新兴免疫阻断分子在肝细胞癌发生发展中的作用

陶莹; 廖长秀

doi:10.3969/j.issn.1001-5256.2023.04.031

新兴免疫阻断分子在肝细胞癌发生发展中的作用

DOI: 10.3969/j.issn.1001-5256.2023.04.031

陶莹^{1, 2},
廖长秀^1, , ,

1.
右江民医学院药学院，广西百色 533000
2.
右江民族医学院基础医学院，广西百色 533000

基金项目:

国家自然科学基金 (81660642);

广西学位与研究生教育改革课题 (JGY2022278)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：陶莹负责选题，拟定写作思路，论文初稿撰写及修改；廖长秀负责选题，拟定写作思路，论文审阅及修订。

详细信息

通信作者:
廖长秀，liaozhangxiu@163.com (ORCID: 0000-0001-5130-0642)

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出版历程
- 收稿日期: 2022-08-03
- 录用日期: 2022-09-07
- 出版日期: 2023-04-20

Role of new potential immune blocking molecules in the development and progression of hepatocellular carcinoma

Ying TAO^{1, 2},
Zhangxiu LIAO^{1
, ,
,}

1.
School of Pharmacy, Youjiang Medical University for Nationalities, Bose, Guangxi 533000, China
2.
School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Bose, Guangxi 533000, China

Research funding:

National Natural Science Foundation of China (81660642);

Degree and Graduate Education Reform Project in Guangxi (JGY2022278)

More Information

Corresponding author: LIAO Zhangxiu, liaozhangxiu@163.com (ORCID: 0000-0001-5130-0642)

摘要

摘要: 肝细胞癌(HCC)是世界范围内最常见的恶性肿瘤之一。程序性死亡受体1及其配体和细胞毒T淋巴细胞相关蛋白4等免疫检查点抑制剂的面世为HCC的治疗带来了重大突破。但由于HCC为高异质性肿瘤，单药治疗仅对少部分患者有效且可能因耐药而无法持久获益，因此仍需探索新的免疫检查点抑制剂在HCC防治中的潜力。本文分析和归纳了新型免疫检查点T淋巴细胞免疫球蛋白和免疫受体酪氨酸抑制基序结构域(TIGIT)、T淋巴细胞激活抑制物免疫球蛋白可变区结构域(VISTA)、B和T淋巴细胞弱化因子(BTLA)及含V-set域T淋巴细胞激活抑制因子(B7-H4)的生物学特性以及在HCC癌组织中的表达与功能。分析表明TIGIT、VISTA、BTLA和B7-H4在HCC癌组织中高表达，与HCC患者预后差相关，靶向阻断相应通路可有效抑制HCC进展，是极具潜力的肿瘤治疗靶点，深入研究可为HCC免疫治疗提供新方向。
- 癌, 肝细胞 /
- 免疫抑制剂 /
- 分子靶向治疗
Abstract: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors around the world. The emergence of immune checkpoint inhibitors targeting programmed death-1/programmed death-ligand 1 and cytotoxic T lymphocyte-associated antigen-4 has brought great breakthroughs in the treatment of HCC. However, since HCC is a type of tumor with high heterogeneity, monotherapy is only effective for a small number of patients and may not be able to achieve long-lasting benefits due to drug resistance, and therefore, it is necessary to explore the potential of new immune checkpoint inhibitors in the prevention and treatment of HCC. This article analyzes and summarizes the biological characteristics of the new immune checkpoints T cell immunoglobulin and ITIM domain (TIGIT), V-domain immunoglobulin suppressor of T-cell activation (VISTA), B and T lymphocyte attenuator (BTLA), and B7 homologous protein-4 (B7-H4) and their expression and function in HCC. The analysis shows that TIGIT, VISTA, BTLA, and B7-H4 are highly expressed in HCC tissue and are associated with the prognosis of HCC patients, and targeted blocking of corresponding pathways can effectively inhibit the progression of HCC, suggesting that these molecules are potential targets for tumor treatment and that in-depth studies can provide new directions for HCC immunotherapy.
- Carcinoma, Hepatocellular /
- Immunosuppressive Agents /
- Molecular Targeted Therapy

