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

Cell | 2018

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.

Pubmed ID: 30388456 RIS Download

Research resources used in this publication

Antibodies used in this publication

Associated grants

  • Agency: NHGRI NIH HHS, United States
    Id: U54 HG003067
  • Agency: NIH HHS, United States
    Id: S10 OD016372
  • Agency: NCI NIH HHS, United States
    Id: U01 CA214381
  • Agency: NIH HHS, United States
    Id: S10 OD012027
  • Agency: NCI NIH HHS, United States
    Id: U54 CA224068
  • Agency: NCRR NIH HHS, United States
    Id: S10 RR023440
  • Agency: NCI NIH HHS, United States
    Id: T32 CA207021
  • Agency: NCI NIH HHS, United States
    Id: R01 CA208756
  • Agency: NIAID NIH HHS, United States
    Id: F32 AI129249
  • Agency: NCI NIH HHS, United States
    Id: R01 CA190394
  • Agency: NCRR NIH HHS, United States
    Id: S10 RR020936

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This is a list of tools and resources that we have found mentioned in this publication.


Bio X Cell (tool)

RRID:SCR_004997

Commercial supplier and developer of in vivo antibodies. Provides antibodies and antibody production services.

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Picard (tool)

RRID:SCR_006525

Java toolset for working with next generation sequencing data in the BAM format.

View all literature mentions

SAM format (tool)

RRID:SCR_012093

A generic alignment format for storing read alignments against reference sequences, supporting short and long reads (up to 128 Mbp) produced by different sequencing platforms.

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STAR (tool)

RRID:SCR_004463

Software performing alignment of high-throughput RNA-seq data. Aligns RNA-seq reads to reference genome using uncompressed suffix arrays.

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Purified anti-human CD8a (antibody)

RRID:AB_2650657

This monoclonal targets CD8a

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PE anti-mouse IL-2 (antibody)

RRID:AB_315301

This monoclonal targets IL-2

View all literature mentions

InVivoPlus anti-mouse CD8α (antibody)

RRID:AB_1107671

This monoclonal targets CD8α

View all literature mentions

PE anti-human CD45 (antibody)

RRID:AB_314396

This monoclonal targets CD45

View all literature mentions

InVivoPlus anti-mouse PD-1 (CD279) (antibody)

RRID:AB_10949053

This monoclonal targets PD-1 (CD279)

View all literature mentions

APC anti-human/mouse Granzyme B Recombinant (antibody)

RRID:AB_2687027

This recombinant monoclonal targets Granzyme B

View all literature mentions

InVivoPlus anti-mouse TIM-3 (CD366) (antibody)

RRID:AB_10949464

This monoclonal targets TIM-3 (CD366)

View all literature mentions

FITC anti-mouse CD8a (antibody)

RRID:AB_312744

This monoclonal targets CD8a

View all literature mentions

FITC anti-human HLA-A,B,C (antibody)

RRID:AB_314873

This monoclonal targets HLA-A

View all literature mentions

InVivoPlus anti-mouse PD-1 (CD279) (antibody)

RRID:AB_2687796

This monoclonal targets PD-1 (CD279)

View all literature mentions

anti-mouse CD8α (antibody)

RRID:AB_1125541

This monoclonal targets CD8α

View all literature mentions

InVivoPlus anti-mouse CTLA-4 (CD152) (antibody)

RRID:AB_10949609

This monoclonal targets CTLA-4 (CD152)

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InVivoPlus rat IgG2a isotype control (antibody)

RRID:AB_1107769

This isotype control targets Trinitrophenol

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FITC anti-mouse CD45.2 (antibody)

RRID:AB_313443

This monoclonal targets CD45.2

View all literature mentions

Anti-TNF-α-APC (antibody)

RRID:AB_2661079

This monoclonal targets TNF-?

View all literature mentions

APC anti-human CD3 (antibody)

RRID:AB_314066

This monoclonal targets CD3

View all literature mentions

rat IgG2b I sotype control (antibody)

RRID:AB_1107780

This isotype control targets KLH

View all literature mentions

anti-mouse CD4 (antibody)

RRID:AB_1107636

This monoclonal targets CD4

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Anti-IFN-?-FITC, human (antibody)

RRID:AB_2661059

This monoclonal targets IFN-?

