Targeting PD-1 and CD85j can restore intratumoral CD4+ GzmB+ T-cell functions to combat MHC-II-expressing tumors.

IF 10.3 1区 医学 Q1 IMMUNOLOGY
Boyu Wang, Xu Wang, Tianlai Wang, Kelin Meng, Taiyan Yu, Yu Xi, Shaojie Hu, Hui Xiong, Rirong Qu, Zhiwei Yuan, Xue Wang, Chenxi Zeng, Wenbin Zou, Yitao Tian, Yixin Cai, Shengling Fu, Xiangning Fu, Lequn Li
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引用次数: 0

Abstract

Background: A subset of CD4+ T cells with cytotoxic activity has been identified, and these cells exert their effects by expressing perforin and granzymes. Despite the progress made in characterizing cytotoxic CD4+ T cells in various diseases, the status of cytotoxic CD4+ T cells in non-small cell lung cancer (NSCLC) and the underlying mechanisms involved in promoting intratumoral cytotoxic CD4+ T-cell activation remain unclear.

Methods: We used flow cytometry to examine the phenotypic and functional properties of CD4+GzmB+ T cells in the peripheral blood and tumor tissues of patients with NSCLC. Loss-of-function analyses and RNA sequencing were used to identify the underlying mechanisms involved in the effects of interleukin (IL)-15 on the restoration of CD4+GzmB+ T-cell function in vitro. A patient-derived lung cancer explant model and an animal model were used to verify the effects of immune checkpoint inhibitors on CD4+GzmB+ T-cell activation.

Results: In patients with NSCLC, impaired cytolytic function of tumor-infiltrated granzyme B (GzmB)-expressing CD4+ T cells was restored by IL-15 through activation of the AKT-FOXO1-T-bet axis. Moreover, IL-15 stimulation increased solute carrier family 7 member 5 (SLC7A5) expression in CD4+GzmB+ T cells in an Protein Kinase B (AKT)-dependent manner, and inhibition of SLC7A5 abrogated the effect of IL-15 on CD4+GzmB+ T cells. Additionally, we showed that the immune checkpoint molecules programmed cell death-1 (PD-1) and CD85j were mutually exclusively expressed in CD4+GzmB+ T cells and that dual targeting of PD-1 and CD85j enhanced the effector function of CD4+GzmB+ T cells by activating the AKT pathway. Notably, tumor cells expressing major histocompatibility complex (MHC)-II and IL-15 determine the effectiveness of CD4+GzmB+ T-cell-mediated antitumor immunity in response to immunotherapy.

Conclusions: Our study demonstrated that tumor-infiltrating CD4+GzmB+ T cells fail to eliminate tumors. Dual blockade of PD-1 and CD85j alongside IL-15 restores the effector function of CD4+GzmB+ T cells and drives CD4+GzmB+ T-cell transformation in the tumor microenvironment to combat MHC-II-expressing tumors.

靶向PD-1和CD85j可恢复瘤内CD4+ GzmB+ t细胞功能,对抗表达mhc - ii的肿瘤。
背景:CD4+ T细胞的一个亚群具有细胞毒性活性,这些细胞通过表达穿孔素和颗粒酶来发挥作用。尽管在各种疾病中细胞毒性CD4+ T细胞的表征方面取得了进展,但细胞毒性CD4+ T细胞在非小细胞肺癌(NSCLC)中的状态以及促进瘤内细胞毒性CD4+ T细胞活化的潜在机制仍不清楚。方法:采用流式细胞术检测非小细胞肺癌患者外周血和肿瘤组织中CD4+GzmB+ T细胞的表型和功能特性。功能丧失分析和RNA测序用于鉴定白细胞介素(IL)-15对体外CD4+GzmB+ t细胞功能恢复影响的潜在机制。采用患者源性肺癌外植体模型和动物模型验证免疫检查点抑制剂对CD4+GzmB+ t细胞活化的影响。结果:在NSCLC患者中,IL-15通过激活akt - fox01 -T-bet轴恢复肿瘤浸润颗粒酶B (GzmB)表达CD4+ T细胞的细胞溶解功能受损。此外,IL-15刺激增加了溶质载体家族7成员5 (SLC7A5)在CD4+GzmB+ T细胞中的表达,并以蛋白激酶B (AKT)依赖的方式增加,抑制SLC7A5消除了IL-15对CD4+GzmB+ T细胞的影响。此外,我们发现免疫检查点分子程序性细胞死亡-1 (PD-1)和CD85j在CD4+GzmB+ T细胞中相互排他性表达,并且PD-1和CD85j的双重靶向通过激活AKT通路增强了CD4+GzmB+ T细胞的效应功能。值得注意的是,表达主要组织相容性复合体(MHC)-II和IL-15的肿瘤细胞决定了CD4+GzmB+ t细胞介导的抗肿瘤免疫在免疫治疗应答中的有效性。结论:我们的研究表明肿瘤浸润性CD4+GzmB+ T细胞不能消除肿瘤。PD-1和CD85j与IL-15的双重阻断恢复了CD4+GzmB+ T细胞的效应功能,并驱动CD4+GzmB+ T细胞在肿瘤微环境中的转化,以对抗表达mhc - ii的肿瘤。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal for Immunotherapy of Cancer
Journal for Immunotherapy of Cancer Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
17.70
自引率
4.60%
发文量
522
审稿时长
18 weeks
期刊介绍: The Journal for ImmunoTherapy of Cancer (JITC) is a peer-reviewed publication that promotes scientific exchange and deepens knowledge in the constantly evolving fields of tumor immunology and cancer immunotherapy. With an open access format, JITC encourages widespread access to its findings. The journal covers a wide range of topics, spanning from basic science to translational and clinical research. Key areas of interest include tumor-host interactions, the intricate tumor microenvironment, animal models, the identification of predictive and prognostic immune biomarkers, groundbreaking pharmaceutical and cellular therapies, innovative vaccines, combination immune-based treatments, and the study of immune-related toxicity.
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