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Cell. 2018 Nov 1;175(4):998-1013.e20. doi: 10.1016/j.cell.2018.10.038.

Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma.

Author information

1
Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Department of Medicine, Massachusetts General Hospital, HMS, Boston, MA, USA.
2
Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.
3
Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.
4
Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Department of Medicine, Massachusetts General Hospital, HMS, Boston, MA, USA; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
5
Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Department of Pathology, Massachusetts General Hospital, HMS, Boston, MA, USA.
6
Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA.
7
Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Department of Biomedical Informatics, HMS, Boston, MA, USA.
8
Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
9
Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Brigham & Women's Hospital, Division of Rheumatology, Immunology and Allergy, Boston, MA, USA.
10
Department of Medicine, Massachusetts General Hospital, HMS, Boston, MA, USA; Belfer Center for Applied Cancer Science, Dana Farber Cancer Institute, Boston, MA, USA.
11
Department of Pathology, Massachusetts General Hospital, HMS, Boston, MA, USA.
12
Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Department of Virology, Harvard Medical School, Boston, MA, USA.
13
Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
14
Department of Medicine, Massachusetts General Hospital, HMS, Boston, MA, USA.
15
Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Department of Medicine, Massachusetts General Hospital, HMS, Boston, MA, USA.
16
Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, HMS, Boston, MA, USA.
17
Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Department of Pathology, Massachusetts General Hospital, HMS, Boston, MA, USA; Department of Pathology, Harvard Medical School, Boston, MA, USA. Electronic address: gadgetz@broadinstitute.org.
18
Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA; Department of Medicine, Massachusetts General Hospital, HMS, Boston, MA, USA. Electronic address: nhacohen@mgh.harvard.edu.

Abstract

Treatment of cancer has been revolutionized by immune checkpoint blockade therapies. Despite the high rate of response in advanced melanoma, the majority of patients succumb to disease. To identify factors associated with success or failure of checkpoint therapy, we profiled transcriptomes of 16,291 individual immune cells from 48 tumor samples of melanoma patients treated with checkpoint inhibitors. Two distinct states of CD8+ T cells were defined by clustering and associated with patient tumor regression or progression. A single transcription factor, TCF7, was visualized within CD8+ T cells in fixed tumor samples and predicted positive clinical outcome in an independent cohort of checkpoint-treated patients. We delineated the epigenetic landscape and clonality of these T cell states and demonstrated enhanced antitumor immunity by targeting novel combinations of factors in exhausted cells. Our study of immune cell transcriptomes from tumors demonstrates a strategy for identifying predictors, mechanisms, and targets for enhancing checkpoint immunotherapy.

KEYWORDS:

CD8(+) T cells; TCF7; cancer immunotherapy; checkpoint blockade; single-cell RNA-seq

Comment in

PMID:
30388456
PMCID:
PMC6641984
[Available on 2019-11-01]
DOI:
10.1016/j.cell.2018.10.038
[Indexed for MEDLINE]

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