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Systematic lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade [scTCR-seq]

ABSTRACT: Systematic lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade [scTCR-seq]

PROVIDER: PRJNA768293 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16173300.fastq.gz	Fastqsanger.gz
	SRR16173301.fastq.gz	Fastqsanger.gz
	SRR16173302.fastq.gz	Fastqsanger.gz
	SRR16173303.fastq.gz	Fastqsanger.gz
	SRR16173304.fastq.gz	Fastqsanger.gz

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Systematic lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade [scTCR-seq]

Project description:Paired single-cell RNA and T cell receptor sequencing (scRNA/TCR-seq) has allowed for enhanced resolution of clonal T cell dynamics in cancer. Here, we report scRNA/TCR-seq analysis of 187,650 T cells from 31 tissue regions, including tumor, adjacent normal tissues, and lymph nodes (LN), from 3 patients with lung cancer after immune checkpoint blockade (ICB). Regions with viable cancer cells were enriched for exhausted CD8+ T cells, regulatory CD4+ T cells (Treg), and follicular helper CD4+ T cells (TFH). Tracking T cell clonotypes across tissues, combined with neoantigen specificity assays, revealed that TFH and tumor-specific exhausted CD8+ T cells could be clonally linked to TCF7+ SELL+ progenitors in tumor draining LNs, and progressive exhaustion trajectories of CD8+ T, Treg, and TFH cells with proximity to the tumor microenvironment. Finally, longitudinal tracking of tumor-specific CD8+ and CD4+ T cell clones revealed persistence in the peripheral blood for years after ICB therapy.

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Systematic lineage tracing reveals clonal progenitors and long-term persistence of1 tumor-specific T cells during immune checkpoint blockade

Project description:Systematic lineage tracing reveals clonal progenitors and long-term persistence of1 tumor-specific T cells during immune checkpoint blockade

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Systematic lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade

Project description:Systematic lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade

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Systematic lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade [scRNA-seq]

Project description:Systematic lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade [scRNA-seq]

| PRJNA768292 | ENA

Systematic lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade

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Systematic lineage tracing reveals clonal progenitors and long-term persistence of1 tumor-specific T cells during immune checkpoint blockade

2023-02-14 | GSE186446 | GEO

Systematic lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade [scRNA-seq]

2023-02-14 | GSE185204 | GEO

Lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade.

Project description:Paired single-cell RNA and T cell receptor sequencing (scRNA/TCR-seq) has allowed for enhanced resolution of clonal T cell dynamics in cancer. Here, we report a scRNA/TCR-seq analysis of 187,650 T cells from 31 tissue regions, including tumor, adjacent normal tissues, and lymph nodes (LN), from three patients with non-small cell lung cancer after immune checkpoint blockade (ICB). Regions with viable cancer cells are enriched for exhausted CD8+ T cells, regulatory CD4+ T cells (Treg), and follicular helper CD4+ T cells (TFH). Tracking T cell clonotypes across tissues, combined with neoantigen specificity assays, reveals that TFH and tumor-specific exhausted CD8+ T cells are clonally linked to TCF7+SELL+ progenitors in tumor draining LNs, and progressive exhaustion trajectories of CD8+ T, Treg, and TFH cells with proximity to the tumor microenvironment. Finally, longitudinal tracking of tumor-specific CD8+ and CD4+ T cell clones reveals persistence in the peripheral blood for years after ICB therapy.

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scTCR-seq of thymic iNKT cells

Project description:iNKT cells show significant lineage diversity among mouse strains. We used scTCR-seq to analyze the diversity of thymic iNKT cells between BALB/c and B6 mice.

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Clonal tracing reveals diverse patterns of response to immune checkpoint blockade.

Project description:BackgroundImmune checkpoint blockade (ICB) therapy has improved patient survival in a variety of cancers, but only a minority of cancer patients respond. Multiple studies have sought to identify general biomarkers of ICB response, but elucidating the molecular and cellular drivers of resistance for individual tumors remains challenging. We sought to determine whether a tumor with defined genetic background exhibits a stereotypic or heterogeneous response to ICB treatment.ResultsWe establish a unique mouse system that utilizes clonal tracing and mathematical modeling to monitor the growth of each cancer clone, as well as the bulk tumor, in response to ICB. We find that tumors derived from the same clonal populations showed heterogeneous ICB response and diverse response patterns. Primary response is associated with higher immune infiltration and leads to enrichment of pre-existing ICB-resistant cancer clones. We further identify several cancer cell-intrinsic gene expression signatures associated with ICB resistance, including increased interferon response genes and glucocorticoid response genes. These findings are supported by clinical data from ICB treatment cohorts.ConclusionsOur study demonstrates diverse response patterns from the same ancestor cancer cells in response to ICB. This suggests the value of monitoring clonal constitution and tumor microenvironment over time to optimize ICB response and to design new combination therapies. Furthermore, as ICB response may enrich for cancer cell-intrinsic resistance signatures, this can affect interpretations of tumor RNA-seq data for response-signature association studies.

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