17 research outputs found
Improving NK cell-based immunotherapy of cancer by exploration of migration and inhibitory receptor-ligand interactions
No full textThe possibility to utilize the immune system as a mean to target malignantly transformed cells has emerged as a novel treatment modality during the last decades and is a field that is under rapid development. Natural Killer (NK) cells are immune cells with an intrinsic ability to recognize and lyse tumor-transformed cells. Their role in immune surveillance of cancer is well established and clinical studies have also highlighted their treatment potential. However, the efficacy has so far been suboptimal and means to further improve NK cell-based immunotherapy against cancer is under intensive investigation. This thesis mainly focuses on how to enhance NK cell treatment efficacy against acute myeloid leukemia (AML), a disease with poor prognosis that is in urgent need for novel and more efficacious treatment options.The potential to better home NK cells to the tumor environment is a highly appealing, but so far relatively unexplored approach to improve treatment efficacy for adoptive NK cell transfer. In Papers I and II, we have utilized a clinically approved mRNA transfection technique to explore how ex vivo expanded NK cells can be engineered to express the gain-of-function bone marrow (BM) homing receptor variant CXCR4R334X. We have shown that CXCR4R334X-expressing NK cells display an increased in vitro migration potential towards the ligand SDF-1 without compromising functionality in any other aspect. We have further highlighted the importance of the CXCR4-SDF-1 axis for in vivo BM homing using both CXCR4R334X mRNA transfected cells and CXCR4 knocked-out cells generated using the CRISPR/Cas9 technology. Finally, we showed that CXCR4R334X-expressing NK cells can be utilized to improve leukemia clearance in vivo, and furthermore have the potential to mediate a survival benefit in this context.Education is a complicated process in which NK cells are dynamically tuned by surrounding HLA class I molecules facilitating a strong effector response against target cells lacking such molecules. Members of the killer cell immunoglobulin-like receptor (KIR) family and the natural killer group 2 member A (NKG2A) receptor have previously been shown to mediate education. In paper III, we have shown for the first time that the LIR-1 receptor can mediate education in ex vivo expanded NK cells. We have identified an educated LIR-1-expressing NK cell subset that display an elevated degranulation capacity towards HLA class I deficient or low tumor targets and further showed that this subset also has a phenotype which resembles that of educated cells. In addition, we have displayed that the subset can be detuned after blockade with specific LIR-1 monoclonal antibodies in line with the rheostat model. Finally, we revealed that this subset has a potent ADCC capacity that even can overcome inhibitory signals from cognate HLA class I ligands. We have postulated that these traits make this subset highly attractive for NK cell-based immunotherapy and could be utilized in various cancer settings, including AML.Isocitrate dehydrogenase (IDH) 1 and 2 are frequently mutated in AML. IDH inhibitors (IDHi) have emerged as novel therapeutic agents. However, only a portion of the patients respond to treatment and the relapse rate is high. In paper IV, we have employed the TF- 1 AML cell line overexpressing the hotspot mutation IDH2R140Q as a model system to study the epigenetical and transcriptional landscape before and after treatment with an IDHi. We have shown that TF-1 IDH2R140Q cells display a hypermethylated DNA profile leading to differential gene expression, which can be further linked to a dysregulated transcriptional network involving myeloid-related transcription factors. We further displayed that this, at least in part, can be reversed upon treatment with the IDHi. Moreover, we showed that both TF-1 IDH2R140Q cells and primary AML cells carrying IDH mutations have hypermethylated HLA class I genes leading to HLA class I downregulation. This was associated with an increased sensitivity to NK cell-mediated responses against the IDH2R140Q mutated TF-1 cells compared to wild-type (WT) TF-1 cells. Lastly, we showed that HLA class I genes in IDH mutated primary AML cells of patients that did not respond to treatment with IDHi remained hypermethylated, indicating that this patient group may benefit from treatment based on adoptive NK cell infusions.Overall, this thesis provides evidence that NK cell migration can be modulated to redirect NK cells to bone marrow compartments for improved leukemia clearance. Furthermore, it includes a paper where the inhibitory receptor LIR-1 for the first time is shown to mediate education of ex vivo expanded NK cells, and identifies a unique subset of highly educated NK cells with a robust ADCC capacity that have the potential to be utilized against various cancer types including AML. Finally, the thesis includes a manuscript which shows that mutations in IDH can confer an increased NK cell sensitivity, and that IDH mutated AML patients resistant to treatment with IDHi constitute a subgroup of AML that may specifically benefit from NK cell-based immunotherapy. In conclusion, the thesis provides novel insights on how NK cells can be utilized to improve treatment for AML and potentially also other types of BM residing malignancies.List of scientific papersI. Emily Levy, Robert Reger, Filip Segerberg†, Mélanie Lambert†, Caroline Leijonhufvud†, Yvonne Baumer, Mattias Carlsten‡, Richard W. Childs‡. Enhanced Bone Marrow Homing of Natural Killer Cells Following mRNA Transfection With Gain-of-Function Variant CXCR4R334X. Frontiers in Immunology. 