P431: ACTIVATION OF MACROPHAGE STING ENHANCES PHAGOCYTOSIS OF ACUTE MYELOID LEUKAEMIA
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ABSTRACT:
SUBMITTER: Maynard R
PROVIDER: S-EPMC10429523 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
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Project description:The bone marrow (BM) microenvironment regulates acute myeloid leukemia (AML) initiation, proliferation, and chemotherapy resistance. Following cancer cell death, a growing body of evidence suggests an important role for remaining apoptotic debris in regulating the immunologic response to and growth of solid tumors. Here, we investigated the role of macrophage LC3-associated phagocytosis (LAP) within the BM microenvironment of AML. Depletion of BM macrophages (BMMs) increased AML growth in vivo. We show that LAP is the predominate method of BMM phagocytosis of dead and dying cells in the AML microenvironment. Targeted inhibition of LAP led to the accumulation of apoptotic cells (ACs) and apoptotic bodies (ABs), resulting in accelerated leukemia growth. Mechanistically, LAP of AML-derived ABs by BMMs resulted in stimulator of IFN genes (STING) pathway activation. We found that AML-derived mitochondrial damage-associated molecular patterns were processed by BMMs via LAP. Moreover, depletion of mitochondrial DNA (mtDNA) in AML-derived ABs showed that it was this mtDNA that was responsible for the induction of STING signaling in BMMs. Phenotypically, we found that STING activation suppressed AML growth through a mechanism related to increased phagocytosis. In summary, we report that macrophage LAP of apoptotic debris in the AML BM microenvironment suppressed tumor growth.
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Project description:PurposeFungal keratitis (FK) remains a treatment challenge, necessitating new therapeutic targets. Piezo1, a mechanosensitive ion channel, regulates calcium signaling and immune cell function. This study investigates its role in macrophage-mediated antifungal responses in FK.MethodsPiezo1 and Pyrin expression in corneas and bone marrow-derived macrophages (BMDMs) were assessed by RNAseq, quantitative real-time PCR (qRT-PCR), Western blot, and immunofluorescence. Intracellular calcium ion concentration was detected by Fluo-4 AM fluorescent probe staining. Heterozygous Piezo1 deficiency (Piezo1+/-) mice and Yoda1 were performed to regulate the expression of Piezo1.ResultsOur investigation demonstrates elevated expression of Piezo1 in the corneas of patients with FK and infected mice. This upregulation of Piezo1 corresponded with the swift recruitment of macrophages via the limbus. Additionally, Piezo1+/- mice exacerbate the progression of FK in the infection model. Furthermore, Piezo1 knockdown in macrophages exhibit a notable reduction phagocytic capacity, accompanied by an increase in viable colony-forming units in an in vitro model of fungal infection. Moreover, using a pharmacologic activator of Piezo1 (Yoda1), a calcium ion (Ca2+) chelator of BAPTA or Piezo1+/- mice, we demonstrate that Piezo1 activation triggers the Pyrin inflammasome via augmented calcium ion influx, which is required for protection against FK in murine hosts.ConclusionsPiezo1 is crucial for innate immunity in FK, enhancing macrophage recruitment, activation, and Pyrin inflammasome-mediated antifungal activity via calcium signaling. Using Piezo1+/- mice and Yoda1, we confirm Piezo1's role in fungal clearance. Targeting Piezo1 offers a novel strategy to improve FK outcomes by boosting macrophage function and immune response.
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Project description:For several decades, few substantial therapeutic advances have been made for patients with acute myeloid leukaemia. However, since 2017 unprecedented growth has been seen in the number of drugs available for the treatment of acute myeloid leukaemia, with several new drugs receiving regulatory approval. In addition to advancing our therapeutic armamentarium, an increased understanding of the biology and genomic architecture of acute myeloid leukaemia has led to refined risk assessment of this disease, with consensus risk stratification guidelines now incorporating a growing number of recurrent molecular aberrations that aid in the selection of risk-adapted management strategies. Despite this promising recent progress, the outcomes of patients with acute myeloid leukaemia remain unsatisfactory, with more than half of patients ultimately dying from their disease. Enrolment of patients into clinical trials that evaluate novel drugs and rational combination therapies is imperative to continuing this progress and further improving the outcomes of patients with acute myeloid leukaemia.
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Project description:Type I interferon (IFN), essential for spontaneous T cell priming against solid tumors, is generated through recognition of tumor DNA by STING. Interestingly, we observe that type I IFN is not elicited in animals with disseminated acute myeloid leukemia (AML). Further, survival of leukemia-bearing animals is not diminished in the absence of type I IFN signaling, suggesting that STING may not be triggered by AML. However, the STING agonist, DMXAA, induces expression of IFN-β and other inflammatory cytokines, promotes dendritic cell (DC) maturation, and results in the striking expansion of leukemia-specific T cells. Systemic DMXAA administration significantly extends survival in two AML models. The therapeutic effect of DMXAA is only partially dependent on host type I IFN signaling, suggesting that other cytokines are important. A synthetic cyclic dinucleotide that also activates human STING provided a similar anti-leukemic effect. These data demonstrate that STING is a promising immunotherapeutic target in AML.