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APC anti-mouse TNF-alpha (antibody)

RRID:AB_315428

This monoclonal targets TNF-alpha

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PE anti-mouse Perforin (antibody)

RRID:AB_2721638

This monoclonal targets Perforin

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APC anti-mouse CD90.2 (Thy1.2) (antibody)

RRID:AB_10640728

This monoclonal targets CD90.2

View all literature mentions

FITC anti-mouse IFN-gamma (antibody)

RRID:AB_315399

This monoclonal targets IFN-gamma

View all literature mentions

APC/Cyanine7 anti-human CD39 (antibody)

RRID:AB_2571981

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View all literature mentions

InVivoMab anti-mouse IFNγ (antibody)

RRID:AB_1107692

This monoclonal targets IFNγ

View all literature mentions

LEAF™ Purified anti-mouse CD3? (antibody)

RRID:AB_312679

This monoclonal targets CD3epsilon

View all literature mentions

BALB/cJ (organism)

RRID:IMSR_JAX:000651

Mus musculus with name BALB/cJ from IMSR.

View all literature mentions

MuTect (software resource)

RRID:SCR_000559

Software for the reliable and accurate identification of somatic point mutations in next generation sequencing data of cancer genomes.

View all literature mentions

STAR (software resource)

RRID:SCR_015899

Software performing alignment of high-throughput RNA-seq data. Aligns RNA-seq reads to reference genome using uncompressed suffix arrays.

View all literature mentions

GraphPad Prism (software resource)

RRID:SCR_002798

Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.

View all literature mentions

FlowJo (software resource)

RRID:SCR_008520

Software for single-cell flow cytometry analysis. Its functions include management, display, manipulation, analysis and publication of the data stream produced by flow and mass cytometers.

View all literature mentions

C57BL/6J (organism)

RRID:IMSR_JAX:000664

Mus musculus with name C57BL/6J from IMSR.

View all literature mentions

edgeR (software resource)

RRID:SCR_012802

Bioconductor software package for Empirical analysis of Digital Gene Expression data in R. Used for differential expression analysis of RNA-seq and digital gene expression data with biological replication.

View all literature mentions

SAMTOOLS (software resource)

RRID:SCR_002105

Original SAMTOOLS package has been split into three separate repositories including Samtools, BCFtools and HTSlib. Samtools for manipulating next generation sequencing data used for reading, writing, editing, indexing,viewing nucleotide alignments in SAM,BAM,CRAM format. BCFtools used for reading, writing BCF2,VCF, gVCF files and calling, filtering, summarising SNP and short indel sequence variants. HTSlib used for reading, writing high throughput sequencing data.

View all literature mentions

HOMER (software resource)

RRID:SCR_010881

Software tools for Motif Discovery and next-gen sequencing analysis. Used for analyzing ChIP-Seq, GRO-Seq, RNA-Seq, DNase-Seq, Hi-C and numerous other types of functional genomics sequencing data sets. Collection of command line programs for unix style operating systems written in Perl and C++.

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CellProfiler Image Analysis Software (data processing software)

RRID:SCR_007358

Software tool to enable biologists without training in computer vision or programming to quantitatively measure phenotypes from thousands of images automatically. It counts cells and also measures the size, shape, intensity and texture of every cell (and every labeled subcellular compartment) in every image. It was designed for high throughput screening but can perform automated image analysis for images from time-lapse movies and low-throughput experiments. CellProfiler has an increasing number of algorithms to identify and measure properties of neuronal cell types.

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MATLAB (software resource)

RRID:SCR_001622

Multi paradigm numerical computing environment and fourth generation programming language developed by MathWorks. Allows matrix manipulations, plotting of functions and data, implementation of algorithms, creation of user interfaces, and interfacing with programs written in other languages, including C, C++, Java, Fortran and Python. Used to explore and visualize ideas and collaborate across disciplines including signal and image processing, communications, control systems, and computational finance.