2019;10:1262. https://doi.org/10.3389/fimmu.2019.01262 II. Filip Segerberg†, Mélanie Lambert†, Laura Sanz-Ortega, Agneta Andersson, Richard W. Childs, Mattias Carlsten. Improved leukemia clearance following adoptive transfer of natural killer cells engineered with the bone marrow homing receptor CXCR4-R334X. [Manuscript]III. Caroline Leijonhufvud, Robert Reger†, Filip Segerberg†, Jakob Theorell, Heinrich Schlums, Yenan T. Bryceson, Richard W. Childs, Mattias Carlsten. LIR-1 educates expanded human NK cells and defines a unique antitumor NK cell subset with potent antibody-dependent cellular cytotoxicity. Clinical & Translational Immunology. 2021;10(10):e1346. https://doi.org/10.1002/cti2.1346 IV. Anna Palau, Filip Segerberg†, Michael Lidschreiber†, Katja Lidschreiber, Aonghus J. Naughton, Maria Needhamsen, Lisa Anna Ljung, Maja Jagodic, Patrick Cramer, Sören Lehmann‡, Mattias Carlsten‡, Andreas Lennartsson‡. Perturbed epigenetic transcriptional regulation in AML with IDH mutations causes increased susceptibility to NK cells. [Manuscript]</p
Perturbed epigenetic transcriptional regulation in AML with IDH mutations causes increased susceptibility to NK cells
No full textAbstract Isocitrate dehydrogenase (IDH) mutations are found in 20% of acute myeloid leukemia (AML) patients. However, only 30–40% of the patients respond to IDH inhibitors (IDHi). We aimed to identify a molecular vulnerability to tailor novel therapies for AML patients with IDH mutations. We characterized the transcriptional and epigenetic landscape with the IDH2i AG-221, using an IDH2 mutated AML cell line model and AML patient cohorts, and discovered a perturbed transcriptional regulatory network involving myeloid transcription factors that were partly restored after AG-221 treatment. In addition, hypermethylation of the HLA cluster caused a down-regulation of HLA class I genes, triggering an enhanced natural killer (NK) cell activation and an increased susceptibility to NK cell-mediated responses. Finally, analyses of DNA methylation data from IDHi-treated patients showed that non-responders still harbored hypermethylation in HLA class I genes. In conclusion, this study provides new insights suggesting that IDH mutated AML is particularly sensitive to NK cell-based personalized immunotherapy.Cancerfonden https://doi.org/10.13039/501100002794Barncancerfonden https://doi.org/10.13039/501100006313Vetenskapsrådet https://doi.org/10.13039/501100004359Radiumhemmets Forskningsfonder https://doi.org/10.13039/501100007232Science for Life Laboratory https://doi.org/10.13039/50110000925
A completeness proof in full DDL
No full textDynamic doxastic logicians — not a large community — have trodden gingerly within the area of full DDL or, as with the present author, have not trodden at all. However, the latter, after having written up the final version of [6], realised that the proof given in that paper for two varieties of basic DDL can be extended to cover full DDL; in fact, the «full» proof is simpler than the «basic» one. The extended proof is outlined in Section 1–3. In Section 4, the relationship to AGM is considered. Section 5 puts the importance of the proof into perspective.This note — an extended abstract rather than a full-fledged paper — should be read as an appendix to [6]. Although some definitions are repeated here, many are not. Readers who require more detail are referred to [6], a copy of which they should have on hand
CRISPR/Cas9-Based Gene Engineering of Human Natural Killer Cells: Protocols for Knockout and Readouts to Evaluate Their Efficacy
No full textInternational audienc
The myth of 'us': digital networks, political change and the production of collectivity
No full textThis article examines critically the claims that digital networks (digital media infrastructures, especially social media platforms) fundamentally change the conditions of politics over the longerterm. Without doubt digital networks enable faster political mobilization, accelerated cycles of action, and some new forms of collectivity, but how consequential is this in the longer-term when set alongside other longer term consequences of a digitally saturated environment? The author argues that some leading accounts of digital media’s contributions to political change operate with a thin account of the social, the sort of thin account that historically has been supplemented by media’s mythical accounts over the past century of their role in supplying social knowledge. In the digital age, even the most detailed and rigorous accounts of digital networks’ contributions to political action (Bennett & Segerberg, 2012, 2013) fail to show that those networks also facilitate longer-term political action that builds longer-term political transformations: arguably, the resulting acceleration of action encourages short-term loyalties and less stability in political socialization. However, this limitation of existing accounts tends to be masked by a new myth for the age of digital networks: the myth of ‘us’, which encourages us to believe that our gatherings on social media platforms are a natural form of expressive collectivity, even though it is exactly that belief that is at the basis of such platforms’ creation of economic value. The article deconstructs that myth, as the starting-point for more satisfactory future accounts of digital networks’ possible contributions to political change
