Single cell transcriptomics of the tumor immune microenvironment from checkpoint blockade-treated KPC tumors
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE206668 | GEO | 2022/08/01
REPOSITORIES: GEO
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Project description:Single cell transcriptomics of the tumor immune microenvironment from checkpoint blockade-treated KPC tumors
| PRJNA851755 | ENA
Project description:Immune checkpoint blockade is able to achieve durable responses in a subset of patients, however we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4 and anti-PD-1 induced tumor rejection. To address these issues we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor infiltrating T cell populations. Anti-PD-1 predominantly induces the expansion of specific tumor infiltrating exhausted-like CD8 T cell subsets. In contrast, anti-CTLA-4 induces the expansion of an ICOS+ Th1-like CD4 effector population in addition to engaging specific subsets of exhausted-like CD8 T cells. Thus, our findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint blockade induced immune responses are driven by distinct cellular mechanisms.
2017-08-10 | GSE100808 | GEO
Project description:Immune checkpoint blockade is able to achieve durable responses in a subset of patients, however we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4 and anti-PD-1 induced tumor rejection. To address these issues we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor infiltrating T cell populations. Anti-PD-1 predominantly induces the expansion of specific tumor infiltrating exhausted-like CD8 T cell subsets. In contrast, anti-CTLA-4 induces the expansion of an ICOS+ Th1-like CD4 effector population in addition to engaging specific subsets of exhausted-like CD8 T cells. Thus, our findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint blockade induced immune responses are driven by distinct cellular mechanisms.
2017-08-10 | GSE100807 | GEO
Project description:Cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and Programmed death-1 (PD-1) are immunoregulatory receptors expressed on T cells that play important roles in suppressing immune responses to cancer. Although monoclonal antibodies that target CTLA-4 or PD-1 stimulate therapeutic anti-tumour T cell responses, the tumour antigens recognized by checkpoint blockade immunotherapy remain undefined. Herein, we use genomics and bioinformatics approaches to identify tumour-specific mutant proteins as a major class of T cell rejection antigens following αPD-1 and/or αCTLA-4 treatment of mice bearing progressively growing sarcomas. We validate this conclusion by showing that (a) the predicted mutant epitopes associate with MHC class I molecules of the tumour; (b) T cells specific for these mutant epitopes infiltrate tumours; and (c) therapeutic vaccines incorporating these mutant epitopes induce tumour rejection comparably to checkpoint blockade immunotherapy. Whereas, T cells with the same antigen specificity are present in progressively growing tumours in control mice, tumour-specific T cells in αPD-1- and/or αCTLA-4-treated mice express some overlapping but mostly treatment-specific transcriptional profiles that render them capable of tumour rejection. Thus, tumour-specific mutant antigens are not only important targets of checkpoint blockade therapy but also can be used to identify tumour antigen-specific T cells that function as biomarkers of successful anti-tumour responses.
2014-11-07 | GSE62771 | GEO
Project description:This study investigated how the depletion of natural killer (NK) cells in mice treated with a combined PD-1/CTLA-4 blockade affects the molecular profiles of intracranial tumors in a two-site B16-OVA melanoma brain metastases model. This model contains concomitant intracranial and extracranial tumors, to mimic the presence of extracranial metastases in melanoma patients with brain metastases, and intracranial responses to the combined PD-1/CTLA-4 blockade that are observed in the clinic can be reproduced in this model.
