| 1. |
- Akhiani, Aliasghar, 1957, et al.
(författare)
-
Idelalisib Rescues Natural Killer Cells from Monocyte-Induced Immunosuppression by Inhibiting NOX2-Derived Reactive Oxygen Species.
- 2020
-
Ingår i: Cancer immunology research. - 2326-6074. ; 8:12, s. 1532-1541
-
Tidskriftsartikel (refereegranskat)abstract
- The phosphatidylinositol-4,5-bisphosphate-3 kinase-δ (PI3Kδ) inhibitor idelalisib, used alone or in combination with anti-CD20, is clinically efficacious in B-cell lymphoma and chronic lymphocytic leukemia (CLL) by promoting apoptosis of malignant B cells. PI3K regulates the formation of reactive oxygen species (ROS) by the myeloid NADPH oxidase NOX2, but the role of PI3Kδ in myeloid cell-induced immunosuppression is unexplored. We assessed the effects of idelalisib on the spontaneous and IgG antibody-induced ROS production by human monocytes, on ROS-induced cell death of human natural killer (NK) cells, and on tumor cell clearance in an NK cell-dependent mouse model of metastasis. Idelalisib potently and efficiently inhibited the formation of NOX2-derived ROS from monocytes and rescued NK cells from ROS-induced cell death. Idelalisib also promoted NK cell cytotoxicity against anti-CD20-coated primary human CLL cells and cultured malignant B cells. Experiments using multiple PI3K inhibitors implicated the PI3Kδ isoform in regulating NOX2-induced ROS formation and immunosuppression. In B6 mice, systemic treatment with idelalisib significantly reduced the formation of lung metastases from intravenously injected melanoma cells but did not affect metastasis in B6.129S6-Cybbtm1Din (Nox2-/-) mice or in NK cell-deficient mice. Our results imply that idelalisib rescues NK cells from NOX2/ROS-dependent immunosuppression and thus exerts antineoplastic efficacy beyond B-cell inhibition.
|
|
| 2. |
- Aydin, Ebru, et al.
(författare)
-
A hypomorphic Cbx3 allele causes prenatal growth restriction and perinatal energy homeostasis defects
- 2015
-
Ingår i: Journal of Biosciences. - : Springer Science and Business Media LLC. - 0250-5991 .- 0973-7138. ; 40:2, s. 325-338
-
Tidskriftsartikel (refereegranskat)abstract
- Mammals have three HP1 protein isotypes HP1 beta (CBX1), HPl gamma (CBX3) and HP1 alpha (CBX5) that are encoded by the corresponding genes Cbx1, Cbx3 and Cbx5. Recent work has shown that reduction of CBX3 protein in homozygotes for a hypomorphic allele (Cbx3(hypo)) causes a severe postnatal mortality with around 99% of the homozygotes dying before weaning. It is not known what the causes of the postnatal mortality are. Here we show that Cbx3(hypo/hypo) conceptuses are significantly reduced in size and the placentas exhibit a haplo-insufficiency. Late gestation Cbx3(hypo/hypo) placentas have reduced mRNA transcripts for genes involved in growth regulation, amino acid and glucose transport. Blood vessels within the Cbx3(hypo/hypo) placental labyrinth are narrower than wild-type. Newborn Cbx3(hypo/hypo) pups are hypoglycemic, the livers are depleted of glycogen reserves and there is almost complete loss of stored lipid in brown adipose tissue (BAT). There is a 10-fold reduction in expression of the BAT-specific Ucp1 gene, whose product is responsible for non-shivering themogenesis. We suggest that it is the small size of the ChX3(hypo/hypo) neonates, a likely consequence of placental growth and transport defects, combined with a possible inability to thermoregulate that causes the severe postnatal mortality.
|
|
| 3. |
- Aydin, Ebru, et al.
