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- Gorchs, L, et al.
(författare)
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Chemokine Receptor Expression on T Cells Is Modulated by CAFs and Chemokines Affect the Spatial Distribution of T Cells in Pancreatic Tumors
- 2022
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:15
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Tidskriftsartikel (refereegranskat)abstract
- The accumulation of T cells is associated with a better prognosis in pancreatic cancer. However, the immunosuppressive tumor microenvironment, largely composed by cancer-associated fibroblasts (CAFs), can prevent T cells from reaching the tumor nests. We examined how human CAFs modulated chemokine receptors known to be associated with T cell trafficking, CXCR3 and CCR5, and T cell exclusion, CXCR4. CAFs decreased the expression of CXCR3 and CCR5 but increased CXCR4 expression in both 2D and 3D cultures, affecting the migratory capacity of T cells towards CXCL10. An immunohistochemistry analysis showed that very few T cells were found in the tumor nests. Within the stroma, CD8+ T cells were localized more distantly from the malignant cells whereas CD4+ T cells were more equally distributed. Tumor tissues with a high production of chemokines were associated with less T cell infiltration when the whole tissue was analyzed. However, when the spatial localization of CD8+ T cells within the tissue was taken into account, levels of CXCR3 ligands and the CCR5 ligand CCL8 showed a positive association with a high relative T cell infiltration in tumor-rich areas. Thus, CXCR3 ligands could mediate T cell trafficking but CAFs could prevent T cells from reaching the malignant cells.
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- Gorchs, L, et al.
(författare)
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Interactions between Cancer-Associated Fibroblasts and T Cells in the Pancreatic Tumor Microenvironment and the Role of Chemokines
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:12
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Tidskriftsartikel (refereegranskat)abstract
- Less than 10% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) survive 5 years or more, making it one of the most fatal cancers. Accumulation of T cells in pancreatic tumors is associated with better prognosis, but immunotherapies to enhance the anti-tumor activity of infiltrating T cells are failing in this devastating disease. Pancreatic tumors are characterized by a desmoplastic stroma, which mainly consists of activated cancer-associated fibroblasts (CAFs). Pancreatic CAFs have emerged as important regulators of the tumor microenvironment by contributing to immune evasion through the release of chemokines, cytokines, and growth factors, which alters T-cell migration, differentiation and cytotoxic activity. However, recent discoveries have also revealed that subsets of CAFs with diverse functions can either restrain or promote tumor progression. Here, we discuss our current knowledge about the interactions between CAFs and T cells in PDAC and summarize different therapy strategies targeting the CAF–T cell axis with focus on CAF-derived soluble immunosuppressive factors and chemokines. Identifying the functions of different CAF subsets and understanding their roles in T-cell trafficking within the tumor may be fundamental for the development of an effective combinational treatment for PDAC.
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- Gorchs, L, et al.
(författare)
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The vitamin D analogue calcipotriol promotes an anti-tumorigenic phenotype of human pancreatic CAFs but reduces T cell mediated immunity
- 2020
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 17444-
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Tidskriftsartikel (refereegranskat)abstract
- The pancreatic tumour stroma is composed of phenotypically heterogenous cancer-associated fibroblasts (CAFs) with both pro- and anti-tumorigenic functions. Here, we studied the impact of calcipotriol, a vitamin D3 analogue, on the activation of human pancreatic CAFs and T cells using 2- and 3-dimensional (2D, 3D) cell culture models. We found that calcipotriol decreased CAF proliferation and migration and reduced the release of the pro-tumorigenic factors prostaglandin E2, IL-6, periostin, and leukemia inhibitory factor. However, calcipotriol promoted PD-L1 upregulation, which could influence T cell mediated tumour immune surveillance. Calcipotriol reduced T cell proliferation and production of IFN-γ, granzyme B and IL-17, but increased IL-10 secretion. These effects were even more profound in the presence of CAFs in 2D cultures and in the presence of CAFs and pancreatic tumour cell line (PANC-1) spheroids in 3D cultures. Functional assays on tumour infiltrating lymphocytes also showed a reduction in T cell activation by calcipotriol. This suggests that calcipotriol reduces the tumour supportive activity of CAFs but at the same time reduces T cell effector functions, which could compromise the patients’ tumour immune surveillance. Thus, vitamin D3 analogues appear to have dual functions in the context of pancreatic cancer, which could have important clinical implications.
