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SRP170756
Mus musculus
27 Downloadable Samples
NextSeq 500, Illumina HiSeq 2500
Description
An improved understanding of the anti-tumor CD8+ T cell response after checkpoint blockade would enable more informed and effective therapeutic strategies. Here we examined the dynamics of the effector response of CD8+ tumor-infiltrating lymphocytes (TILs) after checkpoint blockade therapy. Bulk and single-cell RNA profiles of CD8+ TILs after combined Tim-3+PD-1 blockade in preclinical models revealed significant changes in the transcriptional profile of PD-1? TILs. These cells could be divided into subsets bearing characterstics of naive-, effector-, and memory-precursor-like cells. Effector- and memory-precursor-like TILs contained tumor-antigen-specific cells, exhibited proliferative and effector capacity, and expanded in response to different checkpoint blockade therapies across different tumor models. The memory-precursor-like subset shared features with CD8+ T cells associated with response to checkpoint blockade in patients and was compromised in the absence of Tcf7. Expression of Tcf7 was requisite for the efficacy of diverse immunotherapies, highlighting the importance of this transcriptional regulator in the development of effective CD8+ T cell responses upon immunotherapy. Overall design: (i) RNAseq of Wild Type Naïve-like, Memory-like and Effector-like subpopulations of PD1-CD8+ Tumor infiltrating lymphocytes isolated from MC38-OVA. CD62LhiSlamf7-CX3CR1-, CD62L-Slamf7hiCX3CR1- and CD62L-Slamf7hiCX3CR1+ subsets within PD-1-CD8+ TILs (ii) RNAseq from WT mice, Tim-3+PD-1+ and Tim-3-PD-1- CD8+ TILs were isolated by cell sorting from MC38-OVA tumor-bearing mice that were treated with anti-PD-1 and anti-Tim-3 antibodies or isotype controls. (iii) Droplet-based single-cell RNA-Seq of Tim-3-PD-1- CD8+ TILs from MC38-OVA tumor-bearing WT mice that were treated with anti-PD-1 and anti-Tim-3 antibodies or isotype controls.
Publication Title
Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD-1<sup>-</sup>CD8<sup>+</sup> Tumor-Infiltrating T Cells.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Mus musculus
- 16 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 384 Downloadable Samples
- NextSeq 500
Description
Reversing the dysfunctional T cell state that arises in cancer and chronic viral infections is the focus of therapeutic interventions; however, current therapies are effective in only some patients and some tumor types. To gain a deeper molecular understanding of the dysfunctional T cell state, we analyzed population and single-cell RNA profiles of CD8+ tumor-infiltrating lymphocytes (TILs) and used genetic perturbations to identify a distinct gene module for T cell dysfunction that can be uncoupled from T cell activation. This distinct dysfunction module is downstream of intracellular metallothioneins that regulate zinc metabolism and can be identified at single-cell resolution. We further identify Gata-3, a zinc-finger transcription factor in the dysfunctional module, as a regulator of dysfunction, and use CRISPR/Cas9 genome editing to show that it drives a dysfunctional phenotype in CD8+ TILs. Our results open novel avenues for targeting dysfunctional T cell states, while leaving activation programs intact. Overall design: CD8 TILs from WT and MTKO mice were sequenced at single-cell resolution
Publication Title
A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 383 Downloadable Samples
- NextSeq 500
Description
Reversing the dysfunctional T cell state that arises in cancer and chronic viral infections is the focus of therapeutic interventions; however, current therapies are effective in only some patients and some tumor types. To gain a deeper molecular understanding of the dysfunctional T cell state, we analyzed population and single-cell RNA profiles of CD8+ tumor-infiltrating lymphocytes (TILs) and used genetic perturbations to identify a distinct gene module for T cell dysfunction that can be uncoupled from T cell activation. This distinct dysfunction module is downstream of intracellular metallothioneins that regulate zinc metabolism and can be identified at single-cell resolution. We further identify Gata-3, a zinc-finger transcription factor in the dysfunctional module, as a regulator of dysfunction, and use CRISPR/Cas9 genome editing to show that it drives a dysfunctional phenotype in CD8+ TILs. Our results open novel avenues for targeting dysfunctional T cell states, while leaving activation programs intact. Overall design: CD8 TILs from WT and MTKO mice were sequenced at single-cell resolution
Publication Title
A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 384 Downloadable Samples
- NextSeq 500
Description
Reversing the dysfunctional T cell state that arises in cancer and chronic viral infections is the focus of therapeutic interventions; however, current therapies are effective in only some patients and some tumor types. To gain a deeper molecular understanding of the dysfunctional T cell state, we analyzed population and single-cell RNA profiles of CD8+ tumor-infiltrating lymphocytes (TILs) and used genetic perturbations to identify a distinct gene module for T cell dysfunction that can be uncoupled from T cell activation. This distinct dysfunction module is downstream of intracellular metallothioneins that regulate zinc metabolism and can be identified at single-cell resolution. We further identify Gata-3, a zinc-finger transcription factor in the dysfunctional module, as a regulator of dysfunction, and use CRISPR/Cas9 genome editing to show that it drives a dysfunctional phenotype in CD8+ TILs. Our results open novel avenues for targeting dysfunctional T cell states, while leaving activation programs intact. Overall design: CD8 TILs from WT and MTKO mice were sequenced at single-cell resolution
