Glioblastoma-Infiltrating CD8+ T Cells Are Predominantly a Clonally Expanded GZMK+ Effector Population.

Autor:	Wang AZ; Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, Missouri.; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Brain Tumor Immunology and Immunotherapy Program, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Mashimo BL; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Brain Tumor Immunology and Immunotherapy Program, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Schaettler MO; Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, Missouri.; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts., Sherpa ND; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Brain Tumor Immunology and Immunotherapy Program, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Biological and Biomedical Sciences Graduate Program, Harvard University, Cambridge, Massachusetts., Leavitt LA; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Brain Tumor Immunology and Immunotherapy Program, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Department of Neurosurgery, University of Louisville, Louisville, Kentucky., Livingstone AJ; Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, Missouri., Khan SM; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Brain Tumor Immunology and Immunotherapy Program, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Li M; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Brain Tumor Immunology and Immunotherapy Program, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Anzaldua-Campos MI; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Brain Tumor Immunology and Immunotherapy Program, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Neuroscience Undergraduate Program, Harvard University, Cambridge, Massachusetts., Bradley JD; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Leuthardt EC; Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri.; Brain Tumor Center, Washington University School of Medicine/Siteman Cancer Center, St. Louis, Missouri., Kim AH; Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri.; Brain Tumor Center, Washington University School of Medicine/Siteman Cancer Center, St. Louis, Missouri., Dowling JL; Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri.; Brain Tumor Center, Washington University School of Medicine/Siteman Cancer Center, St. Louis, Missouri., Chicoine MR; Department of Neurological Surgery, University of Missouri-Columbia, Columbia, Missouri., Jones PS; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Choi BD; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Brain Tumor Immunology and Immunotherapy Program, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Cahill DP; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Carter BS; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Petti AA; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Brain Tumor Immunology and Immunotherapy Program, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Johanns TM; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.; Brain Tumor Center, Washington University School of Medicine/Siteman Cancer Center, St. Louis, Missouri., Dunn GP; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Brain Tumor Immunology and Immunotherapy Program, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2024 Jun 03; Vol. 14 (6), pp. 1106-1131.
DOI:	10.1158/2159-8290.CD-23-0913
Abstrakt:	Recent clinical trials have highlighted the limited efficacy of T cell-based immunotherapy in patients with glioblastoma (GBM). To better understand the characteristics of tumor-infiltrating lymphocytes (TIL) in GBM, we performed cellular indexing of transcriptomes and epitopes by sequencing and single-cell RNA sequencing with paired V(D)J sequencing, respectively, on TILs from two cohorts of patients totaling 15 patients with high-grade glioma, including GBM or astrocytoma, IDH-mutant, grade 4 (G4A). Analysis of the CD8+ TIL landscape reveals an enrichment of clonally expanded GZMK+ effector T cells in the tumor compared with matched blood, which was validated at the protein level. Furthermore, integration with other cancer types highlights the lack of a canonically exhausted CD8+ T-cell population in GBM TIL. These data suggest that GZMK+ effector T cells represent an important T-cell subset within the GBM microenvironment and may harbor potential therapeutic implications. Significance: To understand the limited efficacy of immune-checkpoint blockade in GBM, we applied a multiomics approach to understand the TIL landscape. By highlighting the enrichment of GZMK+ effector T cells and the lack of exhausted T cells, we provide a new potential mechanism of resistance to immunotherapy in GBM. This article is featured in Selected Articles from This Issue, p. 897. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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