Increased co-expression of PD1 and TIM3 is associated with poor prognosis and immune microenvironment heterogeneity in gallbladder cancer.
Increased co-expression of PD1 and TIM3 is associated with poor prognosis and immune microenvironment heterogeneity in gallbladder cancer.
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DOI：
10.1186/s12967-023-04589-3
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发表时间：
2023-10-12
影响因子：
7.4
通讯作者：
Li, Wenbin
中科院分区：
文献类型：
--
作者：
He, Xing;Peng, Yaorong;He, Gui;Ye, Huilin;Liu, Liqiang;Zhou, Qixian;Shi, Juanyi;Fu, Sha;Wang, Jie;Zhou, Zhenyu;Li, Wenbin
关键词：
免疫检查点抑制剂治疗胆囊癌（GBC）的有效性仍然不令人满意。最近，已经确定了几个新的免疫检查点。然而，探索GBC中这些免疫检查点的研究是有限的。在这项研究中，我们的目的是研究各种免疫检查点的表达模式和临床意义，并进一步表征GBC中免疫组分的空间和定量异质性。我们采用单一和多重免疫组化来评估五种免疫检查点标志物和四种免疫细胞标志物在原发性肿瘤核心、肝浸润边缘和肝转移中的表达。随后，我们分析了它们之间的相互关系及其预后意义。我们观察到GBC中PD 1/TIM 3表达之间存在强正相关（R = 0.614，P < 0.001）。PD 1/TIM 3共表达在预测GBC患者术后不良预后方面具有协同作用。进一步分析发现，在CD 8 + T细胞高浸润的亚组中，PD 1/TIM 3的预后意义显著（P < 0.001）。多重免疫组织化学显示，PD 1 + TIM 3 + FOXP 3+细胞构成GBC组织中FOXP 3 + TIL的显著比例。此外，PD 1和TIM 3的共高表达与CD 8 + TIL在肝浸润边缘的积聚呈正相关。最后，我们的研究结果表明，与原发性肿瘤相比，肝转移瘤中免疫检查点的表达水平降低，免疫细胞浸润减少。PD 1/TIM 3共表达增加与GBC患者预后不良相关，并与GBC原发肿瘤与其肝浸润边缘或肝转移灶之间免疫微环境的异质性有关，这可能是GBC未来免疫治疗的潜在靶点。在线版本包含补充材料，可通过10.1186/s12967-023-04589-3获得。
The effectiveness of immune checkpoint inhibitors in treating gallbladder cancer (GBC) remains unsatisfactory. Recently, several new immune checkpoints have been identified. However, investigations exploring these immune checkpoints in GBC are limited. In this study, we aim to investigate the expression patterns and clinical implications of various immune checkpoints, and further characterize the spatial and quantitative heterogeneity of immune components in GBC. We employed single and multiplex immunohistochemistry to evaluate the expression of five immune checkpoint markers and four immune cell markers in the primary tumor core, hepatic invasion margin, and liver metastasis. Subsequently, we analyzed their interrelationships and their prognostic significance. We observed a robust positive correlation between PD1/TIM3 expression in GBC (R = 0.614, P < 0.001). The co-expression of PD1/TIM3 exhibited a synergistic effect in predicting poor prognosis among postoperative GBC patients. Further analysis revealed that the prognostic significance of PD1/TIM3 was prominent in the subgroup with high infiltration of CD8 + T cells (P < 0.001). Multiplex immunohistochemistry reveals that PD1 + TIM3 + FOXP3 + cells constitute a significant proportion of FOXP3 + TILs in GBC tissue. Moreover, the co-high expression of PD1 and TIM3 is positively correlated with the accumulation of CD8 + TILs at the hepatic invasion margin. Lastly, our findings indicated reduced expression levels of immune checkpoints and diminished immune cell infiltration in liver metastases compared to primary tumors. Increased co-expression of PD1/TIM3 is associated with poor prognosis in GBC patients and is related to the heterogeneity of immune microenvironment between GBC primary tumor and its hepatic invasion margin or liver metastases, which may be a potential target for future immunotherapy of GBC. The online version contains supplementary material available at 10.1186/s12967-023-04589-3.
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影响因子：
120.1
作者：
Kim, Tae Kon;Vandsemb, Esten N.;Chen, Lieping
通讯作者：
Chen, Lieping
影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
DOI：
10.1158/1078-0432.ccr-15-3071
发表时间：
2017-02-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Cheng H;Janakiram M;Borczuk A;Lin J;Qiu W;Liu H;Chinai JM;Halmos B;Perez-Soler R;Zang X
通讯作者：
Zang X
DOI：
10.1038/s41572-022-00403-4
发表时间：
2022-10-27
期刊：
Nature reviews. Disease primers
影响因子：
--
作者：
通讯作者：
--
影响因子：
11.2
作者：
Halama, Niels;Michel, Sara;Jaeger, Dirk
通讯作者：
Jaeger, Dirk