Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, 380 S. University Ave, Hill 316, Philadelphia, PA, 19104, USA.
Aging, Cancer, and Immuno-Oncology Program, NCI Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
Cancer Immunol Immunother. 2023 Apr;72(4):815-826. doi: 10.1007/s00262-022-03286-2. Epub 2022 Sep 5.
Immune suppressive factors of the tumor microenvironment (TME) undermine viability and exhaust the activities of the intratumoral cytotoxic CD8 + T lymphocytes (CTL) thereby evading anti-tumor immunity and decreasing the benefits of immune therapies. To counteract this suppression and improve the efficacy of therapeutic regimens, it is important to identify and understand the critical regulators within CD8 + T cells that respond to TME stress and tumor-derived factors. Here we investigated the regulation and importance of activating transcription factor-4 (ATF4) in CTL using a novel Atf4 mouse model lacking ATF4 specifically in CD8 + cells. Induction of ATF4 in CD8 + T cells occurred in response to antigenic stimulation and was further increased by exposure to tumor-derived factors and TME conditions. Under these conditions, ATF4 played a critical role in the maintenance of survival and activities of CD8 + T cells. Conversely, selective ablation of ATF4 in CD8 + T cells in mice rendered these Atf4 hosts prone to accelerated growth of implanted tumors. Intratumoral ATF4-deficient CD8 + T cells were under-represented compared to wild-type counterparts and exhibited impaired activation and increased apoptosis. These findings identify ATF4 as an important regulator of viability and activity of CD8 + T cells in the TME and argue for caution in using agents that could undermine these functions of ATF4 for anti-cancer therapies.
肿瘤微环境（TME）中的免疫抑制因子削弱了肿瘤内细胞毒性 CD8+T 淋巴细胞（CTL）的活力并使其耗竭，从而逃避了抗肿瘤免疫，并降低了免疫治疗的益处。为了抵消这种抑制作用并提高治疗方案的疗效，重要的是要识别和了解 CD8+T 细胞内对 TME 应激和肿瘤衍生因子作出反应的关键调节因子。在这里，我们使用一种新型的 Atf4 小鼠模型，该模型特异性地在 CD8+细胞中缺乏 ATF4，研究了 CTL 中激活转录因子 4（ATF4）的调节和重要性。ATF4 在 CD8+T 细胞中响应抗原刺激而被诱导，并且通过暴露于肿瘤衍生因子和 TME 条件而进一步增加。在这些条件下，ATF4 在维持 CD8+T 细胞的存活和活性方面起着关键作用。相反，在小鼠中选择性地消除 CD8+T 细胞中的 ATF4 会使这些 Atf4 宿主更容易加速植入肿瘤的生长。与野生型相比，肿瘤内 ATF4 缺陷型 CD8+T 细胞的代表性降低，并且表现出激活受损和凋亡增加。这些发现确定了 ATF4 是 TME 中 CD8+T 细胞活力和活性的重要调节因子，并呼吁在使用可能破坏 ATF4 这些功能的抗肿瘤治疗药物时要谨慎。
