Transcriptome analysis of tumor-specific CD8 T cells in murine solid tumors
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE89307 | GEO | 2017/05/17
SECONDARY ACCESSION(S): PRJNA351718
REPOSITORIES: GEO
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2017-05-17 | GSE89308 | GEO
Project description:Gene expression analysis of tumor-specific CD8 T cells encountering a tumor-specific antigen in pre-malignant lesions in the liver at different time points post tumor initiation. The overall goal of this mouse study was to elucidate the molecular program in tumor-specific T cells encountering a tumor-specific antigen in pre-malignant lesions. The study identifies the genes and pathways that are dysregulated in tumor-specific T cells associated with T cell unresponsiveness in tumors. To identify the genes and pathways that are dysregulated in tumor-specific T cells. Gene signatures of the following sample groups were compared: 1. Naïve CD8 T cells; 2. Effector CD8 T cells; 3. Dysfunctional tumor-specific CD8 T cells isolated from pre-malignant lesions 8-12 days after tumor induction. 4. Dysfunctional tumor-specific CD8 T cells isolated from pre-malignant lesions 32-34 days after tumor initiation. The mouse tumor model that was used is an autochthonous, tamoxifen-inducible liver cancer model (ASTxCre-ERT2; AST=Albumin-floxStop-SV40 large T antigen; Cre-ERT2 = TAM-dependent Cre-recombinase) in which the SV40 large T antigen serves as the oncogenic driver and tumor-specific antigen; SV40-I TCR transgenic mice, whose CD8 T cells express a Db-restricted TCR specific for the Tag epitope I were used as source of naïve tumor-specific CD8 T cells (TCRSV40-I) Total RNA was isolated from flow-sorted transgenic CD8 TCRSV40-I T cells from the following sample groups: Naïve, effector, D8-12-pre-malignant lesions, and D32-34 pre-malignant lesions.
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Project description:Tumor immune cell compositions play a major role in response to immunotherapy but the heterogeneity and dynamics of immune infiltrates in human cancer lesions remain poorly characterized. Here we identify conserved intratumoral CD4 and CD8 T cell behaviors in scRNA-seq data from 25 melanoma patients. We discover a large population of CD8 T cells showing continuous progression from an early effector “transitional” into a dysfunctional T cell state. CD8 T cells that express a complete cytotoxic gene set are rare, and TCR sharing data suggest their independence from the transitional and dysfunctional cell states. Notably, we demonstrate that dysfunctional T cells are the major intratumoral proliferating immune cell compartment and that the intensity of the dysfunctional signature is associated with tumor-reactivity. Our data demonstrate that CD8 T cells previously defined as exhausted, are in fact a highly proliferating, clonal and dynamically differentiating cell population within the human tumor microenvironment.
2018-12-27 | GSE123139 | GEO
Project description:Tumor immune cell compositions play a major role in response to immunotherapy but the heterogeneity and dynamics of immune infiltrates in human cancer lesions remain poorly characterized. Here we identify conserved intratumoral CD4 and CD8 T cell behaviors in scRNA-seq data from 25 melanoma patients. We discover a large population of CD8 T cells showing continuous progression from an early effector "transitional" into a dysfunctional T cell state. CD8 T cells that express a complete cytotoxic gene set are rare, and TCR sharing data suggest their independence from the transitional and dysfunctional cell states. Notably, we demonstrate that dysfunctional T cells are the major intratumoral proliferating immune cell compartment and that the intensity of the dysfunctional signature is associated with tumor-reactivity. Our data demonstrate that CD8 T cells previously defined as exhausted, are in fact a highly proliferating, clonal and dynamically differentiating cell population within the human tumor microenvironment.
