| 1. |
- Chen, Ziqing, et al.
(författare)
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Phosphodiesterase 4A confers resistance to PGE2-mediated suppression in CD25(+)/CD54(+) NK cells
- 2021
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Ingår i: EMBO Reports. - : EMBO Press. - 1469-221X .- 1469-3178. ; 22:3
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Tidskriftsartikel (refereegranskat)abstract
- Inadequate persistence of tumor-infiltrating natural killer (NK) cells is associated with poor prognosis in cancer patients. The solid tumor microenvironment is characterized by the presence of immunosuppressive factors, including prostaglandin E2 (PGE2), that limit NK cell persistence. Here, we investigate if the modulation of the cytokine environment in lung cancer with IL-2 or IL-15 renders NK cells resistant to suppression by PGE2. Analyzing Cancer Genome Atlas (TCGA) data, we found that high NK cell gene signatures correlate with significantly improved overall survival in patients with high levels of the prostaglandin E synthase (PTGES). In vitro, IL-15, in contrast to IL-2, enriches for CD25(+)/CD54(+) NK cells with superior mTOR activity and increased expression of the cAMP hydrolyzing enzyme phosphodiesterase 4A (PDE4A). Consequently, this distinct population of NK cells maintains their function in the presence of PGE2 and shows an increased ability to infiltrate lung adenocarcinoma tumors in vitro and in vivo. Thus, strategies to enrich CD25(+)/CD54(+) NK cells for adoptive cell therapy should be considered.
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| 2. |
- Evren, Elza, et al.
(författare)
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Distinct developmental pathways from blood monocytes generate human lung macrophage diversity
- 2021
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Ingår i: Immunity. - : Elsevier. - 1074-7613 .- 1097-4180. ; 51, s. 35-35
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Tidskriftsartikel (refereegranskat)abstract
- The study of human macrophages and their ontogeny is an important unresolved issue. Here, we use a humanized mouse model expressing human cytokines to dissect the development of lung macrophages from human hematopoiesis in vivo. Human CD34+ hematopoietic stem and progenitor cells (HSPCs) generated three macrophage populations, occupying separate anatomical niches in the lung. Intravascular cell labeling, cell transplantation, and fate-mapping studies established that classical CD14+ blood monocytes derived from HSPCs migrated into lung tissue and gave rise to human interstitial and alveolar macrophages. In contrast, non-classical CD16+ blood monocytes preferentially generated macrophages resident in the lung vasculature (pulmonary intravascular macrophages). Finally, single-cell RNA sequencing defined intermediate differentiation stages in human lung macrophage development from blood monocytes. This study identifies distinct developmental pathways from circulating monocytes to lung macrophages and reveals how cellular origin contributes to human macrophage identity, diversity, and localization in vivo.
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| 3. |
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| 4. |
- Gultekin, Okan, et al.
(författare)
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FOXP3+ T cells in uterine sarcomas are associated with favorable prognosis, low extracellular matrix expression and reduced YAP activation
- 2021
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Ingår i: npj Precision Oncology. - : Springer Nature. - 2397-768X. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- Uterine sarcomas are rare but deadly malignancies without effective treatment. Immunotherapy is a promising new approach to treat these tumors but has shown heterogeneous effects in sarcoma patients. With the goal of identifying key factors for improved patient treatment, we characterized the tumor immune landscape in 58 uterine sarcoma cases with full clinicopathological annotation. Immune cell characterization revealed the overall prevalence of FOXP3+ cells and pro-tumor M2-like macrophages. Hierarchical clustering of patients showed four tumor type-independent immune signatures, where infiltration of FOXP3+ cells and M1-like macrophages associated with favorable prognosis. High CD8+/FOXP3+ ratio in UUS and ESS correlated with poor survival, upregulation of immunosuppressive markers, extracellular matrix (ECM)-related genes and proteins, and YAP activation. This study shows that uterine sarcomas present distinct immune signatures with prognostic value, independent of tumor type, and suggests that targeting the ECM could be beneficial for future treatments.
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| 5. |
- He, Fei, et al.
