +82-2-34102619
Received: February 21, 2019
Peer-review started: February 22, 2019
First decision: March 27, 2019
Revised: April 12, 2019
Accepted: April 19, 2019
Article in press: April 19, 2019
Published online: May 28, 2019

Hepatocellular carcinoma (HCC) is the fifth most common cancer, and its incidence is rapidly increasing in North America and Western Europe as well as South-East Asia. Patients with advanced stage HCC have very poor outcomes; therefore, the discovery of new innovative approaches is urgently needed. Cancer immunotherapy has become a game-changer and revolutionized cancer treatment. A comprehensive understanding of tumor-immune interactions led to the development of immune checkpoint inhibitors (ICIs) as new therapeutic tools, which have been used with great success. Targeting immune checkpoint molecules such as programmed cell death-1 (PD-1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) reinvigorates anti-tumor immunity by restoring exhausted T cells. Despite their effectiveness in several types of cancer, of the many immune suppressive mechanisms limit the efficacy of ICI monotherapy. Radiation therapy (RT) is an essential local treatment modality for a broad range of malignancies, and it is currently gaining extensive attention as a promising combination partner with ICIs because of its ability to trigger immunogenic cell death. The efficacy of combination approaches using RT and ICIs has been well documented in numerous preclinical and clinical studies on various types of cancers but not HCC. The application of ICIs has now expanded to HCC, and RT is recognized as a promising modality in HCC. This review will highlight the current roles of PD-1 and CTLA-4 therapies and their combination with RT in the treatment of cancers, including HCC. In addition, this review will discuss the future perspectives of the combination of ICIs and RT in HCC treatment.

Keywords: Hepatocellular carcinoma, Radiation therapy, Immune checkpoint inhibitors, Abscopal effect

Core tip: In the era of cancer immunotherapy, the roles of radiation therapy (RT) are not limited to the direct killing of cancerous cells but have expanded to immune modulation. Numerous proof-of-concept preclinical studies have proven that combination approaches of RT and immune checkpoint inhibitors (ICIs) are highly promising for many types of cancers, and currently, many related clinical trials are ongoing. Historically, RT was considered ineffective for hepatocellular carcinoma (HCC), but the efficacy of RT in HCC has improved greatly with technical advances. Our goal of this review is to provide a rationale for the combined treatment with RT and ICIs in HCC.