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Project description:Although acute myeloid leukaemia (AML) has long been recognized for its morphological and cytogenetic heterogeneity, recent high-resolution genomic profiling has demonstrated a complexity even greater than previously imagined. This complexity can be seen in the number and diversity of genetic alterations, epigenetic modifications, and characteristics of the leukaemic stem cells. The broad range of abnormalities across different AML subtypes suggests that improvements in clinical outcome will require the development of targeted therapies for each subtype of disease and the design of novel clinical trials to test these strategies. It is highly unlikely that further gains in long-term survival rates will be possible by mere intensification of conventional chemotherapy. In this review, we summarize recent studies that provide new insight into the genetics and biology of AML, discuss risk stratification and therapy for this disease, and profile some of the therapeutic agents currently under investigation.
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Project description:Acute Myeloid Leukaemia (AML) carries a 5 year survival rate of just 24%. Toxic chemotherapy regimens remain the backbone of standard of care for AML. The FLT3 tyrosine kinase is a recognised AML oncogene, with FLT3 activating mutations occurring in approximately one third of all AML patients. However, therapeutic targeting of FLT3 has proven difficult as monotherapy, with the development of drug resistance and relapse. Characterisation of the signalling pathways regulated by mutant FLT3 is required to identify better therapeutic strategies.
2019-12-20 | MSV000084730 | MassIVE
Project description:Although innate immunity is critical for antifungal host defense against the human opportunistic fungal pathogen Aspergillus fumigatus, potentially damaging inflammation must be controlled. Adiponectin (APN) is an adipokine produced mainly in adipose tissue that exerts anti-inflammatory effects in adipose-distal tissues such as the lung. We observed 100% mortality and increased fungal burden and inflammation in neutropenic mice with invasive aspergillosis (IA) that lack APN or the APN receptors AdipoR1 or AdipoR2. Alveolar macrophages (AMs), early immune sentinels that detect and respond to lung infection, express both receptors, and APN-/- AMs exhibited an inflammatory/M1 phenotype that was associated with decreased fungal killing. Pharmacological stimulation of AMs with AdipoR agonist AdipoRon partially rescued deficient killing in APN-/- AMs that was dependent on both receptors. Finally, APN-enhanced fungal killing was associated with increased activation of the non-canonical LC3 pathway of autophagy. Thus, our study identifies a novel role for APN in LC3-mediated killing of A. fumigatus.
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Project description:Acute myeloid leukaemia (AML) is a molecularly and clinically heterogeneous disease, and its incidence is increasing as the populations in Western countries age. Despite major advances in understanding the genetic landscape of AML and its impact on the biology of the disease, standard therapy has not changed significantly in the last three decades. Allogeneic haematopoietic stem cell transplantation remains the best chance for cure, but can only be offered to a minority of younger fit patients. Molecularly targeted drugs aiming at restoring apoptosis in leukaemic cells have shown encouraging activity in early clinical trials and some of these drugs are currently being evaluated in randomised controlled trials. In this review, we discuss the current development of drugs designed to trigger cell death in AML.
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Project description:Acute myeloid leukaemia (AML) is a group of malignant diseases of the haematopoietic system. AML occurs as the result of mutations in haematopoietic stem/progenitor cells, which upregulate Wnt signalling through a variety of mechanisms. Other mechanisms of Wnt activation in AML have been described such as Wnt antagonist inactivation through promoter methylation. Wnt signalling is necessary for the maintenance of leukaemic stem cells. Several molecules involved in or modulating Wnt signalling have a prognostic value in AML. These include: β-catenin, LEF-1, phosphorylated-GSK3β, PSMD2, PPARD, XPNPEP, sFRP2, RUNX1, AXIN2, PCDH17, CXXC5, LLGL1 and PTK7. Targeting Wnt signalling for tumour eradication is an approach that is being explored in haematological and solid tumours. A number of preclinical studies confirms its feasibility, albeit, so far no reliable clinical trial data are available to prove its utility and efficacy.
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Project description:Acute myeloid leukaemia (AML) is a heterogeneous disease that is, in general, associated with a very poor prognosis. Multiple cytogenetic and molecular abnormalities that characterize different forms of AML have been used to better prognosticate patients and inform treatment decisions. Indeed, risk status in patients with this disease has classically been based on cytogenetic findings; however, additional molecular characteristics have been shown to inform risk assessment, including FLT3, NPM1, KIT, and CEBPA mutation status. Advances in sequencing technology have led to the discovery of novel somatic mutations in tissue samples from patients with AML, providing deeper insight into the mutational landscape of the disease. The majority of patients with AML (>97%) are found to have a clonal somatic abnormality on mutational profiling. Nevertheless, our understanding of the utility of mutation profiling in clinical practice remains incomplete and is continually evolving, and evidence-based approaches to application of these data are needed. In this Review, we discuss the evidence-base for integrating mutational data into treatment decisions for patients with AML, and propose novel therapeutic algorithms in the era of molecular medicine.
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