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Clin Cancer Res. 2018 Sep 1;24(17):4175-4186. doi: 10.1158/1078-0432.CCR-17-1846. Epub 2018 Feb 7.

T-Cell Exhaustion Signatures Vary with Tumor Type and Are Severe in Glioblastoma.

Author information

1
Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.
2
Department of Pathology, Duke University Medical Center, Durham, North Carolina.
3
Department of Medical Oncology and Cancer Vaccine Center, Dana Farber Cancer Institute, Boston, Massachusetts.
4
Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland.
5
Department of Pharmacology and Molecular Cancer Biology, Duke University, Durham, North Carolina.
6
Division of Medical Oncology, Department of Medicine, Washington University, St. Louis, Missouri.
7
Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.
8
Department of Medicine, Duke University Medical Center, Durham, North Carolina.
9
Neuro-oncology Division, National Institutes of Health, Bethesda, Maryland.
10
Department of Biostatistics, Duke University, Durham, North Carolina.
11
Department of Surgery, Duke University Medical Center, Durham, North Carolina.
12
Department of Neurological Surgery, Center for Human Immunology and Immunotherapy Programs, Washington University, St. Louis, Missouri.
13
Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina. peter.fecci@duke.edu.

Abstract

Purpose: T-cell dysfunction is a hallmark of glioblastoma (GBM). Although anergy and tolerance have been well characterized, T-cell exhaustion remains relatively unexplored. Exhaustion, characterized in part by the upregulation of multiple immune checkpoints, is a known contributor to failures amid immune checkpoint blockade, a strategy that has lacked success thus far in GBM. This study is among the first to examine, and credential as bona fide, exhaustion among T cells infiltrating human and murine GBM.Experimental Design: Tumor-infiltrating and peripheral blood lymphocytes (TILs and PBLs) were isolated from patients with GBM. Levels of exhaustion-associated inhibitory receptors and poststimulation levels of the cytokines IFNγ, TNFα, and IL2 were assessed by flow cytometry. T-cell receptor Vβ chain expansion was also assessed in TILs and PBLs. Similar analysis was extended to TILs isolated from intracranial and subcutaneous immunocompetent murine models of glioma, breast, lung, and melanoma cancers.Results: Our data reveal that GBM elicits a particularly severe T-cell exhaustion signature among infiltrating T cells characterized by: (1) prominent upregulation of multiple immune checkpoints; (2) stereotyped T-cell transcriptional programs matching classical virus-induced exhaustion; and (3) notable T-cell hyporesponsiveness in tumor-specific T cells. Exhaustion signatures differ predictably with tumor identity, but remain stable across manipulated tumor locations.Conclusions: Distinct cancers possess similarly distinct mechanisms for exhausting T cells. The poor TIL function and severe exhaustion observed in GBM highlight the need to better understand this tumor-imposed mode of T-cell dysfunction in order to formulate effective immunotherapeutic strategies targeting GBM. Clin Cancer Res; 24(17); 4175-86. ©2018 AACRSee related commentary by Jackson and Lim, p. 4059.

PMID:
29437767
PMCID:
PMC6081269
[Available on 2019-09-01]
DOI:
10.1158/1078-0432.CCR-17-1846

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