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Oncotator (service resource)

RRID:SCR_005183

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ContEst (software resource)

RRID:SCR_000595

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Bowtie (software resource)

RRID:SCR_005476

Software ultrafast memory efficient tool for aligning sequencing reads. Bowtie is short read aligner.

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RSEM (software resource)

RRID:SCR_013027

Software package for quantifying gene and isoform abundances from single end or paired end RNA Seq data. Accurate transcript quantification from RNA Seq data with or without reference genome. Used for accurate quantification of gene and isoform expression from RNA-Seq data.

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MATLAB (software resource)

RRID:SCR_001622

Multi paradigm numerical computing environment and fourth generation programming language developed by MathWorks. Allows matrix manipulations, plotting of functions and data, implementation of algorithms, creation of user interfaces, and interfacing with programs written in other languages, including C, C++, Java, Fortran and Python. Used to explore and visualize ideas and collaborate across disciplines including signal and image processing, communications, control systems, and computational finance.

View all literature mentions

STAR (software resource)

RRID:SCR_015899

Software performing alignment of high-throughput RNA-seq data. Aligns RNA-seq reads to reference genome using uncompressed suffix arrays.

View all literature mentions

Bowtie (software resource)

RRID:SCR_005476

Software ultrafast memory efficient tool for aligning sequencing reads. Bowtie is short read aligner.

View all literature mentions

RSEM (software resource)

RRID:SCR_013027

Software package for quantifying gene and isoform abundances from single end or paired end RNA Seq data. Accurate transcript quantification from RNA Seq data with or without reference genome. Used for accurate quantification of gene and isoform expression from RNA-Seq data.

View all literature mentions

SAMTOOLS (software resource)

RRID:SCR_002105

Original SAMTOOLS package has been split into three separate repositories including Samtools, BCFtools and HTSlib. Samtools for manipulating next generation sequencing data used for reading, writing, editing, indexing,viewing nucleotide alignments in SAM,BAM,CRAM format. BCFtools used for reading, writing BCF2,VCF, gVCF files and calling, filtering, summarising SNP and short indel sequence variants. HTSlib used for reading, writing high throughput sequencing data.

View all literature mentions

Oncotator (service resource)

RRID:SCR_005183

A tool for annotating human genomic point mutations and indels with data relevant to cancer researchers. Genomic Annotations, Protein Annotations, and Cancer Annotations are aggregated from many resources. A standalone version of Oncotator is being developed.

View all literature mentions

ContEst (software resource)

RRID:SCR_000595

A software tool (and method) for estimating the amount of cross-sample contamination in next generation sequencing data.

View all literature mentions

HOMER (software resource)

RRID:SCR_010881

Software tools for Motif Discovery and next-gen sequencing analysis. Used for analyzing ChIP-Seq, GRO-Seq, RNA-Seq, DNase-Seq, Hi-C and numerous other types of functional genomics sequencing data sets. Collection of command line programs for unix style operating systems written in Perl and C++.

View all literature mentions

MuTect (software resource)

RRID:SCR_000559

Software for the reliable and accurate identification of somatic point mutations in next generation sequencing data of cancer genomes.

View all literature mentions

edgeR (software resource)

RRID:SCR_012802

Bioconductor software package for Empirical analysis of Digital Gene Expression data in R. Used for differential expression analysis of RNA-seq and digital gene expression data with biological replication.

View all literature mentions

GraphPad Prism (software resource)

RRID:SCR_002798

Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.

View all literature mentions

FlowJo (software resource)

RRID:SCR_008520

Software for single-cell flow cytometry analysis. Its functions include management, display, manipulation, analysis and publication of the data stream produced by flow and mass cytometers.

View all literature mentions

CellProfiler Image Analysis Software (data processing software)

RRID:SCR_007358

Software tool to enable biologists without training in computer vision or programming to quantitatively measure phenotypes from thousands of images automatically. It counts cells and also measures the size, shape, intensity and texture of every cell (and every labeled subcellular compartment) in every image. It was designed for high throughput screening but can perform automated image analysis for images from time-lapse movies and low-throughput experiments. CellProfiler has an increasing number of algorithms to identify and measure properties of neuronal cell types.