(författare)
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FPR2 Shapes an Immune-Excluded Pancreatic Tumor Microenvironment and Drives T-cell Exhaustion in a Sex-Dependent Manner
- 2023
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Ingår i: Cancer Research. - : American Association for Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 83:10, s. 1628-1645
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Tidskriftsartikel (refereegranskat)abstract
- Sex-driven immune differences can affect tumor progression and the landscape of the tumor microenvironment. Deeper understanding of these differences in males and females can inform patient selection to improve sex-optimized immunotherapy treatments. In this study, single-cell RNA sequencing and protein analyses uncovered a subpopulation of myeloid cells in pancreatic lesions associated with an immune-excluded tumor phenotype and effector T-cell exhaustion exclusively in females. This myeloid subpopulation was positively correlated with poor survival and genetic signatures of M2-like macrophages and T-cell exhaustion in females. The G-protein coupled receptor formyl peptide receptor 2 (FPR2) mediated these immunosuppressive effects. In vitro, treatment of myeloid cells with a specific FPR2 antagonist prevented exhaustion and enhanced cytotoxicity of effector cells. Proteomic analysis revealed high expression of immunosuppressive secretory proteins PGE2 and galectin-9, enriched integrin pathway, and reduced proinflammatory signals like TNFα and IFNγ in female M2-like macrophages upon FPR2 agonist treatment. In addition, myeloid cells treated with FPR2 agonists induced TIM3 and PD-1 expression only in female T cells. Treatment with anti-TIM3 antibodies reversed T-cell exhaustion and stimulated their ability to infiltrate and kill pancreatic spheroids. In vivo, progression of syngeneic pancreatic tumors was significantly suppressed in FPR2 knockout (KO) female mice compared with wild-type (WT) female mice and to WT and FPR2 KO male mice. In female mice, inoculation of tumors with FPR2 KO macrophages significantly reduced tumor growth compared with WT macrophages. Overall, this study identified an immunosuppressive function of FPR2 in females, highlighting a potential sex-specific precision immunotherapy strategy.
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| 6. |
- He, Fei, et al.
(författare)
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Sex dimorphism in the tumor microenvironment : From bench to bedside and back
- 2022
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Ingår i: Seminars in Cancer Biology. - : Elsevier. - 1044-579X .- 1096-3650. ; 86:3, s. 166-179
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Forskningsöversikt (refereegranskat)abstract
- Cancer represents a significant cause of death and suffering in both the developed and developing countries. Key underlying issues in the mortality of cancer are delayed diagnosis and resistance to treatments. However, improvements in biomarkers represent one important step that can be taken for alleviating the suffering caused by malignancy. Precision-based medicine is promising for revolutionizing diagnostic and treatment strategies for cancer patients worldwide. Contemporary methods, including various omics and systems biology approaches, as well as advanced digital imaging and artificial intelligence, allow more accurate assessment of tumor characteristics at the patient level. As a result, treatment strategies can be specifically tailored and adapted for individual and/or groups of patients that carry certain tumor characteristics. This includes immunotherapy, which is based on characterization of the immunosuppressive tumor microenvironment (TME) and, more specifically, the presence and activity of immune cell subsets. Unfortunately, while it is increasingly clear that gender strongly affects immune regulation and response, there is a knowledge gap concerning differences in sex-specific immune responses and how these contribute to the immunosuppressive TME and the response to immunotherapy. In fact, sex dimorphism is poorly understood in cancer progression and is typically ignored in current clinical practice. In this review, we aim to survey the available literature and highlight the existing knowledge gap in order to encourage further studies that would contribute to understanding both gender-biased immunosuppression in the TME and the driver of tumor progression towards invasive and metastatic disease. The review highlights the need to include sex optimized/genderized medicine as a new concept in future medicine cancer diagnostics and treatments.
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| 7. |
- La Fleur, Linnea, et al.
