Characteristics and significance of tertiary lymphoid structures in oral cancer

doi:10.3877/cma.j.issn.1674-1366.2023.05.001

Abstract

Abstract:

Tertiary lymphoid structures (TLSs) are organized aggregates of immune cells that form postnatally in nonlymphoid tissues. TLSs are not found under physiological conditions but arise in the context of chronic inflammation, such as autoimmune diseases, chronic infection, and cancer. In the setting of cancer development, TLSs facilitate the influx of immune cells into the cancer site and have therefore attracted interest as a means of improving anticancer immunity and favorable treatment response in patients. In spite of their presumed importance, the drivers of TLSs formation in cancer and the contribution of these structures to intratumoral immune response remain incompletely understood. In this article, the biology of TLSs and their recent advances in oral cancer research were reviewed.

Key words: Tumor microenvironment, Mouth neoplasms, Carcinoma, squamous cell, Immunotherapy, Cancer immunology

Chenxi Li, Xiaorong Tan, Wei Wei, Muqiu Li, Zhongcheng Gong. Characteristics and significance of tertiary lymphoid structures in oral cancer[J]. Chinese Journal of Stomatological Research(Electronic Edition), 2023, 17(05): 315-321.

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References 55

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项目类别	结构/细胞	标志物
常见内容	高内皮微静脉	无特异性，MECA-79
	树突状细胞	DC-LAMP
	B细胞	CD20
	T细胞	CD3
可能组成部分	生发中心	Ki-67
	增殖性B细胞	Ki-67
	滤泡辅助性T细胞	CD4、CXCR5、CD40L、IL-21、IL-6
与TLS相关的其他标志物	趋化因子	CCL-2、3、4、5、8、18、19、21
	细胞毒性T细胞	CXCL-9、10、11、13
	调节性T细胞	CD8
	内皮细胞	FOXP3
	滤泡树突状细胞	CD31
	成熟B细胞	CD23

项目类别	结构/细胞	标志物
常见内容	高内皮微静脉	无特异性，MECA-79
	树突状细胞	DC-LAMP
	B细胞	CD20
	T细胞	CD3
可能组成部分	生发中心	Ki-67
	增殖性B细胞	Ki-67
	滤泡辅助性T细胞	CD4、CXCR5、CD40L、IL-21、IL-6
与TLS相关的其他标志物	趋化因子	CCL-2、3、4、5、8、18、19、21
	细胞毒性T细胞	CXCL-9、10、11、13
	调节性T细胞	CD8
	内皮细胞	FOXP3
	滤泡树突状细胞	CD31
	成熟B细胞	CD23

驱动方式	具体表现	参考文献
LTi细胞	LTi细胞是CD4⁺/CD3^-/CD45⁺先天性淋巴样细胞，表达RORγt和Id2转录因子，LTi细胞聚集后，依赖于TNF家族成员启动TLS形成的初始步骤。随后CCL19⁺和（或）CCL21⁺ FRC和CXCL13⁺ FDC共同调节表达相应CCR7和CXCR5的淋巴细胞募集到淋巴生态位，以及调控HEV的血管形成，从而允许形成T细胞区和B细胞区。	[17，18，19]
替代LTi细胞	Th17细胞、ILC3、CD8⁺ T细胞、自然杀伤细胞、B细胞和巨噬细胞均可能替代癌症中的LTi细胞，其中T细胞产生的IL-17可诱导基质细胞表达CXCL13和CCL19，从而促进淋巴组织的形成。但是，这些淋巴聚集物中的T和B细胞区没有间隔，且缺乏HEV。因此，通常认为这是不正常的TLS。	[20，21，22，23，24，25]
替代LTo细胞	肿瘤内CAF群可作为LTo细胞产生CXCL13、CCL19、CCL21等淋巴趋化因子和BAFF、IL-7、April等生存因素诱导形成TLS。	[14，23]

驱动方式	具体表现	参考文献
LTi细胞	LTi细胞是CD4⁺/CD3^-/CD45⁺先天性淋巴样细胞，表达RORγt和Id2转录因子，LTi细胞聚集后，依赖于TNF家族成员启动TLS形成的初始步骤。随后CCL19⁺和（或）CCL21⁺ FRC和CXCL13⁺ FDC共同调节表达相应CCR7和CXCR5的淋巴细胞募集到淋巴生态位，以及调控HEV的血管形成，从而允许形成T细胞区和B细胞区。	[17，18，19]
替代LTi细胞	Th17细胞、ILC3、CD8⁺ T细胞、自然杀伤细胞、B细胞和巨噬细胞均可能替代癌症中的LTi细胞，其中T细胞产生的IL-17可诱导基质细胞表达CXCL13和CCL19，从而促进淋巴组织的形成。但是，这些淋巴聚集物中的T和B细胞区没有间隔，且缺乏HEV。因此，通常认为这是不正常的TLS。	[20，21，22，23，24，25]
替代LTo细胞	肿瘤内CAF群可作为LTo细胞产生CXCL13、CCL19、CCL21等淋巴趋化因子和BAFF、IL-7、April等生存因素诱导形成TLS。	[14，23]

标志物分子	作用特点	参考文献
IL-7、LTβ、CXCL13	只有IL-7、LTβ、CXCL13在TLS⁺中的表达较TLS^-更强，而其余编码炎症细胞因子和趋化因子的基因如IL-1B、IL-6、TNF、IFNG、CXCL1、CXCL9、CXCL10、CXCL11、CCL2、CCL3、CCL5、CCL19和CCL21在新生TLS中未发现有明显改变。	[27]
CCL19、CCL21、CXCL12	包含TLS的主要标志物HEV⁺的标本中CCL19、CCL21、CXCL12的表达显著高于HEV^-的标本。	[38]
CCR7、LTβ、CTLA4、TIM3、LAG3	TCF7⁺ T细胞位于TLS内及周围，且TCF7⁺ T细胞组中TLS相关基因表达水平较高，其中CCR7、LTβ为高表达；CTLA4、TIM3、LAG3为低表达。	[39]
CCL20、CCR6	缺乏TLS即HEV^-的标本中CCL20出现高表达，CCL20招募表达CCR6的细胞及调节性T细胞，而肿瘤细胞也表达CCR6，因此CCL20被认为和肿瘤的出现及转移有关，阻碍抗肿瘤的免疫反应。是否可以据此推断如果在OSCC肿瘤标本中检测出CCL20则预示着TLS的消失及肿瘤的进展。	[40]

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