Spatial distribution and functional analysis define the action pathway of Tim-3/Tim-3 ligands in tumor development

被引：10

作者：

Wang, Tixiao ^{[1
,2
]}

Zhang, Jie ^{[1
,2
]}

Li, Na ^{[1
,2
]}

Li, Mengzhen ^{[1
,2
]}

Ma, Shuaiya ^{[1
,2
]}

Tan, Siyu ^{[1
,2
]}

Guo, Xiaowei ^{[1
,2
]}

Wang, Zehua ^{[1
,2
]}

Wu, Zhuanchang ^{[1
,2
]}

Gao, Lifen ^{[1
,2
]}

Ma, Chunhong ^{[1
,2
,3
]}

Liang, Xiaohong ^{[1
,2
,3
]}

机构：

[1] Shandong Univ, Key Lab Expt Teratol, Minist Educ,Sch Basic Med Sci, Key Lab Infect & Immun Shandong Prov,Cheeloo Med, Jinan 250012, Shandong, Peoples R China

[2] Shandong Univ, Cheeloo Med Coll, Sch Basic Med Sci, Dept Immunol, Jinan 250012, Shandong, Peoples R China

[3] Shandong Collaborat Innovat Ctr Technol & Equipme, Jinan 250012, Shandong, Peoples R China

来源：

MOLECULAR THERAPY | 2022年 / 30卷 / 03期

基金：

中国国家自然科学基金;

关键词：

T-CELL EXHAUSTION; LUNG-CANCER; NK CELLS; TIM-3; EXPRESSION; PD-1; COEXPRESSION; PROGRESSION; RESISTANCE; PROMOTION;

D O I：

10.1016/j.ymthe.2021.11.015

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

The spatial organization of immune cells within the tumor microenvironment (TME) largely determines the anti-tumor immunity and also highly predicts tumor progression and ther-apeutic response. Tim-3 is a well-accepted immune checkpoint and plays multifaceted immunoregulatory roles via interaction with distinct Tim-3 ligands (Tim-3L), showing great potential as an immunotherapy target. However, the cell sociology mediated by Tim-3/Tim-3L and their contribution to tumor development remains elusive. Here, we analyzed the spatial distribution of Tim-3/Tim-3L in TME using multiplex fluores-cence staining and revealed that despite the increased Tim-3 expression in various tumor-infiltrated lymphocytes, Tim-3(+)CD4(+) cells were more accumulated in parenchymal/tumor region compared with stromal region and exhibited more close association with patient survival. Strikingly, CD4 T cells sur-rounding Tim-3L(+) cells expressed higher Tim-3 than other cells in cancerous tissues. In vivo studies confirmed that depletion of CD4 T cells completely abrogated the inhibition of tumor growth and metastasis, as well as the functional improvement of CD8 T and NK, mediated by Tim-3 blockade, which was further validated in peripheral lymphocytes from patients with hepatocellular carcinoma. In conclusion, our findings un-ravel the importance of CD4 T cells in Tim-3/Tim-3L-mediated immunosuppression and provide new thoughts for Tim-3 targeted cancer immunotherapy.

引用

页码：1135 / 1148

页数：14

共 48 条

[31] T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions [J].