2024-08-29 | GSE264376 | GEO
Project description:T cells receive numerous positive and negative signals during primary antigen encounter that control their proliferation and function, but how these signals are integrated to modulate T cell memory has not been fully characterized. In these studies, we demonstrate that combining seemingly opposite signals, CTLA-4 blockade and rapamycin-mediated mTOR inhibition, during in vivo T cell priming leads to both an increase in the frequency of memory CD8+ T cells and improved memory responses to tumors and bacterial challenges. This enhanced efficacy corresponds to increased early expansion and memory precursor differentiation of CD8+ T cells and increased mitochondrial biogenesis and spare respiratory capacity in memory CD8+ T cells in mice treated with anti-CTLA-4 and rapamycin during immunization. Collectively, these results reveal that mTOR inhibition cooperates with rather than antagonizes blockade of CTLA-4, promoting unrestrained effector function and proliferation and an optimal metabolic program for CD8+ T cell memory. Total RNA was isolated from FACS-sorted, antigen-specific CD8+T cells from different treatment conditions at 5 or 35 days after primary T cell activation
2015-01-31 | E-GEOD-63022 | biostudies-arrayexpress
Project description:Previously we found that Irf4-deficient T cells were dysfunctional and unable to reject heart allografts and checkpoint blockade treatment could reinvigorate dysfunctional Irf4-deficient T cells and enable them reject heart allografts. But shortly after the reinvigoration those T cells went back to dysfunctional state. TCR-transgenic TEa CD4+ T cells (B6 background) recognize a Balb/c I-Eα allopeptide presented by B6 antigen presenting cells, and were used to assess the effects of immune checkpoint blockades on Irf4-deficient alloreactive T cells. WT, Irf4-/- and checkpoint blockade treated Irf4-/- TEa CD4+ T cells were isolated from Balb/c heart transplanted B6 mice, followed by microarray analysis. To define un-restored gene expressions in Irf4-deficient alloreactive T cells upon immune checkpoint blockades, we compared genes expression level among three groups. We revealed that checkpoint blockade restored the expression levels of the majority of wild-type T cell-expressed genes in Irf4-/- T cells, indicating the reinvigoration of Irf4-/- T cells. The remaining un-restored genes following checkpoint blockade, though minimal in number, may be responsible for the reinvigorated Irf4-/- T cells to become re-dysfunction.
2019-03-11 | GSE111757 | GEO
Project description:<p>Blockade of T cell coinhibitory molecules such as CTLA-4 and PD-1, can activate T cell antitumor response. Although these immune checkpoint blockades (CTLA-4 blockade and PD-1 blockade) have shown durable response, response rate is modest. Therefore, there is a need to find stable biomarkers predictive of response to immune checkpoint blockades and to understand underlying resistance mechanisms. We collected longitudinal tumor biopsies from a cohort of metastatic melanoma patients treated with sequential immune checkpoint blockades and performed whole exome sequencing of this cohort. The comprehensive genomic characterization of tumors enabled identification of higher copy number loss burden as a resistance mechanism and clonal T cell repertoire as a predictive biomarker.</p>
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Project description:To characterized the effect of IL-27 on the tumor immune microenvironment in vivo, we selected the subcutaneous tumor-infiltrating CD45+ lymphocytes from tumor in vehicle or recombinant mouse IL-27 treated mice,and performed single-cell RNA sequencing on lymphocytes.
2022-12-31 | GSE210591 | GEO
Project description:Recently, Bailey et al (2016, Nature) defined four subtypes of pancreatic cancer that are associated with distinct histopathological characteristics and differential survival, namely, Squamous, Pancreatic Progenitor, Immunogenic, and ADEX (Aberrantly Differentiated Endocrine eXocrine). We set out to assess by RNASeq whether loss of CXCR2 was significantly associated with a specific PDAC subtype. Pancreatic tumors were harvested from KPC or KPC Cxcr2-/- mice at endpoint (n=5 v 5), RNA prepared, and RNASeq analysis carried out. Reads were analysed using the bcbio-nextgen framework (https://bcbio-nextgen.readthedocs.org/en/latest/). After quality control and adaptor trimming, reads were aligned to the mouse genome build (UCSC mouse mm10) using STAR. Counts for known genes were generated using the function featureCounts in the R/Bioconductor package \Rsubread\. The R/Bioconductor package edgeR was used to identify differentially expressed genes.
2018-03-31 | E-MTAB-4659 | biostudies-arrayexpress