| 1. |
- Lindqvist, Camilla A, et al.
(författare)
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FoxP3+ T-Cells in Patients with B-Cell Chronic Lymphocytic Leukemia Express Cytolytic Markers and Kill Autologous B-Cells
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Recent reports indicate that infiltration of FoxP3+ cells into the tumor area may be associated with better overall survival of patients with B-cell malignancies, which is in contrast to patients with non-hematopoetic tumors. Here, we demonstrate a possible mechanism to these findings. Since the tumor cell in lymphoma originates from the immune system we hypothesized that FoxP3+ T regulatory cells (Tregs) may have a suppressive role in tumor progression in patients with B-cell malignancies. Peripheral blood was collected from 14 patients with B-cell chronic lymphocytic leukemia (B-CLL) and their Tregs were evaluated for cytolytic markers such as FasL and CD107a. We found that both conventional Tregs (CD4+ FoxP3+CD127low T-cells) and FoxP3+CD127high T-cells were significantly increased in patients with B-CLL compared to healthy controls. Further, both groups of FoxP3+ cells displayed higher expression of the degranulation marker CD107a indicating perforin/granzyme release. A flow cytometry-based cytotoxicity assay demonstrated that purified Tregs from both patients and healthy controls could kill autologous B-cells in vitro. In conclusion, FoxP3+ T-cells in patients with CLL show effector phenotype and may be involved in tumor cell control by their natural capacity to kill B-cells.
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| 2. |
- Eriksson, Emma, et al.
(författare)
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Activation of myeloid and endothelial cells by CD40L gene therapy supports T-cell expansion and migration into the tumor microenvironment
- 2017
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Ingår i: Gene Therapy. - : Springer Science and Business Media LLC. - 0969-7128 .- 1476-5462. ; 24:2, s. 92-103
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Tidskriftsartikel (refereegranskat)abstract
- CD40 is an interesting target in cancer immunotherapy due to its ability to stimulate T-helper 1 immunity via maturation of dendritic cells and to drive M2 to M1 macrophage differentiation. Pancreatic cancer has a high M2 content that has shown responsive to anti-CD40 agonist therapy and CD40 may thus be a suitable target for immune activation in these patients. In this study, a novel oncolytic adenovirus armed with a trimerized membrane-bound extracellular CD40L (TMZ-CD40L) was evaluated as a treatment of pancreatic cancer. Further, the CD40L mechanisms of action were elucidated in cancer models. The results demonstrated that the virus transferring TMZ-CD40L had oncolytic capacity in pancreatic cancer cells and could control tumor progression. TMZ-CD40L was a potent stimulator of human myeloid cells and T-cell responses. Further, CD40L-mediated stimulation increased tumor-infiltrating T cells in vivo, which may be due to a direct activation of endothelial cells to upregulate receptors for lymphocyte attachment and transmigration. In conclusion, CD40L-mediated gene therapy is an interesting concept for the treatment of tumors with high levels of M2 macrophages, such as pancreatic cancer, and an oncolytic virus as carrier of CD40L may further boost tumor killing and immune activation.
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| 3. |
- Lindqvist, Camilla A, et al.
(författare)
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Peripheral T Lymphocytes, Including FoxP3+ T-Cells, Exhibit a Cytotoxic Phenotype in Patients with B-Cell Lymphoma
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Recent studies have shown that high levels of FoxP3+ cells within lymphoma-affected lymph nodes are associated with a better outcome of patients with B-cell lymphoma. This finding is opposite to what has been seen in patients with solid non-hematopoietic tumors. In an attempt to better understand the role of FoxP3+ cell in lymphoma, we collected peripheral blood from 17 patients and determined the level of T regulatory cells (CD3+CD4+FoxP3+CD127low lymphocytes) and FoxP3+CD127high T-cells (CD3+CD4+FoxP3+CD127high lymphocytes). The two subgroups of FoxP3+ T-cells, as well as conventional FoxP3- T-cells, were further analyzed for presence of cytotoxic markers such as FasL and CD107a. Patient plasma was analyzed for the immunosuppressive cytokines IL-10 and TGF-β. Finally, the proliferative capacity of T-cells was assessed using Alamar Blue assay. In lymphoma patients, both FoxP3+ T-cells and conventional T-cells had elevated levels of cytotoxic markers. No significant increase in IL-10 or TGF-β was detected and most patient T-cells had a normal proliferative capacity. This is the first, to our knowledge, study showing a cytotoxic phenotype of FoxP3+ T-cells in patients with B-cell lymphoma.
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| 4. |
- Lindqvist, Camilla A., et al.
(författare)
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T regulatory cells control T-cell proliferation partly by the release of soluble CD25 in patients with B-cell malignancies
- 2010
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Ingår i: Immunology. - : Wiley. - 0019-2805 .- 1365-2567. ; 131:3, s. 371-376
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin-2 (IL-2) is one of the most studied cytokines driving T-cell proliferation, activation and survival. It binds to the IL-2 receptor consisting of three chains, the alpha (CD25), beta and common gamma (gammac). The binding of the CD25 chain to IL-2 is necessary to expose high-affinity binding sites for the beta and gammac chains, which, in turn, are responsible for downstream signalling. A high level of soluble CD25 (sCD25) has been associated with a poor prognosis in patients with non-Hodgkin's lymphoma. The function and source of origin of this soluble receptor is not well investigated. In the present study we hypothesized that T regulatory (Treg) cells may release CD25 to act as a decoy receptor for IL-2, thereby depriving T-effector cells of IL-2. Peripheral blood from patients with B-cell malignancies (n = 26) and healthy controls (n = 27) was investigated for the presence and function of FoxP3(+) Treg cells and sCD25 by multi-colour flow cytometry and enzyme-linked immunosorbent assay. Further, the proliferative capacity of T cells was evaluated with or without the presence of recombinant sCD25. The results demonstrate that Treg cells from patients had lower CD25 expression intensity and that they released CD25 in vitro. Further, high levels of Treg cells correlated with sCD25 plasma concentration. Recombinant sCD25 could suppress T-cell proliferation in vitro. In conclusion, the release of sCD25 by Treg cells may be a mechanism to deprive IL-2 and thereby inhibit anti-tumour T-cell responses.
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