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系统分析 CD39、CD103、CD137 和 PD-1 作为天然肿瘤抗原特异性 TIL 的生物标志物。

Systematic analysis of CD39, CD103, CD137, and PD-1 as biomarkers for naturally occurring tumor antigen-specific TILs.

机构信息

Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Center for Cellular Immunotherapies, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

出版信息

Eur J Immunol. 2022 Jan;52(1):96-108. doi: 10.1002/eji.202149329. Epub 2021 Sep 18.


DOI:10.1002/eji.202149329
PMID:34505280
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8755575/
Abstract

The detection of tumor-specific T cells in solid tumors is integral to interrogate endogenous antitumor responses and to advance downstream therapeutic applications. Multiple biomarkers are reported to identify endogenous tumor-specific tumor-infiltrating lymphocytes (TILs), namely CD137, PD-1, CD103, and CD39; however, a direct comparison of these molecules has yet to be performed. We evaluated these biomarkers in primary human ovarian tumor samples using single-cell mass cytometry to compare their relative phenotypic profiles, and examined their response to autologous tumor cells ex vivo. PD-1 , CD103 , and CD39 TILs all contain a CD137 cell subset, while CD137 TILs highly co-express the aforementioned markers. CD137 TILs exhibit the highest expression of cytotoxic effector molecules compared to PD-1 , CD103 , or CD39 TILs. Removal of CD137 cells from PD-1 , CD103 , or CD39 TILs diminish their IFN-γ secretion in response to autologous tumor cell stimulation, while CD137 TILs maintain high HLA-dependent IFN-γ secretion. CD137 TILs exhibited an exhausted phenotype but with CD28 co-expression, suggesting possible receptiveness to reinvigoration via immune checkpoint blockade. Together, our findings demonstrate that the antitumor abilities of PD-1 , CD103 , and CD39 TILs are mainly derived from a subset of CD137-expressing TILs, implicating CD137 as a more selective biomarker for naturally occurring tumor-specific TILs.

摘要

在实体瘤中检测肿瘤特异性 T 细胞对于探究内源性抗肿瘤反应并推进下游治疗应用至关重要。已有多种生物标志物被报道可用于鉴定内源性肿瘤特异性肿瘤浸润淋巴细胞(TILs),包括 CD137、PD-1、CD103 和 CD39;然而,这些分子之间的直接比较尚未进行。我们使用单细胞质谱流式细胞术评估了这些生物标志物在原发性人卵巢肿瘤样本中的表达,以比较它们相对的表型特征,并研究它们对外源肿瘤细胞的反应。PD-1、CD103 和 CD39 TILs 均包含 CD137 细胞亚群,而 CD137 TILs 高度共表达上述标志物。与 PD-1、CD103 或 CD39 TILs 相比,CD137 TILs 表达更高水平的细胞毒性效应分子。从 PD-1、CD103 或 CD39 TILs 中去除 CD137 细胞会降低其对外源肿瘤细胞刺激的 IFN-γ 分泌,而 CD137 TILs 则保持高水平的 HLA 依赖性 IFN-γ 分泌。CD137 TILs 表现出耗竭表型,但伴有 CD28 共表达,提示其可能通过免疫检查点阻断重新激活。综上所述,我们的研究结果表明,PD-1、CD103 和 CD39 TILs 的抗肿瘤能力主要源自 CD137 表达 TILs 的一个亚群,表明 CD137 是自然发生的肿瘤特异性 TILs 的更具选择性的生物标志物。

相似文献

[1]
Systematic analysis of CD39, CD103, CD137, and PD-1 as biomarkers for naturally occurring tumor antigen-specific TILs.

Eur J Immunol. 2022-1

[2]
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[3]
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[4]
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[5]
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[6]
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[7]
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[8]
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[9]
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[10]
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引用本文的文献

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Neoantigen-driven personalized tumor therapy: An update from discovery to clinical application.

Chin Med J (Engl). 2025-9-5

[2]
Beyond the tumor microenvironment: Orchestrating systemic T‑cell response for next‑generation cancer immunotherapy (Review).

Int J Oncol. 2025-7

[3]
A therapeutic regimen using neoantigen-specific TCR-T cells for HLA-A*2402-positive solid tumors.

EMBO Mol Med. 2025-2

[4]
The Potential of PD-1 and PD-L1 as Prognostic and Predictive Biomarkers in Colorectal Adenocarcinoma Based on TILs Grading.

Curr Oncol. 2024-11-25

[5]
Clinical-scale, modular manufacturing of tumor-reactive TILs using a closed and automated culture system.

Front Immunol. 2024-12-9

[6]
CD39 Is Expressed on Functional Effector and Tissue-resident Memory CD8+ T Cells.

J Immunol. 2024-9-1

[7]
[Establishment of a 21-color Panel for the Detection of Immune Cell Subsets 
in Human Non-small Cell Lung Cancer Tumor Tissues with Flow Cytometry].

Zhongguo Fei Ai Za Zhi. 2024-1-20

[8]
CD137+ tumor infiltrating lymphocytes predicts ovarian cancer survival.

Gynecol Oncol. 2024-5

[9]
Inosine induces stemness features in CAR-T cells and enhances potency.

Cancer Cell. 2024-2-12

[10]
Heterogeneity-induced NGF-NGFR communication inefficiency promotes mitotic spindle disorganization in exhausted T cells through PREX1 suppression to impair the anti-tumor immunotherapy with PD-1 mAb in hepatocellular carcinoma.

Cancer Med. 2024-2

本文引用的文献

[1]
FS222, a CD137/PD-L1 Tetravalent Bispecific Antibody, Exhibits Low Toxicity and Antitumor Activity in Colorectal Cancer Models.

Clin Cancer Res. 2020-8-1

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Nat Rev Immunol. 2018-10

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Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors.

Nat Commun. 2018-7-13

[10]
Epigenomic-Guided Mass Cytometry Profiling Reveals Disease-Specific Features of Exhausted CD8 T Cells.

Immunity. 2018-5-15

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