(författare)
-
NOX2 inhibition reduces oxidative stress and prolongs survival in murine KRAS-induced myeloproliferative disease
- 2019
-
Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 38:9, s. 1534-1543
-
Tidskriftsartikel (refereegranskat)abstract
- Mutations leading to constitutive RAS activation contribute in myeloid leukemogenesis. RAS mutations in myeloid cells are accompanied by excessive formation of reactive oxygen species (ROS), but the source of ROS and their role for the initiation and progression of leukemia have not been clearly defined. To determine the role of NOX2-derived ROS in RAS-driven leukemia, double transgenic LSL-Kras(G12D) x Mx1-Cre mice expressing oncogenic KRAS in hematopoietic cells (M-Kras(G12D)) were treated with N-alpha-methyl-histamine (NMH) that targeted the production of NOX2-derived ROS in leukemic cells by agonist activity at histamine H-2 receptors. M-Kras(G12D) mice developed myeloid leukemia comprising mature CD11b(+)Gr1(+) myeloid cells that produced NOX2-derived ROS. Treatment of M-Kras(G12D) mice with NMH delayed the development of myeloproliferative disease and prolonged survival. In addition, NMH-treated M-Kras(G12D) mice showed reduction of intracellular ROS along with reduced DNA oxidation and reduced occurence of double-stranded DNA breaks in myeloid cells. The in vivo expansion of leukemia was markedly reduced in triple transgenic mice where KRAS was expressed in hematopoietic cells of animals with genetic NOX2 deficiency (Nox2(-/-) x LSL-Kras(G12D) x Mx1-Cre). Treatment with NMH did not alter in vivo expansion of leukemia in these NOX2-deficient transgenic mice. We propose that NOX2-derived ROS may contribute to the progression of KRAS-induced leukemia and that strategies to target NOX2 merit further evaluation in RAS-mutated hematopoietic cancer.
|
|
| 4. |
- Aydin, Ebru, et al.
(författare)
-
Phosphoinositide 3-Kinase Signaling in the Tumor Microenvironment: What Do We Need to Consider When Treating Chronic Lymphocytic Leukemia With PI3K Inhibitors?
- 2021
-
Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 11
-
Tidskriftsartikel (refereegranskat)abstract
- Phosphoinositide 3-kinases (PI3Ks) and their downstream proteins constitute a signaling pathway that is involved in both normal cell growth and malignant transformation of cells. Under physiological conditions, PI3K signaling regulates various cellular functions such as apoptosis, survival, proliferation, and growth, depending on the extracellular signals. A deterioration of these extracellular signals caused by mutational damage in oncogenes or growth factor receptors may result in hyperactivation of this signaling cascade, which is recognized as a hallmark of cancer. Although higher activation of PI3K pathway is common in many types of cancer, it has been therapeutically targeted for the first time in chronic lymphocytic leukemia (CLL), demonstrating its significance in B-cell receptor (BCR) signaling and malignant B-cell expansion. The biological activity of the PI3K pathway is not only limited to cancer cells but is also crucial for many components of the tumor microenvironment, as PI3K signaling regulates cytokine responses, and ensures the development and function of immune cells. Therefore, the success or failure of the PI3K inhibition is strongly related to microenvironmental stimuli. In this review, we outline the impacts of PI3K inhibition on the tumor microenvironment with a specific focus on CLL. Acknowledging the effects of PI3K inhibitor-based therapies on the tumor microenvironment in CLL can serve as a rationale for improved drug development, explain treatment-associated adverse events, and suggest novel combinatory treatment strategies in CLL.
|
|
| 5. |
- Aydin, Ebru, et al.
