Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Nat Commun. 2024 Nov 28;15(1):10312. doi: 10.1038/s41467-024-54569-4.
In solid cancers, T cells typically function as cytotoxic effectors to limit tumor growth, prompting therapies that capitalize upon this antineoplastic property (immune checkpoint inhibition; ICI). Unfortunately, ICI treatments have been largely ineffective for high-grade brain tumors (gliomas; HGGs). Leveraging several single-cell RNA sequencing datasets, we report greater CD8 exhausted T cells in human pediatric low-grade gliomas (LGGs) relative to adult and pediatric HGGs. Using several preclinical mouse LGG models (Nf1-OPG mice), we show that these PD1/TIGIT CD8 exhausted T cells are restricted to the tumor tissue, where they express paracrine factors necessary for OPG growth. Importantly, ICI treatments with α-PD1 and α-TIGIT antibodies attenuate Nf1-OPG tumor proliferation through suppression of two cytokine (Ccl4 and TGFβ)-mediated mechanisms, rather than by T cell-mediated cytotoxicity, as well as suppress monocyte-controlled T cell chemotaxis. Collectively, these findings establish a previously unrecognized function for CD8 exhausted T cells as specialized regulators of LGG maintenance.
在实体瘤中，T 细胞通常作为细胞毒性效应物发挥作用，以限制肿瘤生长，促使人们利用这种抗肿瘤特性（免疫检查点抑制；ICI）开发治疗方法。不幸的是，ICI 治疗在很大程度上对高级别脑肿瘤（神经胶质瘤；HGGs）无效。利用几个单细胞 RNA 测序数据集，我们报告说，与成人和儿科 HGG 相比，人类小儿低级别神经胶质瘤（LGGs）中存在更多的 CD8 耗竭 T 细胞。使用几种临床前小鼠 LGG 模型（NF1-OPG 小鼠），我们表明这些 PD1/TIGIT CD8 耗竭 T 细胞仅限于肿瘤组织，在那里它们表达 OPG 生长所需的旁分泌因子。重要的是，用α-PD1 和α-TIGIT 抗体进行 ICI 治疗可通过抑制两种细胞因子（Ccl4 和 TGFβ）介导的机制来减弱 NF1-OPG 肿瘤的增殖，而不是通过 T 细胞介导的细胞毒性，以及抑制单核细胞控制的 T 细胞趋化性。总之，这些发现确立了 CD8 耗竭 T 细胞作为 LGG 维持的专门调节剂的先前未被认识到的功能。