(författare)
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Targeting MARCO and IL-37R on immunosuppressive macrophages in lung cancer blocks regulatory T cells and supports cytotoxic lymphocyte function
- 2021
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Ingår i: Cancer Research. - : American Association For Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 81:4, s. 956-967
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Tidskriftsartikel (refereegranskat)abstract
- The progression and metastatic capacity of solid tumors are strongly influenced by immune cells in the tumor microenvironment. In non-small cell lung cancer (NSCLC), accumulation of anti-inflammatory tumor-associated macrophages (TAMs) is associated with worse clinical outcome and resistance to therapy. Here we investigated the immune landscape of NSCLC in the presence of pro-tumoral TAMs expressing the macrophage receptor with collagenous structure (MARCO). MARCO-expressing TAM numbers correlated with increased occurrence of regulatory T cells and effector T cells and decreased Natural Killer (NK) cells in these tumors. Furthermore, transcriptomic data from the tumors uncovered a correlation between MARCO expression and the anti-inflammatory cytokine IL-37. In vitro studies subsequently showed that lung cancer cells polarized macrophages to express MARCO and gain an immune-suppressive phenotype through the release of IL-37. MARCO-expressing TAMs blocked cytotoxic T cell and NK cell activation, inhibiting their proliferation, cytokine production, and tumor killing capacity. Mechanistically, MARCO+ macrophages enhanced regulatory T (Treg) cell proliferation and IL-10 production and diminished CD8 T cell activities. Targeting MARCO or IL-37 receptor (IL-37R) by antibody or CRISPR knockout of IL-37 in lung cancer cell lines repolarized TAMs, resulting in recovered cytolytic activity and anti-tumoral capacity of NK cells and T cells and down-modulated Treg cell activities. In summary, our data demonstrate a novel immune therapeutic approach targeting human TAMs immune suppression of NK and T cell anti-tumor activities.
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| 8. |
- Lövgren, Tanja, et al.
(författare)
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Enhanced stimulation of human tumor-specific T cells by dendritic cells matured in the presence of interferon-gamma and multiple toll-like receptor agonists
- 2017
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Ingår i: Cancer Immunology and Immunotherapy. - : SPRINGER. - 0340-7004 .- 1432-0851. ; 66:10, s. 1333-1344
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Tidskriftsartikel (refereegranskat)abstract
- Dendritic cell (DC) vaccines have been demonstrated to elicit immunological responses in numerous cancer immunotherapy trials. However, long-lasting clinical effects are infrequent. We therefore sought to establish a protocol to generate DC with greater immunostimulatory capacity. Immature DC were generated from healthy donor monocytes by culturing in the presence of IL-4 and GM-CSF and were further differentiated into mature DC by the addition of cocktails containing different cytokines and toll-like receptor (TLR) agonists. Overall, addition of IFN gamma and the TLR7/8 agonist R848 during maturation was essential for the production of high levels of IL-12p70 which was further augmented by adding the TLR3 agonist poly I:C. In addition, the DC matured with IFN gamma, R848, and poly I:C also induced upregulation of several other pro-inflammatory and Th1-skewing cytokines/chemokines, co-stimulatory receptors, and the chemokine receptor CCR7. For most cytokines and chemokines the production was even further potentiated by addition of the TLR4 agonist LPS. Concurrently, upregulation of the anti-inflammatory cytokine IL-10 was modest. Most importantly, DC matured with IFN gamma, R848, and poly I:C had the ability to activate IFN gamma production in allogeneic T cells and this was further enhanced by adding LPS to the cocktail. Furthermore, epitope-specific stimulation of TCR-transduced T cells by peptide- or whole tumor lysate-loaded DC was efficiently stimulated only by DC matured in the full maturation cocktail containing IFN gamma and the three TLR ligands R848, poly I:C, and LPS. We suggest that this cocktail is used for future clinical trials of anti-cancer DC vaccines.
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| 9. |
- Sarhan, Dhifaf, et al.