Autoantibodies to Killer Cell Immunoglobulin-Like Receptors in Patients With Systemic Lupus Erythematosus Induce Natural Killer Cell Hyporesponsiveness
No full textNatural killer (NK) cell cytotoxicity toward self-cells is restrained by the inhibitory HLA class I-binding receptors CD94/NKG2A and the killer cell immunoglobulin-like receptors (KIRs). CD94/NKG2A and KIRs are also essential for NK cell education, which is a dynamic functional maturation process where a constitutive binding of inhibitory receptors to cognate HLA class I molecules is required for NK cells to maintain their full cytotoxic capacity. Previously, we described autoantibodies to CD94/NKG2A in patients with systemic lupus erythematosus (SLE). In this study we analyzed sera from 191 patients with SLE, 119 patients with primary Sjogren's syndrome (pSS), 48 patients with systemic sclerosis (SSc), and 100 healthy donors (HD) for autoantibodies to eight different KIRs. Anti-KIR autoantibodies were identified in sera from 23.0% of patients with SLE, 10.9% of patients with pSS, 12.5% of patients with SSc, and 3.0% of HD. IgG from anti-KIR-positive SLE patients reduced the degranulation and cytotoxicity of NK cells toward K562 tumor cells. The presence of anti-KIR-autoantibodies reacting with >3 KIRs was associated with an increased disease activity (p < 0.0001), elevated serum levels of IFN-alpha (p < 0.0001), nephritis (p = 0.001), and the presence of anti-Sm (p = 0.007), and anti-RNP (p = 0.003) autoantibodies in serum. Together these findings suggest that anti-KIR autoantibodies may contribute to the reduced function of NK cells in SLE patients, and that a defective NK cell function may be a risk factor for the development of lupus nephritis
Local Finiteness in Varieties of MS4-Algebras
No full textThis thesis belongs to the field of Algebraic Logic, which studies logical systems via algebraic semantics using tools from universal algebra. The contents are based on the papers [7] (joint by the author and G. Bezhanishvili), and [29] (by the author). We we study certain modal logics, which have algebraic semantics provided by Boolean algebras with operators.
One of the most well-known systems of modal logic is called S4, which extends classical propositional logic with a unary operator ♢, where the intended reading of ♢p is “p is possibly true”. Algebraic models for the system S4 are also known as closure algebras, as they consist of a Boolean algebra equipped with a closure operator. A logic is locally tabular if it can only express finitely many pairwise inequivalent formulas using at most n propositional variables (for any finite n), and this can be understood as a measure of the expressivity of the logic. This property is equivalent to local finiteness of its corresponding variety of algebras – that is, the property that any finitely generated algebra from the variety is finite. A classical theorem of Segerberg and Maksimova gives a full characterization of exactly when a variety of S4-algebras is locally finite – namely, if it validates a certain formula Pn that asserts that the algebras in the variety are of bounded depth n.
Any modal propositional logic has a predicate extension, obtained by adding first-order quantifiers to the system. Though these systems are often difficult to study, a lot of the difficulties already present in the monadic fragment, obtained by restricting to unary predicates and quantification over a single fixed variable. This monadic fragment can actually be studied as a modal logic, by modeling the monadic quantification as a particular modal operator.
This thesis studies how and to what extent the Segerberg–Maksimova theorem may be generalized to the system MS4 (monadic S4). In Chapter 1, we give the relevant background on modal logic, algebraic semantics, and relational semantics via Jónsson–Tarski duality. In Chapter 2 and Chapter 3, we give background on the specific theory of the variety S4 of S4-algebras and the monadic extension MS4, respectively. In Chapter 4, we establish the finite model property for some particular subvarieties of MS4. In Chapter 5, we present negative results concerning local finiteness in MS4 – we give a detailed construction of the dual space of a one-generated and infinite algebra of depth 1, and a translation of the variety S52 into two relatively small subvarieties of MS4 that suggests a full characterization of local finiteness will be difficult. The remaining chapters Chapter 6, Chapter 7, Chapter 8 present positive results, giving full syntactic characterizations of local finiteness below certain subvarieties of MS4. Of particular note is Chapter 7, which is more involved than the others and undertakes a detailed study of the subvariety of MS4 obtained by asserting the Casari axiom, an axiom of predicate logic related to intuitionistic logic and provability.</p
Local Finiteness in Varieties of MS4-Algebras
No full textThis thesis belongs to the field of Algebraic Logic, which studies logical systems via algebraic semantics using tools from universal algebra. The contents are based on the papers [7] (joint by the author and G. Bezhanishvili), and [29] (by the author). We we study certain modal logics, which have algebraic semantics provided by Boolean algebras with operators.
