RNA-seq of tumor-specific CD8+ T cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE228387 | GEO | 2023/03/29
REPOSITORIES: GEO
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Project description:Tumor-specific CD8+ T cells are heterogeneous; Tcf1+ stem-like CD8+ T cells give rise to cytotoxic Tim-3+ terminally differentiated CD8+ T cells. The goal of this study is to determine the capacity of CD69 to regulate differentiation of tumor-specific CD8+ T cells in the tumor microenvironment and tumor-draining lymph nodes. Our single-cell RNA-seq and RNA-seq analyses of tumor-specific CD8+ T cells reveal the important function of CD69 in anti-tumor CD8+ T cell immunity. Thus, CD69 is an attractive target for cancer immunotherapy.
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Project description:CD8 T cells play an essential role in anti-tumor immunity and chronic viral infections. Recent findings have delineated the differentiation pathway of CD8 T cells in accordance with the progenitor-progeny relationship of TCF1+ stem-like and Tim-3+TCF1- more differentiated T cells. Here we investigated the characteristics of stem-like and differentiated CD8 T cells isolated from several murine tumor models and human lung cancer samples in terms of phenotypic and transcriptional features as well as their location compared to virus-specific CD8 T cells in the chronically LCMV-infected mice. We found that CD8 tumor-infiltrating lymphocytes (TILs) in both murine and human tumors exhibited overall similar phenotypic and transcriptional characteristics compared to corresponding subsets in the spleen of chronically infected mice.
2023-04-02 | GSE228419 | GEO
Project description:Stem-like CD8 + T cells are regulated by the transcription factor TCF1 and are key players in the response to immune checkpoint blockade (ICB). However, recent findings indicate that reliance on TCF1 + CD8 + stem-like T cells for ICB efficacy may not be equal across patients or tumor contexts. Here, we uncovered that TCF1-deficient CD8 + T cells showed defective priming in the tumor-draining lymph node of mice bearing poorly immunogenic tumors and that TCF1 regulates optimal T cell responsiveness to low TCR triggering. Importantly, we found that TCF1 was dispensable for therapy response in settings where ICB expanded intra-tumoral transitory effector-like cells. Conversely, TCF1 was required for ICB response in tumors that failed to expand cytotoxic effectors and accumulated Tox + dysfunctional T cells. In the absence of TCF1, dysfunctional T cells became destabilized and shared features with CD8 + T cells found in patients that fail ICB. Our study highlights a role for TCF1 in the early stages of the anti-tumor CD8 + T cell response with important implications for guiding optimal therapeutic interventions in cancers with low frequency of TCF1 + CD8 + T cells and low neoantigen levels.
2023-08-24 | GSE217038 | GEO
Project description:“Stem-like” TCF1+ CD8+ T cells (TSL) are necessary for long-term maintenance of T cell responses and the efficacy of immunotherapy but, as tumors contain signals that should drive T-cell terminal-differentiation, how these cells are maintained in tumors remains unclear. In this study, we found that a small number of TCF1+ tumor-specific CD8+ T cells were present in lung tumors throughout their development. Yet, most intratumoral T cells differentiated as tumors progressed, corresponding with an immunologic shift in the tumor microenvironment (TME) from “hot” (T cell-inflamed) to “cold” (non-T cell-inflamed). By contrast, most tumor-specific CD8+ T cells in tumor-draining lymph nodes (dLNs) had functions and gene expression signatures similar to TSL from chronic LCMV infection, and this population was stable over time, despite the changes in the TME. dLN T cells were the developmental precursors of, and were clonally related to, their more-differentiated intratumoral counterparts. Our data support the hypothesis that dLN T cells are the developmental precursors of the TCF1+ T cells in tumors which are maintained by continuous migration. Finally, CD8+ T cells similar to TSL were also present in LNs from lung adenocarcinoma patients, suggesting a similar model may be relevant in human disease. Thus, we propose that the dLN TSL reservoir has a critical function in sustaining antitumor T cells during tumor development and protecting them from the terminal differentiation that occurs in the TME. Methods: We analyzed single-cell RNA-sequencing to assess the differentiation state and trajectory of the cell subsets present after FACs sorting on endogenous GP33-specific CD8+ T cells from tumors and draining lymph nodes of tumor-bearing KP-NINJA mice, comparing them to GP33-specific CD8+ T cells from spleens of mice infected with acute or chronic LCMV. In order to determine the clonal relationship of these cells from tumors and draining lymph nodes, we analyzed paired single-cell TCR sequencing.
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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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Project description:The goal of this study is to characterize the transcriptional profile of PD-1+ stem-like (Tim-3-CD73+) versus terminally-differentiated (Tim-3+CD73-) CD8 T cells following two week αPD-1 blockade.
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Project description:In chronic infections and cancer, exhausted CD8 T cells exhibit heterogeneous subpopulations. TCF1+PD-1+ progenitor exhausted CD8 T cells (Tpex) can self-renew and give rise to Tim-3+PD-1+ terminally differentiated CD8 T cells that retain their effector functions. Tpex cells are thus essential to maintaining a pool of antigen-specific CD8 T cells during persistent antigenic stimulation, and only they respond to PD-1-targeted therapy. Despite their potential as a crucial therapeutic target for immune interventions, the mechanisms controlling the maintenance of virus-specific Tpex cells remain to be determined. We observed approximately 10-fold fewer Tpex cells in the spleens of mice chronically infected with lymphocytic choriomeningitis virus (LCMV) one-year post-infection (p.i.) than at three months p.i. Similar to memory CD8 T cells, Tpex cells have been found to undergo self-renewal in the lymphoid organs, prominently the bone marrow, during chronic LCMV infection. Furthermore, ex vivo treatment with IL-15 preferentially induced the proliferation of Tpex cells rather than the terminally differentiated subsets. Interestingly, single-cell RNA sequencing analysis of LCMV-specific exhausted CD8 T cells after ex vivo IL-15 treatment compared with those before treatment revealed upregulation of ribosome-related genes and downregulation of genes associated with the TCR signaling pathway and apoptosis in both Tpex and Ttex subsets. The exogenous administration of IL-15 to chronically LCMV-infected mice also significantly increased self-renewal of Tpex cells in the spleen and bone marrow. In addition, we assessed the responsiveness of CD8 tumor-infiltrating lymphocytes (TILs) from renal cell carcinoma patients to IL-15. Similar to the data we obtained from chronic viral infection in mice, the expansion of the Tpex subset of PD-1+ CD8 TILs upon ex vivo IL-15 treatment was significantly higher than that of the terminally differentiated subset. These results show that IL-15 could promote self-renewal of Tpex cells, which has important therapeutic implications.
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Project description:Persistent exposure to high levels of antigen results in the progressive exhaustion of T cells and has been thought to preclude the formation of memory. In contrast to the latter assumption, we show here that tumor-specific CD8 T cells residing in the tumor microenvironment include a Tcf1 expressing sub population that has key characteristics of central memory cells, lack an effector cell signature but display hallmarks of exhausted T cells, including the expression co-inhibitory receptors such as PD1. Similar memory-like cells are identified in melanoma patients. Preclinical mouse models reveal that the expansion of tumor-specific CD8 T cells, the production of terminally differentiated exhausted CD8 T cells and sustained tumor control in response to therapeutic vaccination or immune checkpoint blockade critically depends on the presence of these memory-like CD8 T cells. Tumor immune responses thus harbor tumor resident memory-like CD8 T cell populations, which can be therapeutically targeted to improve immune control of cancer.
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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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