(författare)
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885 Targeting FPR2 as a novel approach for immunotherapy in pancreatic cancer female patients : studies of sexual immune dimorphism in the tumor microenvironment
- 2021
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Ingår i: Journal for ImmunoTherapy of Cancer. - : BMJ. - 2051-1426. ; 9:Suppl 2, s. A927-A927
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundImmunotherapy for pancreatic cancer (PC) is inefficient due to a highly immune-suppressive tumor microenvironment (TME) orchestrated by myeloid suppressor cells, which limit the infiltration and function of cytotoxic immune cells. We have evidence that accumulation of a subpopulation of myeloid cells in human pancreatic lesions is associated with immune-exclusive tumor phenotype and effector T cell exhaustion by mechanisms involving the G-coupled protein receptor formyl peptide receptor 2 (FPR2), exclusively in women. We hypothesize that female FPR2+ myeloid cells in tumors induce immune exhaustion and contribute to immune-cold tumor phenotype.MethodsTo test our hypothesis, we first investigated the FPR2 RNA and protein expression in PC transcriptomic data and in murine and human PC tissues. Further, in vitro cytokine differentiated, alternatively tumor conditioned myeloid cells (TCM) were co-cultured with T cells to mimic their interaction in the TME. In vivo, PC cells were injected subcutaneously in FPR2 WT and KO mice to study tumor progression and the immune landscape in male vs. female mice. Later, human myeloid cells were treated with FPR2 agonists and antagonists to study the interaction mechanisms in detail.ResultsWe found high FPR2 expression in tumor compared to healthy tissues and higher in women compared to men. In mice and human, FPR2+ myeloid cells were associated with immune cold-exclusive and cold-ignored tumor phenotype in women and men, respectively. Notably, analysis in PC and other gastrointestinal (GI)-tract cancers revealed a significant association of FPR2 expression and poor survival only in women, emerging the potential impact of sex factors in the TME. Such sexual dimorphism in the TME was associated with T cell exhaustion apparent by high expression of TIM3 and PD1. In vitro, FPR2-agonist treated myeloid-suppressive cells induced TIM3 and PD1 expression in T cells specifically in female T cells. However, a significant repression of TIM3 and a trend of PD1 expression was observed in T cells when interacting with FPR2-inhibited or -deficient myeloid cells. Finally, tumor progression was significantly slower in FPR2 KO female mice compared to WT and male FPR2 WT and KO mice.ConclusionsIn this study, we have shown that sex differences are involved in shaping the TME in PC, where sexual dimorphism is still a largely unknown area allowing novel personalized/sex-specific immunotherapies. We found that FPR2 is highly involved in T cell exhaustion and can potentially be a therapeutic target for immunotherapy in women developing PC and other GI-tract cancers.
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| 10. |
- Sarhan, Dhifaf, et al.
(författare)
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A novel inhibitor of proteasome deubiquitinating activity renders tumor cells sensitive to TRAIL-mediated apoptosis by natural killer cells and T cells
- 2013
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Ingår i: Cancer Immunology, Immunotherapy. - Stockholm : Karolinska Institutet, Dept of Oncology-Pathology. - 1432-0851 .- 0340-7004.
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Tidskriftsartikel (refereegranskat)abstract
- The proteasome inhibitor bortezomib simultaneously renders tumor cells sensitive to killing by natural killer (NK) cells and resistant to killing by tumor-specific T cells. Here, we show that b-AP15, a novel inhibitor of proteasome deubiquitinating activity, sensitizes tumors to both NK and T cell-mediated killing. Exposure to b-AP15 significantly increased the susceptibility of tumor cell lines of various origins to NK (p<0.0002) and T cell (p=0.02) –mediated cytotoxicity. Treatment with b-AP15 resulted in increased TRAIL [tumor necrosis factor-related apoptosis-inducing ligand] receptor-2 expression (p=0.03) and decreased cFLIP expression in tumor cells in vitro. In tumor-bearing SCID/Beige mice, treatment with b-AP15 followed by infusion of either human NK cells or tumor-specific T cells resulted in a significantly delayed tumor progression compared with mice treated with NK cells (p=0.006), T cells (p<0.0001), or b-AP15 alone (p=0.003). Combined infusion of NK and T cells in tumor-bearing BALB/c mice following treatment with b-AP15 resulted in a significantly prolonged long-term survival compared with mice treated with b-AP15 and NK or T cells (p≤0.01). Our findings show that b-AP15-induced sensitization to TRAIL-mediated apoptosis could be used as a novel strategy to augment the anti-cancer effects of adoptively infused NK and T cells in patients with cancer.
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