Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland.
Department of Oncology, University of Lausanne and Lausanne University Hospital Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
Front Immunol. 2022 Sep 20;13:976628. doi: 10.3389/fimmu.2022.976628. eCollection 2022.
Despite the tremendous success of adoptive T-cell therapies (ACT) in fighting certain hematologic malignancies, not all patients respond, a proportion experience relapse, and effective ACT of most solid tumors remains elusive. In order to improve responses to ACT suppressive barriers in the solid tumor microenvironment (TME) including insufficient nutrient availability must be overcome. Here we explored how enforced expression of the high-affinity glucose transporter GLUT3 impacted tumor-directed T cells. Overexpression of GLUT3 in primary murine CD8 T cells enhanced glucose uptake and increased glycogen and fatty acid storage, and was associated with increased mitochondrial fitness, reduced ROS levels, higher abundance of the anti-apoptotic protein Mcl-1, and better resistance to stress. Importantly, GLUT3-OT1 T cells conferred superior control of B16-OVA melanoma tumors and, in this same model, significantly improved survival. Moreover, a proportion of treated mice were cured and protected from re-challenge, indicative of long-term T cell persistence and memory formation. Enforcing expression of GLUT3 is thus a promising strategy to improve metabolic fitness and sustaining CD8 T cell effector function in the context of ACT.
尽管过继性 T 细胞疗法（ACT）在治疗某些血液恶性肿瘤方面取得了巨大成功，但并非所有患者都有反应，一部分患者会复发，大多数实体瘤的有效 ACT 仍然难以实现。为了提高 ACT 的反应，必须克服实体瘤微环境（TME）中的抑制性障碍，包括营养物质的不足。在这里，我们研究了强制表达高亲和力葡萄糖转运蛋白 GLUT3 如何影响肿瘤定向 T 细胞。在原代小鼠 CD8 T 细胞中过表达 GLUT3 可增强葡萄糖摄取并增加糖原和脂肪酸储存，与增加线粒体适应性、降低 ROS 水平、增加抗凋亡蛋白 Mcl-1 的丰度以及更好地抵抗应激有关。重要的是，GLUT3-OT1 T 细胞可更好地控制 B16-OVA 黑色素瘤肿瘤，并且在相同模型中，可显著提高生存率。此外，一部分接受治疗的小鼠被治愈并免受再次挑战，这表明 T 细胞具有长期的持久性和记忆形成。因此，强制表达 GLUT3 是一种有前途的策略，可以改善代谢适应性，并在 ACT 背景下维持 CD8 T 细胞的效应功能。