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Project description:Gene expression analysis of tumor-specific CD8 T cells encountering a tumor-specific antigen in pre-malignant lesions in the liver at different time points post tumor initiation. The overall goal of this mouse study was to elucidate the molecular program in tumor-specific T cells encountering a tumor-specific antigen in pre-malignant lesions. The study identifies the genes and pathways that are dysregulated in tumor-specific T cells associated with T cell unresponsiveness in tumors. To identify the genes and pathways that are dysregulated in tumor-specific T cells. Gene signatures of the following sample groups were compared: 1. Naïve CD8 T cells; 2. Effector CD8 T cells; 3. Dysfunctional tumor-specific CD8 T cells isolated from pre-malignant lesions 8-12 days after tumor induction. 4. Dysfunctional tumor-specific CD8 T cells isolated from pre-malignant lesions 32-34 days after tumor initiation. The mouse tumor model that was used is an autochthonous, tamoxifen-inducible liver cancer model (ASTxCre-ERT2; AST=Albumin-floxStop-SV40 large T antigen; Cre-ERT2 = TAM-dependent Cre-recombinase) in which the SV40 large T antigen serves as the oncogenic driver and tumor-specific antigen; SV40-I TCR transgenic mice, whose CD8 T cells express a Db-restricted TCR specific for the Tag epitope I were used as source of naïve tumor-specific CD8 T cells (TCRSV40-I)
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2023-07-10 | GSE209710 | GEO
Project description:TGFb signaling is a major pathway associated with poor clinical outcome in patients with
advanced metastatic cancers and non-response to immune checkpoint blockade, particularly in the immune-excluded tumor phenotype. While previous pre-clinical studies demonstrated that converting tumors from an excluded to an inflamed phenotype and curative anti-tumor immunity require attenuation of both PD-L1 and TGFb signaling, the underlying cellular mechanisms remain unclear. Recent studies suggest that stem cell-like CD8 T cells (TSCL) can differentiate into non-exhausted CD8 T effector cells that drive durable anti-tumor immunity. Here, we show that TGFb and PD-L1 restrain TSCL expansion as well as replacement of progenitor exhausted and dysfunctional CD8 T cells with non-exhausted IFNghi CD8 T effector cells in the tumor microenvironment (TME). Blockade of TGFb and PD-L1 generated IFNghi CD8 T effector cells with enhanced motility, enabling both their accumulation in the TME and increased interaction with other cell types. Ensuing IFNg signaling markedly transformed myeloid, stromal, and tumor niches to yield a broadly immune-supportive ecosystem. Blocking IFNg completely abolished the effect of anti-PD-L1/ TGFb combination therapy. Our data suggest that TGFb works in concert with PD-L1 to prevent TSCL expansion and replacement of exhausted CD8 T cells with fresh CD8
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2023-06-16 | MSV000092193 | MassIVE
Project description:Listeria monocytogenes is a foodborne intracellular bacterial model pathogen. Protective immunity against Listeria depends on an effective CD8 T-cell responses, but very few T cell epitopes are known in mice as most common animal infection model for listeriosis. To identify epitopes we screened for Listeria epitopes presented in the spleen of infected mice by mass spectrometry-based immunopeptidomics. In between more than 6,000 mouse self-peptides presented on MHC Class I molecules, we detected 26 Listeria peptides from 25 different bacterial proteins, including previously reported antigens. Bacterial immunopeptides with confirmed fragmentation spectra were further tested for their potential to CD8 T cells, revealing VTYNYINI from the putative cell wall surface anchor family protein LMON_0576 as a novel bona fide peptide epitope. Despite its high biological potency in a prime boost model, this epitope did not protect against challenge infection but can be used as a research tool to probe CD8 T cell responses in mouse models of Listeria infection. Our results demonstrate the power of immunopeptidomics for bacterial antigen identification but highlight the need for in-depth immune characterization for vaccine candidate selection.
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Project description:Hepatitis B virus-specific (HBV-specific) CD8+ T cells fail to acquire effector functions after priming in the liver, but the molecular basis for the dysfunction is poorly understood. By comparing the gene expression profile of intrahepatically primed, dysfunctional HBV-specific CD8+ T cells with that of systemically primed, functional effector counterparts, we found that the expression of interferon-stimulated genes (ISGs) is selectively suppressed in the dysfunctional CD8+ T cells. The ISG suppression was associated with impaired phosphorylation of STAT1 in response to IFN-α treatment. Importantly, a strong induction of type I interferons (IFN-Is) in the liver facilitated the functional differentiation of intrahepatically primed HBV-specific CD8+ T cells in association with the restoration of ISGs' expression in the T cells. These results suggest that intrahepatic priming suppresses IFN-I signaling in CD8+ T cells, which may contribute to the dysfunction. The data also suggest a therapeutic value of the robust induction of intrahepatic IFN-Is for the treatment of chronic HBV infection.
2021-02-09 | GSE159748 | GEO
Project description:<p>The efficacy of the adaptive immune response declines dramatically with age, but the cell-intrinsic mechanisms driving the changes characteristic of immune aging in humans remain poorly understood. One hallmark of immune aging is the loss of self-renewing naive cells and the accumulation of differentiated but dysfunctional cells within the CD8 T cell compartment. Using ATAC-seq, we first inferred the transcription factor binding activities that maintain the naive and central and effector memory CD8 T cell states in young adults. Integrating our results with RNA-seq, we determined that BATF, ETS1, Eomes, and Sp1 govern transcription networks associated with specific CD8 T cell subset properties, including activation and proliferative potential. Extending our analysis to aged humans, we found that the differences between memory and naive CD8 T cells were largely preserved across age, but that naive and central memory cells from older individuals exhibited a shift toward a more differentiated pattern of chromatin openness. Additionally, aged naive cells displayed a loss in chromatin openness at gene promoters, a phenomenon that appears to be due largely to a loss in binding by NRF1, leading to a marked drop-off in the ability of the naive cell to initiate transcription of mitochondrial genes. Our findings identify BATF- and NRF1-driven gene regulation as targets for delaying CD8 T cell aging and restoring T cell function.</p>
| phs001187 | dbGaP