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ScRNA-seq of antigen-specific CD8+ T cells from tumor draining LN, TIL and PBMC of melanoma bearing mice

ABSTRACT: CD8+ T cell-mediated immune response plays a pivotal role in controlling tumor growth.However, within the tumor microenvironment (TME), prolonged antigen exposure, as well as immunosuppressive factors, drive infiltrated tumor-specific CD8+ T cells into a hyporesponsive state known as “exhaustion”. These Tex cells are mainly characterized by the sustained and elevated expression of a series of inhibitory receptors as well as the hierarchical loss of effector functions. Further, the impaired proliferative capacity of exhausted CD8+ T cells results in decreasing numbers of tumor-specific T cells, such that the residual CD8+ T cells within the TME can barely provide sufficient protective immunity against tumor progression. Thus, the maintenance or reinforcement of intratumoral antigen-specific CD8+ T cells is indispensable for tumor repression. Here, we profiled the transcriptional signatures of antigen-specific CD8+ T cells from tumor draining LN, TIL and PBMC of melanoma bearing mice at single-cell level, aiming to draw a comprehensive immune-atlas of tumor-specific CD8 T cells during tumorigenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE180094 | GEO | 2022/10/10

REPOSITORIES: GEO

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ATAC-seq of antigen-specific CD8+ T cells from tumor draining LNs of melanoma bearing mice II

Project description:CD8+ T cell-mediated immune response plays a pivotal role in controlling tumor growth.However, within the tumor microenvironment (TME), prolonged antigen exposure, as well as immunosuppressive factors, drive infiltrated tumor-specific CD8+ T cells into a hyporesponsive state known as “exhaustion”. Notably, our current understanding of tumor-specific CD8+ T cells mainly comes from experiments focusing on tumor infiltrated T cells, less is known about those in tumor draining LNs. Hence, we profiled the chromosome accessibilities of antigen-specific CD8+ T cells from tumor draining LNs of melanoma bearing mice in this project, aiming to draw a comprehensive immune-atlas of tumor-specific CD8+ T cells during tumorigenesis.

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ATAC-seq of antigen-specific CD8+ T cells from tumor draining LNs of melanoma bearing mice

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RNASeq of Plasmacytoid Dendritic Cells in Head and Neck Squamous Cell Cancer

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LN-stem, tumor stem, tumor terminally differentiated CD8 T cells from human kidney cancer

Project description:This work aimed to understand the source of TCF1+ CD8 T cells in tumors. By studying human tumor draining lymph-nodes (TDLNs), we find that CD8 T cells activate in TDLN but fail to acquire the normal effector program. Instead, these CD8 T cells share functional, transcriptional, and epigenetic traits with TCF1+ stem-like cells in the tumor. This suggests that these activated cells are a precursor to the stem-like CD8 T cells in tumors. By using mouse models, we show that tumor-specific CD8 T cells are activated in TDLN, but do not acquire an effector phenotype. These cells then migrate into the tumor where they require additional co-stimulation from antigen presenting cells to acquire the effector program. This is strikingly different from canonical CD8 T cell activation to acute viruses, where the effector program is acquired immediately. This model of T cell differentiation has important implications to improve immunotherapy.

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Mus musculus

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Mus musculus strain:b6

Project description:Tumor antigen specific CD8 Tissue Resident Memory (Trm) Cells

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Project description:PD-1 blockade therapy exerts antitumor effects by restoring the infiltration of tumor antigen-specific CD8+ T cells. While neoantigens arising from gene alterations in cancer cells comprise critical tumor antigens in antitumor immunity, a subset of non-small-cell lung cancers (NSCLCs) harboring substantial tumor mutation burden (TMB) lack CD8+ T cells in the tumor microenvironment (TME), resulting in resistance to PD-1 blockade therapy. This resistance is an urgent issue, so the mechanism(s) mediating impaired antitumor immunity in highly mutated NSCLCs need to be explored. Here, we show that activation of the WNT/b-catenin signaling pathway contributes to the development of a noninflamed TME in tumors with high TMB. NSCLCs that lack immune cell infiltration into the TME despite high TMB preferentially upregulate the WNT/b-catenin pathway. Immunological assays revealed that those patients harbored neoantigen-specific CD8+ T cells in the peripheral blood but not in the TME, suggesting impaired T cell infiltration into the TME due to the activation of WNT/b-catenin signaling. In our animal model, the accumulation of gene mutations in cancer cells increased CD8+ T cell infiltration into the TME, slowing tumor growth. However, further accumulation of gene mutations blunted antitumor immunity by excluding CD8+ T cells from tumors in a WNT/b-catenin signaling-dependent manner. Combined treatment with PD-1 blockade and WNT/b-catenin signaling inhibitors induced far stronger antitumor immunity than either treatment alone. We propose a mechanism-oriented combination therapy concept in the cancer immunotherapy field, i.e., the combination of immune checkpoint inhibitors with drugs that target specific molecules in cancer cell-intrinsic oncogenic signaling pathways involved in immune escape.

2021-09-17 | GSE181820 | GEO

Combined PD-L1/TGFb blockade allows expansion and differentiation of stem cell-like CD8 T cells in immune excluded tumors

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 T effector cells, thereby maintaining the CD8 T cell compartment in a dysfunctional state.

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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. NaÃ¯ve 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 naÃ¯ve 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: NaÃ¯ve, effector, D8-12-pre-malignant lesions, and D32-34 pre-malignant lesions.

2016-08-11 | E-GEOD-60501 | biostudies-arrayexpress

IL-33 provision by reprogrammed tumor fibroblastic stromal cells promotes local T cell activity and facilitates melanoma eradication

Project description:The tumor microenvironment (TME) is a complex mixture of tumor cells, immune cells, endothelial cells and fibroblastic stroma cells (FSC). While cancer-associated fibroblasts are generally seen as a tumor-promoting entity, it is conceivable that distinct FSC populations within the TME contribute to immune-mediated tumor control. Here, we show that intra-tumoral injection of a recombinant LCMV-based vaccine vector (r3LCMV) expressing the melanocyte differentiation antigen TRP2 results in T cell-dependent eradication of melanomas. Analysis of the TME revealed that viral vector transduction precipitates activation of particular FSC subsets. Using single-cell RNA-seq analysis, we identified a Cxcl13-expressing FSC population with a pronounced immune-stimulatory signature and increased expression of the inflammatory cytokine IL-33. Genetic ablation of Il33 in Cxcl13-Cre+ FSC impeded functionality of intratumoral T cells and consequently tumor control. Thus, reprogramming of distinct FSC subsets in the TME through LCMV-based vectors efficiently promotes tumor eradication by locally sustaining the activity of tumor-specific T cells.

2021-07-03 | E-MTAB-9407 | biostudies-arrayexpress

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