Quiescent tissue stem cells evade immune surveillance
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ABSTRACT:
PROVIDER: PRJNA431410 | ENA |
REPOSITORIES: ENA
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Project description:Stem cells are critical for the maintenance of many tissues, and thus their integrity is crucial, but whether this integrity is maintained in the face of an immune response is not well defined. Here we set out to determine the outcome of T cell interactions with adult stem cells in their physiological niche. We find that fast cycling epithelial stem cells, including Lgr5+ intestinal stem cells, as well as ovary and mammary stem cells, are eliminated by activated T-cells, but slow cycling stem cells, specifically hair follicle and muscle stem cells, are resistant to T-cell killing. This is an intrinsic property of the quiescent stem cells resulting from systemic downregulation of the antigen presentation machinery, including MHC class I, Tap proteins, and the transactivator Nlrc5, which is reversed upon stem cell entry into the cell cycle. These findings identify a link between tissue stem cell quiescence, antigen presentation, and immune evasion, and may help explain why mutations in long-lived stem cells would not lead to immune editing. They also suggest how cancer-initiating cells may evade immune surveillance
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Project description:Tumors exploit FTO-mediated regulation of glycolytic metabolism to evade immune surveillance
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Project description:We present a novel mathematical model involving various immune cell populations and tumor cellpopulations. The model describes how tumor cells evolve and survive the brief encounter with theimmune system mediated by natural killer (NK) cells and the activated CD8þcytotoxic T lymphocytes(CTLs). The model is composed of ordinary differential equations describing the interactions betweenthese important immune lymphocytes and various tumor cell populations. Based on up-to-dateknowledge of immune evasion and rational considerations, the model is designed to illustrate how tu-mors evade both arms of host immunity (i.e.innate and adaptive immunity). The model predicts that(a) an influx of an external source of NK cells might play a crucial role in enhancing NK-cell immunesurveillance; (b) the host immune system alone is not fully effective against progression of tumor cells;(c) the development of immunoresistance by tumor cells is inevitable in tumor immune surveillance. Ourmodel also supports the importance of infiltrating NK cells in tumor immune surveillance, which can beenhanced by NK cell-based immunotherapeutic approaches.
2020-03-20 | MODEL2003040001 | BioModels
Project description:Ever-increasing understanding about the complexity of factors and regulatory layers that contribute to immune evasion facilitates the development of immunotherapies. However, the diversity of malignant tumors limits many known mechanisms in specific genetic and epigenetic contexts, manifesting the need to discover general driver genes. Here, we have identified the m6A demethylase FTO as an essential epitranscriptomic regulator utilized by tumors to escape immune surveillance through regulation of glycolytic metabolism. We show that FTO-mediated m6A demethylation in tumor cells elevates transcription factors c-Jun, JunB, and C/EBPβ, which allows the rewiring of glycolytic metabolism. Fto knockdown impairs the glycolytic activity of tumor cells, which restores the function of CD8+ T cells, thereby inhibiting tumor growth. Furthermore, we developed a small-molecule compound Dac51 that can inhibit the activity of FTO, block FTO-mediated immune evasion, and synergize with checkpoint blockade for better tumor control, suggesting reprogramming RNA epitranscriptome as a potential strategy for immunotherapy.
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Project description:Precociously disseminated cancer cells may seed quiescent sites of future metastasis if they can protect themselves from immune surveillance. However, there is little knowledge about how such sites might be achieved. Here we present evidence that prostate cancer stem-like cells (CSC) can be found in histopathologically negative prostate draining lymph nodes (PDLN) in mice harboring oncogene-driven prostate intraepithelial neoplasia (mPIN). PDLN-derived CSC were phenotypically and functionally identical to CSC obtained from mPIN lesions, but distinct from CSCs obtained from frank prostate tumors. CSC derived from either PDLN or mPIN used the extracellular matrix protein Tenascin-C (TNC) to inhibit T cell receptor-dependent T cell activation, proliferation and cytokine production. Mechanistically, TNC interacted with α5β1 integrin on the cell surface of T cells, inhibiting reorganization of the actin-based cytoskeleton therein required for proper T cell activation. CSC from both PDLN and mPIN lesions also expressed CXCR4 and migrated in response to its ligand CXCL12, which was overexpressed in PDLN upon mPIN development. CXCR4 was critical for the development of PDLN-derived CSC, as in vivo administration of CXCR4 inhibitors prevented establishment in PDLN of an immunosuppressive microenvironment. Taken together, our work establishes a pivotal role for TNC in tuning the local immune response to establish equilibrium between disseminated nodal CSC and the immune system. A total of six sample of TPIN (N = 3) and TNE (N = 3) cultured cells from TRAMP mouse model were analyzed
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Project description:Cancer cells evade host immune surveillance by virtue of poor immunogenicity. We identify a novel oncogene that acts as a promotor of tumor immune resistance, designated as PTIR1. Tumor-intrinsic PTIR1 is induced by RNA splicing and highly correlated with poor outcome of patients with cancer.
2024-02-19 | GSE168862 | GEO
Project description:Precociously disseminated cancer cells may seed quiescent sites of future metastasis if they can protect themselves from immune surveillance. However, there is little knowledge about how such sites might be achieved. Here we present evidence that prostate cancer stem-like cells (CSC) can be found in histopathologically negative prostate draining lymph nodes (PDLN) in mice harboring oncogene-driven prostate intraepithelial neoplasia (mPIN). PDLN-derived CSC were phenotypically and functionally identical to CSC obtained from mPIN lesions, but distinct from CSCs obtained from frank prostate tumors. CSC derived from either PDLN or mPIN used the extracellular matrix protein Tenascin-C (TNC) to inhibit T cell receptor-dependent T cell activation, proliferation and cytokine production. Mechanistically, TNC interacted with α5β1 integrin on the cell surface of T cells, inhibiting reorganization of the actin-based cytoskeleton therein required for proper T cell activation. CSC from both PDLN and mPIN lesions also expressed CXCR4 and migrated in response to its ligand CXCL12, which was overexpressed in PDLN upon mPIN development. CXCR4 was critical for the development of PDLN-derived CSC, as in vivo administration of CXCR4 inhibitors prevented establishment in PDLN of an immunosuppressive microenvironment. Taken together, our work establishes a pivotal role for TNC in tuning the local immune response to establish equilibrium between disseminated nodal CSC and the immune system.
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Project description:Cellular senescence is a homeostatic program associated with tumor suppression, wound healing, and certain age related pathologies. Senescent cells display a repressive chromatin configuration thought to stably silence proliferation-promoting genes, while at the same time activate an unusual form of immune surveillance involving a secretory program referred to as the senescence-associated secretory phenotype (SASP). Here we demonstrate that senescence also involves a global remodeling of the enhancer landscape with recruitment of the chromatin reader BRD4 to newly activated super-enhancers adjacent to key SASP genes. Transcriptional profiling and functional studies indicate that BRD4 is required for the SASP and downstream paracrine signaling. Consequently, BRD4 inhibition disrupts immune cell-mediated targeting and elimination of premalignant senescent cells in vitro and in vivo. Our results identify a critical role for BRD4-bound super-enhancers in senescence immune surveillance and in the proper execution of a tumor-suppressive program.
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