Publication Title
A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 383 Downloadable Samples
- NextSeq 500
Description
Reversing the dysfunctional T cell state that arises in cancer and chronic viral infections is the focus of therapeutic interventions; however, current therapies are effective in only some patients and some tumor types. To gain a deeper molecular understanding of the dysfunctional T cell state, we analyzed population and single-cell RNA profiles of CD8+ tumor-infiltrating lymphocytes (TILs) and used genetic perturbations to identify a distinct gene module for T cell dysfunction that can be uncoupled from T cell activation. This distinct dysfunction module is downstream of intracellular metallothioneins that regulate zinc metabolism and can be identified at single-cell resolution. We further identify Gata-3, a zinc-finger transcription factor in the dysfunctional module, as a regulator of dysfunction, and use CRISPR/Cas9 genome editing to show that it drives a dysfunctional phenotype in CD8+ TILs. Our results open novel avenues for targeting dysfunctional T cell states, while leaving activation programs intact. Overall design: CD8 TILs from WT and MTKO mice were sequenced at single-cell resolution
Publication Title
A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 54 Downloadable Samples
- Illumina HiSeq 2500
Description
Reversing the dysfunctional T cell state that arises in cancer and chronic viral infections is the focus of therapeutic interventions; however, current therapies are effective in only some patients and some tumor types. To gain a deeper molecular understanding of the dysfunctional T cell state, we analyzed population and single-cell RNA profiles of CD8+ tumor-infiltrating lymphocytes (TILs) and used genetic perturbations to identify a distinct gene module for T cell dysfunction that can be uncoupled from T cell activation. This distinct dysfunction module is downstream of intracellular metallothioneins that regulate zinc metabolism and can be identified at single-cell resolution. We further identify Gata-3, a zinc-finger transcription factor in the dysfunctional module, as a regulator of dysfunction, and use CRISPR/Cas9 genome editing to show that it drives a dysfunctional phenotype in CD8+ TILs. Our results open novel avenues for targeting dysfunctional T cell states, while leaving activation programs intact. Overall design: CD8 TILs sorted on PD1 and Tim3 to subpopulations were analyzed from two batches: batch 1: 2 WT and 2 MTKO mice , batch 2: 2 WT and 3 MTKO mice.
Publication Title
A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells.
Sample Metadata Fields
Subject
View Samples- Mus musculus
- 16 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Reversing the dysfunctional T cell state that arises in cancer and chronic viral infections is the focus of therapeutic interventions; however, current therapies are effective in only some patients and some tumor types. To gain a deeper molecular understanding of the dysfunctional T cell state, we analyzed population and single-cell RNA profiles of CD8+ tumor-infiltrating lymphocytes (TILs) and used genetic perturbations to identify a distinct gene module for T cell dysfunction that can be uncoupled from T cell activation. This distinct dysfunction module is downstream of intracellular metallothioneins that regulate zinc metabolism and can be identified at single-cell resolution. We further identify Gata-3, a zinc-finger transcription factor in the dysfunctional module, as a regulator of dysfunction, and use CRISPR/Cas9 genome editing to show that it drives a dysfunctional phenotype in CD8+ TILs. Our results open novel avenues for targeting dysfunctional T cell states, while leaving activation programs intact.
Publication Title
A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 14 Downloadable Samples
- Illumina HiSeq 2500
Description
Reversing the dysfunctional T cell state that arises in cancer and chronic viral infections is the focus of therapeutic interventions; however, current therapies are effective in only some patients and some tumor types. To gain a deeper molecular understanding of the dysfunctional T cell state, we analyzed population and single-cell RNA profiles of CD8+ tumor-infiltrating lymphocytes (TILs) and used genetic perturbations to identify a distinct gene module for T cell dysfunction that can be uncoupled from T cell activation. This distinct dysfunction module is downstream of intracellular metallothioneins that regulate zinc metabolism and can be identified at single-cell resolution. We further identify Gata-3, a zinc-finger transcription factor in the dysfunctional module, as a regulator of dysfunction, and use CRISPR/Cas9 genome editing to show that it drives a dysfunctional phenotype in CD8+ TILs. Our results open novel avenues for targeting dysfunctional T cell states, while leaving activation programs intact. Overall design: naïve and activated CD8 T cells
Publication Title
A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 12 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Induction and transcriptional regulation of the co-inhibitory gene module in T cells.
Sample Metadata Fields
Specimen part
View Samples