One of the most well-known systems of modal logic is called S4, which extends classical propositional logic with a unary operator ♢, where the intended reading of ♢p is “p is possibly true”. Algebraic models for the system S4 are also known as closure algebras, as they consist of a Boolean algebra equipped with a closure operator. A logic is locally tabular if it can only express finitely many pairwise inequivalent formulas using at most n propositional variables (for any finite n), and this can be understood as a measure of the expressivity of the logic. This property is equivalent to local finiteness of its corresponding variety of algebras – that is, the property that any finitely generated algebra from the variety is finite. A classical theorem of Segerberg and Maksimova gives a full characterization of exactly when a variety of S4-algebras is locally finite – namely, if it validates a certain formula Pn that asserts that the algebras in the variety are of bounded depth n.
Any modal propositional logic has a predicate extension, obtained by adding first-order quantifiers to the system. Though these systems are often difficult to study, a lot of the difficulties already present in the monadic fragment, obtained by restricting to unary predicates and quantification over a single fixed variable. This monadic fragment can actually be studied as a modal logic, by modeling the monadic quantification as a particular modal operator.
This thesis studies how and to what extent the Segerberg–Maksimova theorem may be generalized to the system MS4 (monadic S4). In Chapter 1, we give the relevant background on modal logic, algebraic semantics, and relational semantics via Jónsson–Tarski duality. In Chapter 2 and Chapter 3, we give background on the specific theory of the variety S4 of S4-algebras and the monadic extension MS4, respectively. In Chapter 4, we establish the finite model property for some particular subvarieties of MS4. In Chapter 5, we present negative results concerning local finiteness in MS4 – we give a detailed construction of the dual space of a one-generated and infinite algebra of depth 1, and a translation of the variety S52 into two relatively small subvarieties of MS4 that suggests a full characterization of local finiteness will be difficult. The remaining chapters Chapter 6, Chapter 7, Chapter 8 present positive results, giving full syntactic characterizations of local finiteness below certain subvarieties of MS4. Of particular note is Chapter 7, which is more involved than the others and undertakes a detailed study of the subvariety of MS4 obtained by asserting the Casari axiom, an axiom of predicate logic related to intuitionistic logic and provability.</p
Farewell Issue
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Data_Sheet_1_Autoantibodies to Killer Cell Immunoglobulin-Like Receptors in Patients With Systemic Lupus Erythematosus Induce Natural Killer Cell Hyporesponsiveness.docx
No full textNatural killer (NK) cell cytotoxicity toward self-cells is restrained by the inhibitory HLA class I-binding receptors CD94/NKG2A and the killer cell immunoglobulin-like receptors (KIRs). CD94/NKG2A and KIRs are also essential for NK cell education, which is a dynamic functional maturation process where a constitutive binding of inhibitory receptors to cognate HLA class I molecules is required for NK cells to maintain their full cytotoxic capacity. Previously, we described autoantibodies to CD94/NKG2A in patients with systemic lupus erythematosus (SLE). In this study we analyzed sera from 191 patients with SLE, 119 patients with primary Sjögren's syndrome (pSS), 48 patients with systemic sclerosis (SSc), and 100 healthy donors (HD) for autoantibodies to eight different KIRs. Anti-KIR autoantibodies were identified in sera from 23.0% of patients with SLE, 10.9% of patients with pSS, 12.5% of patients with SSc, and 3.0% of HD. IgG from anti-KIR-positive SLE patients reduced the degranulation and cytotoxicity of NK cells toward K562 tumor cells. The presence of anti-KIR-autoantibodies reacting with >3 KIRs was associated with an increased disease activity (p < 0.0001), elevated serum levels of IFN-α (p < 0.0001), nephritis (p = 0.001), and the presence of anti-Sm (p = 0.007), and anti-RNP (p = 0.003) autoantibodies in serum. Together these findings suggest that anti-KIR autoantibodies may contribute to the reduced function of NK cells in SLE patients, and that a defective NK cell function may be a risk factor for the development of lupus nephritis.</p