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图 1 免疫检查点及其抑制剂对HCC的影响

注：CD8⁺T淋巴细胞表达的免疫检查点受体与HCC细胞表面的相应配体结合，直接抑制了CD8⁺T淋巴细胞活性，而高表达免疫检查点的调节性T淋巴细胞(Treg)与HCC细胞配体结合后通过释放IL-6、IL-10间接抑制CD8⁺T淋巴细胞增殖，进一步促进HCC的发生发展；单克隆抗体通过结合肿瘤表面配体或T淋巴细胞表面的免疫检查点，阻断配体与CD8⁺T淋巴细胞的受体结合，解除CD8⁺T淋巴细胞的免疫抑制，恢复机体清除HCC的能力。

Figure 1. The effects of immunocheckpoint and their inhibitors on HCC

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表 1 新兴免疫检查点抑制剂的在研临床试验

Table 1. Clinical trials on new potential immune checkpoint inhibitors

靶点	临床试验编号	药物	联合用药	疾病状况	阶段	项目状态	招募人数(例)	最新发布时间
TIGIT	NCT05390528	HLX301	单药治疗	晚期实体瘤	Ⅰ/Ⅱ	招募中	30	2022-05-25
	NCT05289492	EOS884448	伊伯多胺	多发性骨髓瘤	Ⅰ/Ⅱ	招募中	162	2022-06-21
	NCT05329766	度纳利单抗	阿特珠单抗 (抗PD-L1)	胃肠道恶性肿瘤	Ⅱ	招募中	120	2022-07-27
	NCT05483400	Tiragolumab	阿特珠单抗	头颈部肿瘤	Ⅱ	未招募	97	2022-08-02
	NCT05327530	Avelumab	M6223 (抗TIGIT)	尿路上皮癌	Ⅱ	招募中	252	2022-08-05
	NCT05417321	HB0036	单药治疗	晚期实体肿瘤	Ⅰ/Ⅱ	招募中	80	2022-08-30
VISTA	NCT02671955	JNJ-61610588	单药治疗	晚期癌症	Ⅰ	招募终止	12	2018-03-27
	NCT02812875	CA-170	单药治疗	晚期实体肿瘤或淋巴瘤	Ⅰ	招募完成	71	2020-06-22
	NCT05082610	HMBD-002	派姆单抗 (抗PD-1)	晚期实体瘤	Ⅰ	招募中	240	2022-06-10
	NCT04475523	CI-8993	单药治疗	晚期实体瘤	Ⅰ	招募中	50	2022-07-20
BTLA	NCT04773951	JS004	特瑞普利单抗 (抗PD-1)	黑色素瘤、肾癌、尿路上皮癌	Ⅰ	招募中	156	2021-08-24
	NCT05000684	JS004	特瑞普利单抗	晚期肺癌	Ⅰ/Ⅱ	招募中	66	2021-09-08
	NCT04477772	JS004	JS001	晚期实体瘤	Ⅰ	招募中	170	2022-04-21
	NCT04137900	JS004	特瑞普利单抗	晚期不可切除实体瘤	Ⅰ	招募中	499	2022-06-22
	NCT05427396	JS004	特瑞普利单抗	晚期实体瘤	Ⅰ	未招募	140	2022-06-22
	NCT04929080	JS004	单药治疗	头颈部肿瘤	Ⅰ/Ⅱ	招募中	149	2022-07-18
B7-H4	NCT03514121	FPA150	派姆单抗	晚期实体瘤	Ⅰ	招募完成	95	2022-01-11
	NCT05263479	HS-20089	单药治疗	晚期实体瘤	Ⅰ	招募中	177	2022-03-02
	NCT05180474	GEN1047	单药治疗	非小细胞肺癌	Ⅰ	招募中	220	2022-07-27
	NCT05067972	PF-07260437	单药治疗	卵巢癌、子宫内膜癌、乳腺癌	Ⅰ	招募中	100	2022-08-19
	NCT05194072	SGN-B7H4V	单药治疗	胆道癌	Ⅰ	招募中	355	2022-08-26

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