Human single cell RNA-sequencing reveals a targetable CD8+ exhausted T cell population that maintains mouse low-grade glioma growth

• Published in: Nature communications 2024-11, Vol.15 (1), p.10312-16
• Main Authors: Barakat, Rasha, Chatterjee, Jit, Mu, Rui, Qi, Xuanhe, Gu, Xingxing, Smirnov, Igor, Cobb, Olivia, Gao, Karen, Barnes, Angelica, Kipnis, Jonathan, Gutmann, David H.
• Format: Article
• Language: English
• Subjects: 13/31; 13/51; 45/91; 631/250/1619/554/1834; 631/250/580/1884; 631/67/2332; 631/67/580; 64/60; 692/4028/67/1922; Adult; Animal models; Animals; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - immunology; Brain Neoplasms - pathology; Brain tumors; Cancer; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell culture; Cell Proliferation; Chemotaxis; Child; Cytotoxicity; Disease Models, Animal; Female; Gene sequencing; Glioma; Glioma - genetics; Glioma - immunology; Glioma - pathology; Glioma cells; Humanities and Social Sciences; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Lymphocytes; Lymphocytes T; Male; Mice; Monocytes; multidisciplinary; Osteoprotegerin; Paracrine signalling; PD-1 protein; Pediatrics; Science; Science (multidisciplinary); Sequence Analysis, RNA; Single-Cell Analysis; Tumors
• ISSN: 2041-1723; 2041-1723
• 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. With the emergence of immune checkpoint inhibitor therapies for cancer, the authors use single-cell sequencing to assess exhausted T cell content in human glioma samples and leverage these findings in mouse models to define the mechanisms by which exhausted T cells regulate low-grade glioma growth.