TIM-3 Dictates Functional Orientation of the Immune Infiltrate in Ovarian Cancer
TIM-3 Dictates Functional Orientation of the Immune Infiltrate in Ovarian Cancer
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DOI：
10.1158/1078-0432.ccr-18-4175
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发表时间：
2019-08-01
影响因子：
11.5
通讯作者：
Spisek, Radek
中科院分区：
文献类型：
--
作者：
Fucikova, Jitka;Rakova, Jana;Spisek, Radek
目的：在多种肿瘤学环境中，恶性细胞表达共抑制配体PD-L1和表达共抑制受体（如PD-1、CTLA 4、LAG-3或TIM-3）的免疫细胞浸润肿瘤可传递预后或预测信息。相反，肿瘤微环境的这些特征对高级别浆液性癌（HGSC）患者疾病结局的影响仍存在争议。我们利用80例未经化疗的HGSC患者的回顾性队列研究PD-L1表达和CD 8（+）T细胞、CD 20（+）B细胞、DC-LAMP（+）树突状细胞以及PD-1（+）的肿瘤浸润，CTLA 4（+）、LAG-3（+）和TIM-3（+）细胞与预后和肿瘤微环境功能定位的关系。对新鲜切除的HGSC样本的第二个前瞻性队列进行了转录组学和功能研究，补充了MHC数据。结果：HGSC微环境中高水平的PD-L1和高密度的PD-1（+）细胞与免疫结构密切相关，免疫结构的特征是强大的TH 1极化和细胞毒性方向，使其具有上级临床益处。此外，PD-1（+）TIM-3（+）CD 8（+）T细胞呈现出功能衰竭的所有特征，并与不良疾病结局相关。然而，尽管PD-L1水平和TIM-3（+）细胞的肿瘤浸润改善了基于肿瘤内CD 8（+）T细胞丰度的患者分层，但PD-1（+）细胞的数量未能做到这一点。结论：我们的数据表明，PD-L1和TIM-3分别构成了针对HGSC的活性和抑制免疫应答的特异性相关生物标志物。
Purpose: In multiple oncological settings, expression of the coinhibitory ligand PD-L1 by malignant cells and tumor infiltration by immune cells expressing coinhibitory receptors such as PD-1, CTLA4, LAG-3, or TIM-3 conveys prognostic or predictive information. Conversely, the impact of these features of the tumor microenvironment on disease outcome among high-grade serous carcinoma (HGSC) patients remains controversial.Experimental Design: We harnessed a retrospective cohort of 80 chemotherapy-naive HGSC patients to investigate PD-L1 expression and tumor infiltration by CD8(+) T cells, CD20(+) B cells, DC-LAMP(+) dendritic cells as well as by PD-1(+), CTLA4(+), LAG-3(+), and TIM-3(+) cells in relation with prognosis and function orientation of the tumor microenvironment. IHC data were complemented with transcriptomic and functional studies on a second prospective cohort of freshly resected HGSC samples. In silico analysis of publicly available RNA expression data from 308 HGSC samples was used as a confirmatory approach.Results: High levels of PD-L1 and high densities of PD-1(+) cells in the microenvironment of HGSCs were strongly associated with an immune contexture characterized by a robust TH1 polarization and cytotoxic orientation that enabled superior clinical benefits. Moreover, PD-1(+) TIM-3(+) CD8(+) T cells presented all features of functional exhaustion and correlated with poor disease outcome. However, although PD-L1 levels and tumor infiltration by TIM-3(+) cells improved patient stratification based on the intratumoral abundance of CD8(+) T cells, the amount of PD-1(+) cells failed to do so.Conclusions: Our data indicate that PD-L1 and TIM-3 constitute prognostically relevant biomarkers of active and suppressed immune responses against HGSC, respectively.