Yuna Jo, Ju A Shim, Jin Woo Jeong, Hyori Kim, So Min Lee, Juhee Jeong, Segi Kim, Sun-Kyoung Im, Donghoon Choi, Byung Ha Lee, Yun Hak Kim, Chi Dae Kim, Chan Hyuk Kim, Changwan Hong
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引用次数: 0
摘要
细胞毒性 T 淋巴细胞(CTL)在癌症排斥反应中发挥着至关重要的作用。然而,CTL 在具有免疫抑制作用的肿瘤微环境(TME)中会出现功能障碍和衰竭。虽然富含活性氧(ROS)的肿瘤微环境会削弱 CTL 的功能,但其潜在的分子机制仍鲜为人知。核因子-红细胞 2 相关-2(Nrf2)是 ROS 反应因子,与增加癌症进展的易感性有关。因此,我们研究了在富含 ROS 的 TME 下,Nrf2 如何参与 CD8+ T 细胞和嵌合抗原受体(CAR)-T 细胞的抗肿瘤反应。在这里,我们证明了Nrf2-/-小鼠的肿瘤生长受到显著控制,并通过T细胞耗竭逆转了肿瘤生长,并利用抗原特异性CD8+ T细胞的采纳转移模型进一步证实了T细胞中Nrf2的缺乏促进了抗肿瘤反应。Nrf2缺陷的CTL对ROS有抵抗力,其效应功能在TME中得以维持。此外,在实体瘤异种移植模型中,敲除人CAR-T细胞中的Nrf2可提高瘤内CAR-T细胞的存活率和功能,并有效控制肿瘤生长。ROS传感Nrf2抑制了T细胞的抗肿瘤反应,这表明Nrf2可能是T细胞免疫治疗实体瘤策略的潜在靶点。
Targeting ROS-sensing Nrf2 potentiates anti-tumor immunity of intratumoral CD8+ T and CAR-T cells.
Cytotoxic T lymphocytes (CTLs) play a crucial role in cancer rejection. However, CTLs encounter dysfunction and exhaustion in the immunosuppressive tumor microenvironment (TME). Although the reactive oxygen species (ROS)-rich TME attenuates CTL function, the underlying molecular mechanism remains poorly understood. The nuclear factor erythroid 2-related 2 (Nrf2) is the ROS-responsible factor implicated in increasing susceptibility to cancer progression. Therefore, we examined how Nrf2 is involved in anti-tumor responses of CD8+ T and chimeric antigen receptor (CAR) T cells in the ROS-rich TME. Here, we demonstrated that tumor growth in Nrf2-/- mice was significantly controlled and was reversed by T cell depletion and further confirmed that Nrf2 deficiency in T cells promotes anti-tumor responses using an adoptive transfer model of antigen-specific CD8+ T cells. Nrf2-deficient CTLs are resistant to ROS, and their effector functions are sustained in the TME. Furthermore, Nrf2 knockdown in human CAR-T cells enhanced the survival and function of intratumoral CAR-T cells in a solid tumor xenograft model and effectively controlled tumor growth. ROS-sensing Nrf2 inhibits the anti-tumor T cell responses, indicating that Nrf2 may be a potential target for T cell immunotherapy strategies against solid tumors.
期刊介绍:
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.