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Epstein–Barr virus (EBV) is a ubiquitous herpes virus associated with various cancers. EBV establishes latency with life-long persistence in memory B-cells and can reactivate lytic infection placing immunocompromised individuals at risk for EBV-driven lymphoproliferative disorders (EBV-LPD). Despite the ubiquity of EBV, only a small percentage of immunocompromised patients (~20%) develop EBV-LPD. Engraftment of immunodeficient mice with peripheral blood mononuclear cells (PBMCs) from healthy EBV-seropositive donors leads to spontaneous, malignant, human B-cell EBV-LPD. Only about 20% of EBV+ donors induce EBV-LPD in 100% of engrafted mice (High-Incidence, HI), while another 20% of donors never generate EBV-LPD (No-Incidence, NI). Here, we report HI donors to have significantly higher basal T follicular helper (Tfh) and regulatory T-cells (Treg), and depletion of these subsets prevents/delays EBV-LPD. Transcriptomic analysis of CD4+ T cells from ex vivo HI donor PBMC revealed amplified cytokine and inflammatory gene signatures. HI vs. NI donors showed a marked reduction in IFNγ production to EBV latent and lytic antigen stimulation. In addition, we observed abundant myeloid-derived suppressor cells in HI donor PBMC that decreased CTL proliferation in co-cultures with autologous EBV+ lymphoblasts. Our findings identify potential biomarkers that may identify individuals at risk for EBV-LPD and suggest possible strategies for prevention.

Acute graft-versus-host disease (aGVHD) is a T cell-mediated immunological disorder and the leading cause of nonrelapse mortality in patients who receive allogeneic hematopoietic cell transplants. Based on recent observations that protein arginine methyltransferase 5 (PRMT5) and arginine methylation are upregulated in activated memory T cells, we hypothesized that PRMT5 is involved in the pathogenesis of aGVHD. Here, we show that PRMT5 expression and enzymatic activity were upregulated in activated T cells in vitro and in T cells from mice developing aGVHD after allogeneic transplant. PRMT5 expression was also upregulated in T cells of patients who developed aGVHD after allogeneic hematopoietic cell transplant compared with those who did not develop aGVHD. PRMT5 inhibition using a selective small-molecule inhibitor (C220) substantially reduced mouse and human allogeneic T cell proliferation and inflammatory IFN-γ and IL-17 cytokine production. Administration of PRMT5 small-molecule inhibitors substantially improves survival, reducing disease incidence and clinical severity in mouse models of aGVHD without adversely affecting engraftment. Importantly, we show that PRMT5 inhibition retained the beneficial graft-versus-leukemia effect by maintaining cytotoxic CD8+ T cell responses. Mechanistically, we show that PRMT5 inhibition potently reduced STAT1 phosphorylation as well as transcription of proinflammatory genes, including interferon-stimulated genes and IL-17. Additionally, PRMT5 inhibition deregulates the cell cycle in activated T cells and disrupts signaling by affecting ERK1/2 phosphorylation. Thus, we have identified PRMT5 as a regulator of T cell responses and as a therapeutic target in aGVHD.

BackgroundEach year in the United States, approximately 20,000 new cases of gliomas are diagnosed in children, adolescents, and adults. These disparate brain tumors are heterogeneous and exist on a pathologic continuum. Low-grade gliomas (LGGs) are more prevalent in adolescents and young adults.1 2 While Grade I LGGs are associated with favorable survival rates, Grade II counterparts remain a significant challenge, given their propensity to recur.3–6 The inability of tumor-centric therapies to impair malignant transformation has been attributed to innate mechanisms of resistance within the brain tumor microenvironment (TME), mediated by a robust infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs) and tumor-associated M2-like macrophages (TAM).7–10 Immunosuppressive myeloid cells promote tumor escape mechanisms, while impairing the trafficking and cytotoxicity of Natural Killer (NK) and CD8+ (T) cells.10–15 To that end, immunotherapies demonstrated limited efficacy in improving outcomes for primary and secondary HGGs. HYPOTHESIS. We hypothesize that engineered myeloid cells16 17 that release IL-2 will reprogram the TME to enhance the trafficking and activation of activated effector T and NK cells in low-grade glioma bearing mice.MethodsA single intravenous dose of syngeneic and genetically engineered bone marrow-derived myeloid cells was used to treat immunocompetent LGG AYA animals, and the impact of this cellular therapy on infiltrating immune cells within the tumor microenvironment was investigated by RNA sequencing and gene enrichment analysis, cytokine arrays, and mass cytometry.ResultsThree days post-treatment, we observed GEMys infiltration in the local brain tumor microenvironment. In addition, gene enrichment analyses demonstrated pro-inflammatory reprogramming of tumor infiltrating immune cells. Activation of innate and adaptive immune response signaling pathways and networks associated with IFNy and TLR4 were observed post-treatment. Conversely, immunosuppressive signaling of IL10RA and CITED2 were significantly downregulated. Furthermore, biological functions associated with inflammatory response, immune cell trafficking, cellular proliferation, and cell-to cell signaling were significantly upregulated. Additional analysis of the TME by cytokine array and mass cytometry confirmed the therapeutic association of this cell mediated immunotherapy on promoting a pro-inflammatory TME, underscored with an increased trafficking of activated cytotoxic T and NK cells.ConclusionsThe use of GEMys is a novel cell-mediated approach and may serve as a platform for developing innate immunotherapies for patients with gliomas.ReferencesDiwanji TP, et al. Epidemiology, diagnosis, and optimal management of glioma in adolescents and young adults. Adolesc Health Med Ther, 2017;8: 99–113.Grier JT and T Batchelor. Low-grade gliomas in adults. Oncologist, 2006; 11(6): 681–93.Upadhyaya SA, et al. 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Myeloid derived suppressor cell infiltration of murine and human gliomas is associated with reduction of tumor infiltrating lymphocytes. J Neurooncol, 2015. 122(2): 293–301.Liu CY, et al. Population alterations of L-arginase- and inducible nitric oxide synthase-expressed CD11b+/CD14−/CD15+/CD33+ myeloid-derived suppressor cells and CD8+ T lymphocytes in patients with advanced-stage non-small cell lung cancer. J Cancer Res Clin Oncol, 2010. 136(1): 35–45.Pombo Antunes AR, et al. Understanding the glioblastoma immune microenvironment as basis for the development of new immunotherapeutic strategies. Elife, 2020; 9.Kmiecik J, et al. Elevated CD3+ and CD8+ tumor-infiltrating immune cells correlate with prolonged survival in glioblastoma patients despite integrated immunosuppressive mechanisms in the tumor microenvironment and at the systemic level. Journal of Neuroimmunology, 2013; 264(1): 71–83.Grabowski MM, et al. Immune suppression in gliomas. J Neurooncol, 2021; 151(1): 3–12.Klement JD. et al. Tumor PD-L1 engages myeloid PD-1 to suppress type I interferon to impair cytotoxic T lymphocyte recruitment. Cancer Cell, 2023; 41(3): 620–36 e9.Canella A, and P Rajappa. Therapeutic utility of engineered myeloid cells in the tumor microenvironment. Cancer Gene Ther, 2023.Kaczanowska, S., et al. Genetically engineered myeloid cells rebalance the core immune suppression program in metastasis. Cell, 2021. 184(8): 2033–2052 e21.