Human single cell RNA-sequencing reveals a targetable CD8+ exhausted T cell population that maintains mouse low-grade glioma growth
(2024) Nature Communications, 15 (1), art. no. 10312, .
Barakat, R.a , Chatterjee, J.a , Mu, R.a , Qi, X.a , Gu, X.b , Smirnov, I.b , Cobb, O.a , Gao, K.a , Barnes, A.a , Kipnis, J.b , Gutmann, D.H.a
a Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
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. © The Author(s) 2024.
Funding details
School of Medicine, Washington University in St. LouisWUSM
Alvin J. Siteman Cancer CenterSCC
Office of Research Infrastructure ProgramsORIP, NIH
National Institutes of HealthNIH
National Center for Research ResourcesNCRR
National Cancer InstituteNCICA261939, P30 CA091842
National Cancer InstituteNCI
St. Louis Children’s HospitalSLCHCDI-CORE-2019-813, CDI-CORE-2015-505
St. Louis Children’s HospitalSLCH
National Eye InstituteNEIP30EY002687
National Eye InstituteNEI
Foundation for Barnes-Jewish HospitalFBJH4642, 3770
Foundation for Barnes-Jewish HospitalFBJH
Genome Technology Access CenterGTAC#P30 CA91842
Genome Technology Access CenterGTAC
NIH Office of the DirectorODOD021629
NIH Office of the DirectorOD
Document Type: Article
Publication Stage: Final
Source: Scopus