(författare)
-
Role of NOX2-Derived Reactive Oxygen Species in NK Cell-Mediated Control of Murine Melanoma Metastasis
- 2017
-
Ingår i: Cancer Immunology Research. - : American Association for Cancer Research (AACR). - 2326-6066 .- 2326-6074. ; 5:9, s. 804-811
-
Tidskriftsartikel (refereegranskat)abstract
- The NADPH oxidase of myeloid cells, NOX2, generates reactive oxygen species (ROS) to eliminate pathogens and malignant cells. NOX2-derived ROS have also been proposed to dampen functions of natural killer (NK) cells and other antineoplastic lymphocytes in the microenvironment of established tumors. The mechanisms by which NOX2 and ROS influence the process of distant metastasis have only been partially explored. Here, we utilized genetically NOX2-deficient mice and pharmacologic inhibition of NOX2 to elucidate the role of NOX2 for the hematogenous metastasis of melanoma cells. After intravenous inoculation of B16F1 or B16F10 cells, lung metastasis formation was reduced in B6.129S6 Cybb(m1DinK) (Nox2-KO) versus Nox2-sufficient wild-type (WT) mice. Systemic treatment with the NOX2-inhibitor histamine dihydrochloride (HDC) reduced melanoma metastasis and enhanced the infiltration of IFN gamma-producing NK cells into lungs of WT but not of Nox2-KO mice. IFN gamma-deficient B6.129S7-Ifngt(m1Ts)/ J mice were prone to develop melanoma metastases and did not respond to in vivo treatment with HDC. We propose that NOX2-derived ROS facilitate metastasis of melanoma cells by downmodulating NK-cell function and that inhibition of NOX2 may restore IFN gamma-dependent, NK cell-mediated clearance of melanoma cells.
|
|
| 6. |
- Aydin, Ebru
(författare)
-
Targeting NOX2 in cancer
- 2018
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Reactive oxygen species (ROS) are short-lived, toxic derivatives of oxygen that are produced during mitochondrial respiration and by NADPH oxidases (NOX). By enzymatically generating ROS, the myeloid cell NOX2 plays a critical role in defense against bacteria and other microorganisms. The NOX2-derived ROS have also been ascribed immunosuppressive properties and may damage DNA to induce mutagenesis, but details regarding the role of NOX2 and ROS for the initiation and progression of cancer are partly unexplored. This thesis work utilized genetic and pharmacological tools including transgenic mice, genetically modified cells and pharmacological NOX2 inhibitors to further define the role of NOX2 in cancer. The results presented in paper I implied that a NOX2 inhibitor, histamine dihydrochloride (HDC), promotes the development of monocyte-derived, antigen-presenting dendritic cells to control the in vivo growth of a murine lymphoma (EL-4). Paper II was designed to elucidate the impact of NOX2 on the process of metastasis. The results suggested that extracellularly released NOX2-derived ROS from myeloid cells may dampen natural killer (NK) cell-mediated defense against murine melanoma cells to promote hematogenous metastasis. Paper III aimed at defining the role of NOX2 in a mouse model of chronic myeloid leukemia (CML). It was observed that genetic ablation of NOX2 delayed the in vivo expansion of leukemic cells carrying the BCR-ABL1 mutation. In paper IV, it is shown that genetic and pharmacological inhibition of NOX2 delayed the development of myeloproliferation in a murine model of Kras-induced myeloid leukemia and, also, that inhibition of NOX2 function may confer protection against oxidative stress and DNA damage in cells of the leukemic clone. In summary, these studies identify NOX2 as a conceivable target in cancer therapy.
|
|
| 7. |
- Bernson, Elin, 1987, et al.