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- Lindau, Robert, et al.
(författare)
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Decidual stromal cells support tolerance at the human foetal-maternal interface by inducing regulatory M2 macrophages and regulatory T-cells
- 2021
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Ingår i: Journal of Reproductive Immunology. - : Elsevier Ireland Ltd. - 0165-0378 .- 1872-7603. ; 146
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Tidskriftsartikel (refereegranskat)abstract
- During pregnancy, the semi-allogeneic nature of the foetus requires maternal immune adaption and acquisition of tolerance at the foetal-maternal interface. Macrophages with regulatory properties and regulatory T (Treg) cells are central in promoting foetal tolerance and are enriched in the decidua (the uterine endometrium during pregnancy). Although tissue-resident decidual stromal cells (DSC) have been implicated in regulatory functions, it is not known if they are able to induce the regulatory phenotype of macrophages and T-cells. In this study we report that maternally derived DSC are able to induce homeostatic M2 macrophages and Treg cells. CD14+ monocytes and CD4+ T-cells from healthy non-pregnant women were cultured in the presence or absence of conditioned medium (CM) from DSC isolated from 1st trimester and term placentas. DSC-CM alone was able to promote the survival of macrophages and to induce a regulatory CD14brightCD163+CD209+CD86dim phenotype, typical for decidual macrophages and similar to that induced by M-CSF. Interestingly, DSC-CM was also able to overrule the pro-inflammatory effects of GM-CSF by upregulating CD14, CD163 and CD209. Protein-profiling showed that M-CSF was secreted by DSC, and blocking of M-CSF partially reversed the M2 phenotype and reduced viability. DSC-CM also expanded CD25brightFoxp3+ Treg cells, an expansion that was abolished by a SMAD3-inhibitor, indicating the contribution of TGF-beta signaling. In conclusion, our findings collectively emphasize the role of tissue-resident stromal cells in shaping the tolerogenic environment at the foetal-maternal interface.
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- Magalhaes, I, et al.
(författare)
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MAIT Cells in Health and Disease
- 2020
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Ingår i: Methods in molecular biology (Clifton, N.J.). - New York, NY : Springer US. - 1940-6029. ; 2098, s. 3-21
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Tidskriftsartikel (refereegranskat)
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- Rangelova, Elena, et al.
(författare)
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Immunotherapy in pancreatic cancer-an emerging role: a narrative review
- 2022
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Ingår i: Chinese Clinical Oncology. - : AME Publishing Company. - 2304-3865 .- 2304-3873. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objective: Immunotherapy is the fastest growing branch in oncology that have already revolutionized the treatment of few solid cancers. The number of immunotherapy trials for pancreatic cancer (PC) is growing but the vast number of different agents used make it difficult to comprehend a possible success trait of a certain type of immunotherapy. The aim of this review is to summarize and critically evaluate the outcome of immunotherapy trials for PC intended to aid the comprehensiveness for the treating physicians. Methods: A PubMed search was performed to identify clinical trials in patients with PC, published in English from year 2000 to June 2021 and using combination of the terms immunotherapy, PC, and crosschecked the bibliography of the revised literature as the dublettes have been removed. Studies were divided into three groups depending on what immune components have been applied: passive products (peptides, antibodies, etc.), antigen-presenting cells, and adoptive cell transfer trials. Key Content and Findings: The vast majority of trials, including those from most recent years, used passive products of the immune system-peptide vaccines and antibodies. The administration was often parallel to chemotherapy that was prevalently gemcitabine-based. Although immunological responses have been detected, the clinical efficacy was very limited. Trials with check point inhibitors did not show survival advantage. Dendritic cell (DC) vaccines have been associated with some clinical objective response and prolonged survival in few patients with delayed type hypersensitivity reactions. Trials with adoptive transfer therapy are lacking. The very few trials with lymphokine-activated killer (LAK)/cytokine-induced killer (CIK) cells tested only in Asian population have resulted in some clinical effects with prolonged survival. In none of the trials have the patients been preconditioned before receiving immunotherapy. Conclusions: Although the clinical effectiveness in the majority of the reported trials has been limited, the immunological effects observed in almost all trials show a proof of concept-that immunotherapy can work. Careful re-evaluation of the clinical premises and focus on combination and cell therapy may be the way to achieve improved survival by immunotherapy in PC.
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