Tamai Yasuyuki, Fujiwara Naoto, Tanaka Takamitsu, Mizuno Shugo, Nakagawa Hayato
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu 514-8507, Japan.
Department of Hepatobiliary Pancreatic and Transplant Surgery, Graduate School of Medicine, Mie University, Tsu 514-8507, Japan.
Cancers (Basel). 2023 Oct 20;15(20):5072. doi: 10.3390/cancers15205072.
Hepatocellular carcinoma (HCC) is estimated to be the fourth leading cause of cancer-related deaths globally, and its overall prognosis is dismal because most cases are diagnosed at a late stage and are unamenable to curative treatment. The emergence of immune checkpoint inhibitors (ICIs) has dramatically improved the therapeutic efficacy for advanced hepatocellular carcinoma; however, their response rates remain unsatisfactory, partly because >50% of HCC exhibit an ICI-nonresponsive tumor microenvironment characterized by a paucity of cytotoxic T cells (immune-cold), as well as difficulty in their infiltration into tumor sites (immune excluded). To overcome this limitation, combination therapies with locoregional therapies, including ablation, transarterial embolization, and radiotherapy, which are usually used for early stage HCCs, have been actively explored to enhance ICI efficacy by promoting the release of tumor-associated antigens and cytokines, and eventually accelerating the so-called cancer-immunity cycle. Various combination therapies have been investigated in early- to late-phase clinical trials, and some have shown promising results. This comprehensive article provides an overview of the immune landscape for HCC to understand ICI efficacy and its limitations and, subsequently, reviews the status of combinatorial therapies of ICIs with locoregional therapy for HCC.
据估计，肝细胞癌（HCC）是全球癌症相关死亡的第四大主要原因，其总体预后不佳，因为大多数病例在晚期才被诊断出来，无法进行根治性治疗。免疫检查点抑制剂（ICI）的出现显著提高了晚期肝细胞癌的治疗效果；然而，它们的反应率仍然不尽人意，部分原因是超过50%的HCC表现出ICI无反应性肿瘤微环境，其特征是细胞毒性T细胞数量稀少（免疫冷），以及难以浸润到肿瘤部位（免疫排除）。为了克服这一局限性，人们积极探索将局部区域治疗（包括消融、经动脉栓塞和放疗，这些通常用于早期HCC）与ICI联合使用，通过促进肿瘤相关抗原和细胞因子的释放，最终加速所谓的癌症免疫循环，从而提高ICI的疗效。各种联合治疗方法已在早期至晚期临床试验中进行了研究，一些已显示出有希望的结果。这篇综述文章概述了HCC的免疫格局，以了解ICI的疗效及其局限性，随后回顾了ICI与HCC局部区域治疗联合疗法的现状。