(författare)
-
Cytomegalovirus Serostatus Affects Autoreactive NK Cells and Outcomes of IL2-Based Immunotherapy in Acute Myeloid Leukemia
- 2018
-
Ingår i: Cancer Immunology Research. - : American Association for Cancer Research (AACR). - 2326-6066 .- 2326-6074. ; 6:9, s. 1110-1119
-
Tidskriftsartikel (refereegranskat)abstract
- Human cytomegalovirus (CMV) infection is reported to promote NK cell differentiation and education. The CMV-induced generation of highly differentiated adaptive-like NK cells has been proposed to affect favorably on the maintenance of remission in patients with acute myeloid leukemia (AML) after allogeneic stem cell transplantation (allo-SCT). The impact of CMV infection and adaptive-like NK cells on relapse and survival of patients with AML not receiving allo-SCT remains unknown. We assayed CMV IgG serostatus to determine past CMV infection in 81 nontransplanted AML patients who were receiving relapse-prevention immunotherapy comprising histamine dihydrochloride and low-dose interleukin-2 (HDC/IL2; NCT01347996). CMV seropositivity correlated negatively with leukemia-free and overall survival of patients receiving HDC/IL2, but did not correlate with outcomes in a contemporary control cohort. Analysis of outcome after stratification of patients based on concordant or discordant killer immunoglobulin-like receptor (KIR) and HLA genotypes implied that the negative impact of CMV seropositivity was restricted to patients lacking a ligand to inhibitory KIRs (iKIR). Previous CMV infection was also associated with fewer NK cells expressing only nonself iKIRs (NS-iKIR). We propose that CMV-driven NK cell education depletes the population of NS-iKIR NK cells, which in turn reduces the clinical benefit of relapse-preventive immunotherapy in AML.
|
|
| 8. |
- Grauers Wiktorin, Hanna, 1990, et al.
(författare)
-
Impact of IL-1β and the IL-1R antagonist on relapse risk and survival in AML patients undergoing immunotherapy for remission maintenance.
- 2021
-
Ingår i: Oncoimmunology. - 2162-402X. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- Interleukin-1 beta (IL-1β), a pro-inflammatory cytokine, has been ascribed a role in the expansion of myeloid progenitors in acute myeloid leukemia (AML) and in promoting myeloid cell-induced suppression of lymphocyte-mediated immunity against malignant cells. This study aimed at defining the potential impact of IL-1β in the post-remission phase of AML patients receiving immunotherapy for relapse prevention in an international phase IV trial of 84 patients (ClinicalTrials.gov; NCT01347996). Consecutive serum samples were collected from AML patients in first complete remission (CR) who received cycles of relapse-preventive immunotherapy with histamine dihydrochloride (HDC) and low-dose interleukin-2 (IL-2). Low IL-1β serum levels before and after the first HDC/IL-2 treatment cycle favorably prognosticated leukemia-free survival and overall survival. Serum levels of IL-1β were significantly reduced in patients receiving HDC/IL-2. HDC also reduced the formation of IL-1β from activated human PBMCs in vitro. Additionally, high serum levels of the IL-1 receptor antagonist IL-1RA were associated with favorable outcome, and AML patients with low IL-1β along with high IL-1RA levels were strikingly protected against leukemic relapse. Our results suggest that strategies to target IL-1β might impact on relapse risk and survival in AML.
|
|
| 9. |
- Grauers Wiktorin, Hanna, 1990, et al.
(författare)
-
NOX2-Derived Reactive Oxygen Species in Cancer.
- 2020
-
Ingår i: Oxidative medicine and cellular longevity. - : Hindawi Limited. - 1942-0994 .- 1942-0900. ; 2020
-
Tidskriftsartikel (refereegranskat)abstract
- The formation of reactive oxygen species (ROS) by the myeloid cell NADPH oxidase NOX2 is critical for the destruction of engulfed microorganisms. However, recent studies imply that ROS, formed by NOX2+ myeloid cells in the malignant microenvironment, exert multiple actions of relevance to the growth and spread of neoplastic cells. By generating ROS, tumor-infiltrating myeloid cells and NOX2+ leukemic myeloid cells may thus (i) compromise the function and viability of adjacent cytotoxic lymphocytes, including natural killer (NK) cells and T cells, (ii) oxidize DNA to trigger cancer-promoting somatic mutations, and (iii) affect the redox balance in cancer cells to control their proliferation and survival. Here, we discuss the impact of NOX2-derived ROS for tumorigenesis, tumor progression, regulation of antitumor immunity, and metastasis. We propose that NOX2 may be a targetable immune checkpoint in cancer.
|
|
| 10. |
|
|