View all literature mentions

LEAF™ Purified anti-mouse CD3? (antibody)

RRID:AB_312679

This monoclonal targets CD3epsilon

View all literature mentions

BALB/cJ (organism)

RRID:IMSR_JAX:000651

Mus musculus with name BALB/cJ from IMSR.

View all literature mentions

Anti-TNF-α-APC (antibody)

RRID:AB_2661079

This monoclonal targets TNF-?

View all literature mentions

Anti-IFN-?-FITC, human (antibody)

RRID:AB_2661059

This monoclonal targets IFN-?

View all literature mentions

APC anti-human/mouse Granzyme B Recombinant (antibody)

RRID:AB_2687027

This recombinant monoclonal targets Granzyme B

View all literature mentions

PE anti-mouse Perforin (antibody)

RRID:AB_2721638

This monoclonal targets Perforin

View all literature mentions

FITC anti-mouse IFN-gamma (antibody)

RRID:AB_315399

This monoclonal targets IFN-gamma

View all literature mentions

PE anti-mouse IL-2 (antibody)

RRID:AB_315301

This monoclonal targets IL-2

View all literature mentions

APC anti-mouse TNF-alpha (antibody)

RRID:AB_315428

This monoclonal targets TNF-alpha

View all literature mentions

APC anti-mouse CD90.2 (Thy1.2) (antibody)

RRID:AB_10640728

This monoclonal targets CD90.2

View all literature mentions

FITC anti-mouse CD45.2 (antibody)

RRID:AB_313443

This monoclonal targets CD45.2

View all literature mentions

FITC anti-mouse CD8a (antibody)

RRID:AB_312744

This monoclonal targets CD8a

View all literature mentions

C57BL/6J (organism)

RRID:IMSR_JAX:000664

Mus musculus with name C57BL/6J from IMSR.

View all literature mentions

APC/Cyanine7 anti-human CD39 (antibody)

RRID:AB_2571981

This monoclonal targets CD39

View all literature mentions

FITC anti-human HLA-A,B,C (antibody)

RRID:AB_314873

This monoclonal targets HLA-A

View all literature mentions

APC anti-human CD3 (antibody)

RRID:AB_314066

This monoclonal targets CD3

View all literature mentions

PE anti-human CD45 (antibody)

RRID:AB_314396

This monoclonal targets CD45

View all literature mentions

InVivoPlus anti-mouse CD8α (antibody)

RRID:AB_1107671

This monoclonal targets CD8α

View all literature mentions

InVivoMab anti-mouse IFNγ (antibody)

RRID:AB_1107692

This monoclonal targets IFNγ

View all literature mentions

InVivoPlus anti-mouse PD-1 (CD279) (antibody)

RRID:AB_10949053

This monoclonal targets PD-1 (CD279)

View all literature mentions

rat IgG2b I sotype control (antibody)

RRID:AB_1107780

This isotype control targets KLH

View all literature mentions

anti-mouse CD4 (antibody)

RRID:AB_1107636

This monoclonal targets CD4

View all literature mentions

anti-mouse CD8α (antibody)

RRID:AB_1125541

This monoclonal targets CD8α

View all literature mentions

InVivoPlus anti-mouse CTLA-4 (CD152) (antibody)

RRID:AB_10949609

This monoclonal targets CTLA-4 (CD152)

View all literature mentions

InVivoPlus anti-mouse PD-1 (CD279) (antibody)

RRID:AB_2687796

This monoclonal targets PD-1 (CD279)

View all literature mentions

InVivoPlus anti-mouse TIM-3 (CD366) (antibody)

RRID:AB_10949464

This monoclonal targets TIM-3 (CD366)

View all literature mentions

InVivoPlus rat IgG2a isotype control (antibody)

RRID:AB_1107769

This isotype control targets Trinitrophenol

View all literature mentions

Purified anti-human CD8a (antibody)

RRID:AB_2650657

This monoclonal targets CD8a

View all literature mentions

BALB/cJ (organism)

RRID:IMSR_JAX:000651

Mus musculus with name BALB/cJ from IMSR.

View all literature mentions