CD39 expression defines exhausted CD4+ T cells associated with poor survival and immune evasion in human gastric cancer

IF 4.6 2区 医学 Q2 IMMUNOLOGY Clinical & Translational Immunology Pub Date : 2024-03-18 DOI:10.1002/cti2.1499
Zhen-quan Duan, Yu-xian Li, Yuan Qiu, Yang Shen, Ying Wang, Yuan-yuan Zhang, Bao-hang Zhu, Xiao-hong Yu, Xue-ling Tan, Weisan Chen, Yuan Zhuang, Ping Cheng, Wei-jun Zhang, Quan-ming Zou, Dai-yuan Ma, Liu-sheng Peng
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Abstract

Objectives

CD4+ T cell helper and regulatory function in human cancers has been well characterised. However, the definition of tumor-infiltrating CD4+ T cell exhaustion and how it contributes to the immune response and disease progression in human gastric cancer (GC) remain largely unknown.

Methods

A total of 128 GC patients were enrolled in the study. The expression of CD39 and PD-1 on CD4+ T cells in the different samples was analysed by flow cytometry. GC-infiltrating CD4+ T cell subpopulations based on CD39 expression were phenotypically and functionally assessed. The role of CD39 in the immune response of GC-infiltrating T cells was investigated by inhibiting CD39 enzymatic activity.

Results

In comparison with CD4+ T cells from the non-tumor tissues, significantly more GC-infiltrating CD4+ T cells expressed CD39. Most GC-infiltrating CD39+CD4+ T cells exhibited CD45RACCR7 effector–memory phenotype expressing more exhaustion-associated inhibitory molecules and transcription factors and produced less TNF-α, IFN-γ and cytolytic molecules than their CD39CD4+ counterparts. Moreover, ex vivo inhibition of CD39 enzymatic activity enhanced their functional potential reflected by TNF-α and IFN-γ production. Finally, increased percentages of GC-infiltrating CD39+CD4+ T cells were positively associated with disease progression and patients' poorer overall survival.

Conclusion

Our study demonstrates that CD39 expression defines GC-infiltrating CD4+ T cell exhaustion and their immunosuppressive function. Targeting CD39 may be a promising therapeutic strategy for treating GC patients.

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CD39 表达确定了与人类胃癌生存率低和免疫逃避相关的 CD4+ T 细胞衰竭情况
目标 CD4+ T 细胞在人类癌症中的辅助和调节功能已得到很好的描述。然而,肿瘤浸润性 CD4+ T 细胞衰竭的定义以及它如何导致人类胃癌(GC)的免疫反应和疾病进展在很大程度上仍是未知数。 方法 本研究共纳入了 128 例胃癌患者。流式细胞术分析了不同样本中 CD4+ T 细胞上 CD39 和 PD-1 的表达。根据 CD39 表达对 GC 浸润 CD4+ T 细胞亚群进行了表型和功能评估。通过抑制 CD39 酶的活性,研究了 CD39 在 GC 浸润 T 细胞免疫反应中的作用。 结果 与来自非肿瘤组织的 CD4+ T 细胞相比,表达 CD39 的 GC 浸润 CD4+ T 细胞明显增多。大多数GC浸润的CD39+CD4+ T细胞表现出CD45RA-CCR7-效应记忆表型,表达更多衰竭相关抑制分子和转录因子,产生的TNF-α、IFN-γ和细胞溶解分子少于CD39-CD4+同类细胞。此外,体内抑制 CD39 酶活性可提高它们的功能潜力,这体现在 TNF-α 和 IFN-γ 的产生上。最后,GC 浸润 CD39+CD4+ T 细胞百分比的增加与疾病进展和患者较差的总生存率呈正相关。 结论 我们的研究表明,CD39 的表达决定了 GC 浸润 CD4+ T 细胞的衰竭及其免疫抑制功能。以 CD39 为靶点可能是治疗 GC 患者的一种有前途的治疗策略。
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来源期刊
Clinical & Translational Immunology
Clinical & Translational Immunology Medicine-Immunology and Allergy
CiteScore
12.00
自引率
1.70%
发文量
77
审稿时长
13 weeks
期刊介绍: Clinical & Translational Immunology is an open access, fully peer-reviewed journal devoted to publishing cutting-edge advances in biomedical research for scientists and physicians. The Journal covers fields including cancer biology, cardiovascular research, gene therapy, immunology, vaccine development and disease pathogenesis and therapy at the earliest phases of investigation.
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