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

Autor: Barakat R; Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA., Chatterjee J; Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA., Mu R; Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA., Qi X; Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA., Gu X; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA., Smirnov I; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA., Cobb O; Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA., Gao K; Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA., Barnes A; Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA., Kipnis J; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA., Gutmann DH; Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA. gutmannd@wustl.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Nov 28; Vol. 15 (1), pp. 10312. Date of Electronic Publication: 2024 Nov 28.
DOI: 10.1038/s41467-024-54569-4
Abstrakt: 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.
Competing Interests: Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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