Treatment of dendritic cells and monocytes from immunotherapy treated patients with ONTAK
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Beltrame Luca
PROVIDER: S-ECPF-MTAB-977 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:In this experiment, dendritic cells and monocytes obtained from melanoma patients who underwent immunotherapy were stimulated with a maturation cocktail then either treated or not treated with denlieukin diftitox (DD; ONTAK) and then subjected to transcription profiling to investigate the effects of DD on the maturation and activation of dendritic cells and monocytes.
2013-09-04 | E-MTAB-977 | biostudies-arrayexpress
Project description:Recently, we found that temozolomide (TMZ) can upregulate the expression of the multidrug-resistance protein ABCC3 in NK cells from both glioma-bearing mice and glioblastoma patients treated with dendritic cell immunotherapy combined with TMZ, allowing NK cells to escape apoptosis and favoring their role as antitumor effector cells. Here, we demonstrate that CD56dim NK cells expressing CD16+ are predominant in patients surviving more than 12 months after surgery without disease progression. CD56dim CD16+ NK cells co-expressed high levels of ABCC3 and IFN-. Notably, not only basal but also TMZ-induced ABCC3 expression was related to a strong, long-term NK cell response and a better prognosis of patients. The identification of the single nucleotide polymorphism (SNP) rs35467079 with the deletion of a cytosine (-897DelC) in the promoter region of the ABCC3 gene resulted associated with a better patient outcome. ABCC3 expression in patients carrying DelC compared to patients with reference haplotype was higher and modulated by TMZ. The transcription factor NRF2, involved in ABCC3 induction, was phosphorylated in CD56dim CD16+ NK cells expressing ABCC3 under TMZ treatment. Thus, ABCC3 protein and the SNP -897DelC can play a predictive role in patients affected by GBM, and possibly other cancers, treated with dendritic cell immunotherapy combined with chemotherapy.
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Project description:Circulating monocytes can differentiate into dendritic cells (moDCs), which are potent inducers of adaptive immune responses. Previous reports show that granulocyte macrophage-colony-stimulating factor (GM-CSF) and interleukin-4 induce monocyte differentiation into moDCs in vitro, but little is known about the physiological requirements that initiate moDC differentiation in vivo. Here we show that a unique natural killer (NK) cell subset (CD3(-)CD56(bright)) that accumulates in lymph nodes and chronically inflamed tissues triggers CD14(+) monocytes to differentiate into potent T-helper-1 (T(H)1) promoting DC. This process requires direct contact of monocytes with NK cells and is mediated by GM-CSF and CD154 derived from NK cells. It is noteworthy that synovial fluid (SF) from patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA), but not osteoarthritis (OA), induces monocytes to differentiate into DC. However, this process occurs only in the presence of NK cells. We propose that NK cells play a role in the maintenance of T(H)1-mediated inflammatory diseases such as RA by providing a local milieu for monocytes to differentiate into DC.
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Project description:Although many effects of staphylococcal superantigens (SAg) on T cells are well established, less is known about their effects on APC. In this study, bovine PBMC were stimulated with a low dose of staphylococcal enterotoxin C1 (SEC1). The phenotype of adherent cells (Ac) derived from bovine PBMC cultured with SEC1 [SEC1-stimulated Ac (sAc)] for 192 h was CD14(-), CD68(-), CD163(-), dendritic cell (DC)-specific ICAM-3-grabbing nonintegrin(+), MHC class II (MHC II)(high), CD11a(low), CD11b(high), CD11c(high), and CD1b(high), suggesting these cells were dendritic cells (DC). SEC1 also induced transcription of the CXCL1, -2, and -3 family, CXCL6, CCL2, and CCL5 genes in sAc, which increased rapidly but returned to basal levels by 48 h. In contrast, increased transcription of CCL3, CCL8, and CXCL12, responsible for mononuclear cell migration and chronic inflammation, was sustained. In vitro cell migration assays showed vigorous migration of granulocytes, followed by migration of mononuclear cells. The autologous MLR showed that sAc induced a dose-dependent proliferation of CD4(+) T cells and an even stronger proliferation of CD8(+) T cells. This effect was inhibited or reduced by pretreatment with mAb to CD11b, MHC II, or MHC II plus CD18. These results indicate that stimulation of bovine PBMC by SAg induces differentiation of monocytes into DC.
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Project description:Glioblastoma is the most prevalent and aggressive brain cancer. With a median overall survival of ~15-20 months under standard therapy, novel treatment approaches are desperately needed. A recent phase II clinical trial with a personalized immunotherapy based on tumor lysate-charged dendritic cell (DC) vaccination, however, failed to prolong survival. Here, we investigated tumor tissue from trial patients to explore glioblastoma survival-related factors. We followed an innovative approach of combining mass spectrometry-based quantitative proteomics (n = 36) with microRNA sequencing plus RT-qPCR (n = 38). Protein quantification identified, e.g., huntingtin interacting protein 1 (HIP1), retinol-binding protein 1 (RBP1), ferritin heavy chain (FTH1) and focal adhesion kinase 2 (FAK2) as factor candidates correlated with a dismal prognosis. MicroRNA analysis identified miR-216b, miR-216a, miR-708 and let-7i as molecules potentially associated with favorable tissue characteristics as they were enriched in patients with a comparably longer survival. To illustrate the utility of integrated miRNomics and proteomics findings, focal adhesion was studied further as one example for a pathway of potential general interest. Taken together, we here mapped possible drivers of glioblastoma outcome under immunotherapy in one of the largest DC vaccination tissue analysis cohorts so far-demonstrating usefulness and feasibility of combined proteomics/miRNomics approaches. Future research should investigate agents that sensitize glioblastoma to (immuno)therapy-potentially building on insights generated here.
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Project description:Rationale: Regulatory T cells (Treg) play a pivotal role in the immunosuppressive tumor micro-environment in cancer, including mesothelioma. Recently, the combination of autologous tumor lysate-pulsed dendritic cells (DC) and metronomic cyclophosphamide (mCTX) was reported as a feasible and well-tolerated treatment in malignant pleural mesothelioma patients and further as a method to reduce circulating Tregs. Objectives: The aim of this study was to establish the immunological effects of mCTX alone and in combination with DC-based immunotherapy on circulating Treg and other T cell subsets in mesothelioma patients. Methods: Ten patients received mCTX and DC-based immunotherapy after chemotherapy (n = 5) or chemotherapy and debulking surgery (n = 5). Peripheral blood mononuclear cells before, during and after treatment were analyzed for various Treg and other lymphocyte subsets by flow cytometry. Results: After one week treatment with mCTX, both activated FoxP3hi and naïve CD45RA+ Tregs were effectively decreased in all patients. In addition, a shift from naïve and central memory towards effector memory and effector T cells was observed. Survival analysis showed that overall Treg levels before treatment were not correlated with survival, however, nTreg levels before treatment were positively correlated with survival. After completion of mCTX and DC-based immunotherapy treatment, all cell subsets returned to baseline levels, except for the proportions of proliferating EM CD8 T cells, which increased. Conclusions: mCTX treatment effectively reduced the proportions of circulating Tregs, both aTregs and nTregs, thereby favoring EM T cell subsets in mesothelioma patients. Interestingly, baseline levels of nTregs were positively correlated to overall survival upon complete treatment.
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