TET2 Promotes Tumor Antigen Presentation and T Cell-Directed Tumor Cell Cytotoxicity Which is Enhanced by Vitamin C Treatment
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE227998 | GEO | 2024/05/16
REPOSITORIES: GEO
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Project description:Decreased antigen presentation contributes to the ability of cancer cells to evade the immune system. We used the minimal gene regulatory network of type 1 conventional dendritic cells (cDC1) to reprogram cancer cells into professional antigen- presenting cells (tumor-APCs). Enforced expression of the transcription factors PU.1, IRF8, and BATF3 (PIB) was sufficient to induce cDC1 phenotype in 36 cell lines derived from human and mouse hematological and solid tumors. Within 9 days of reprogramming, tumor-APCs acquired transcriptional and epigenetic programs associated with cDC1 cells. Reprogramming restored the expression of antigen presentation complexes and costimulatory molecules on the surface of tumor cells, allowing the presentation of endogenous tumor antigens on MHC-I, and facilitating targeted killing by CD8+ T cells. Functionally, tumor-APCs engulfed and processed proteins and dead cells, secreted inflammatory cytokines, and cross- presented antigens to naïve CD8+ T cells. Human primary tumor cells could also be reprogrammed to increase their capability to present antigen and to activate patient-specific tumor-infiltrating lymphocytes. In addition to acquiring improved antigen presentation, tumor-APCs had impaired tumorigenicity in vitro and in vivo. Injection of in vitro generated melanoma-derived tumor-APCs into subcutaneous melanoma tumors delayed tumor growth and increased survival in mice. Antitumor immunity elicited by tumor-APCs was synergistic with immune checkpoint inhibitors. Our approach serves as a platform for the development of immunotherapies that endow cancer cells with the capability to process and present endogenous tumor antigens.
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Project description:This model of the immune system response to antigen presentation is based on the publication:
Eduardo D.Sontag (2017) 'A Dynamic Model of Immune Responses to Antigen Presentation Predicts Different Regions of Tumor or Pathogen Elimination', Cell Systems, 4(2)
DOI: 10.1016/j.cels.2016.12.003
Comment:
This model is based on the "toy model" as described by Equations 1A-1C from the manuscript and the system represented by Equation 2, which exhibits a type of incoherent feedforward loop (IFFL).
Abstract:
The immune system must discriminate between agents of disease and an organism’s healthy cells. While the identification of an antigen as self/non-self is critically important, the dynamic features of antigen presentation may also determine the immune system’s response. Here, we use a simple mathematical model of immune activation to explore the idea of antigen discrimination through dynamics. We propose that antigen presentation is coupled to two nodes, one regulatory and one effecting the immune response, through an incoherent feedforward loop and repressive feedback. This circuit would allow the immune system to effectively estimate the increase of antigens with respect to time, a key determinant of immune reactivity in vivo. Our model makes the prediction that tumors growing at specific rates evade the immune system despite the continuous presence of antigens indicating disease, a phenomenon closely related to clinically observed “two-zone tolerance.” Finally, we discuss a plausible biological instantiation of our circuit using combinations of regulatory and effector T cells.
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