Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Immune mechanisms shape the clonal landscape during early progression of prostate cancer

ABSTRACT: Understanding the role of the immune microenvironment in modulating intratumor heterogeneity is essential for effective cancer therapies. Here we show that two types of tumor clonal landscapes emerge during early progression of prostate cancer in genetically-engineered mouse models. Using lineage tracing and single-cell transcriptomics, we find that slowly progressing tumors contain a multiclonal landscape of relatively homogenous subpopulations within a well-organized tumor microenvironment, whereas more advanced and aggressive tumors contain competing dominant and minor clones accompanied by a disordered microenvironment. We demonstrate that the dominant/minor modality is associated with differential immunoediting, in which minor clones are marked by increased expression of IFNγ-response genes and the T-cell activating chemokines Cxcl9 and Cxcl11. Furthermore, immunomodulation of the IFNγ pathway can rescue minor clones from elimination. These findings suggest new immunotherapy approaches to modulate clonal fitness and tumor progression in prostate cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE196371 | GEO | 2023/04/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Myeloid cell-based delivery of IFN-γ reprograms leukemia microenvironment and induces anti-tumoral immune responses

Project description:The immunosuppressive microenvironment surrounding tumor cells represents a key cause of treatment failure. Therefore, immunotherapies aimed at reprogramming the immune system have largely spread in the past years. We employed gene transfer into hematopoietic stem and progenitor cells to selectively express anti-tumoral cytokines in tumor-infiltrating monocytes/macrophages. We show that Interferon-γ (IFNγ) reduced tumor progression in mouse models of B-cell acute lymphoblastic leukemia (B-ALL) and colorectal carcinoma (MC38). Its activity was dependent on the capacity of the immune system to respond to IFNγ and drove counter-selection of leukemia cells expressing surrogate antigens. Gene-based IFNγ delivery induced antigen presentation in the myeloid compartment and on leukemia cells, leading to a wave of T cell recruitment and activation, with enhanced clonal expansion of cytotoxic CD8+ T lymphocytes. The activity of IFNγ was further enhanced by either co-delivery of tumor necrosis factor α (TNFα) or by drugs blocking immunosuppressive escape pathways, with the potential to obtain durable responses.

2021-08-23 | GSE178941 | GEO

Distinct spatiotemporal dynamics of CD8+ T cell-derived cytokines in the tumor microenvironment (6601)

Project description:Tumors consist of a dynamic collection of interacting tumor cells, stromal cells and immune cells. In addition to the direct cell-cell interactions that are mediated by receptor-ligand interactions, cells in the tumor microenvironment (TME) influence each other through the secretion and sensing of soluble mediators, such as cytokines and chemokines. While signaling of the interferon γ (IFNγ) and tumor necrosis factor α (TNFα) cytokines has been shown to be critical in anti-tumor immune responses in a number of settings, our understanding of the spatiotemporal behavior of these cytokines in the TME is limited. Here, we describe a single cell transcriptome-based approach to infer which single or combined signals an individual cell has received and estimate the timing of such exposure. Using this technology, we demonstrate that, contrary to expectations, CD8+ T cell-derived IFNγ is the dominant modifier of the TME relative to TNFα. Furthermore, we demonstrate that cell pools that show abundant IFNγ sensing are characterized by decreased TGFβ signaling, consistent with IFNγ-mediated remodeling of the TME. Collectively, these data provide evidence that CD8+ T cell-secreted cytokines should be distinguished into local and more global modifiers of tumor tissue, and describe a broadly applicable approach to dissect cytokine and chemokine modulation of the tumor microenvironment.

2023-12-07 | GSE220736 | GEO

Distinct spatiotemporal dynamics of CD8+ T cell-derived cytokines in the tumor microenvironment (6600)

2023-12-07 | GSE220735 | GEO

Distinct spatiotemporal dynamics of CD8+ T cell-derived cytokines in the tumor microenvironment (6493)

2023-12-07 | GSE220734 | GEO

Distinct spatiotemporal dynamics of CD8+ T cell-derived cytokines in the tumor microenvironment (6489)

2023-12-07 | GSE220733 | GEO

Distinct spatiotemporal dynamics of CD8+ T cell-derived cytokines in the tumor microenvironment (5892)

2023-12-07 | GSE220731 | GEO

Distinct spatiotemporal dynamics of CD8+ T cell-derived cytokines in the tumor microenvironment (5310)

2023-12-07 | GSE220730 | GEO

Distinct spatiotemporal dynamics of CD8+ T cell-derived cytokines in the tumor microenvironment (6743)