Over the last decade, various new therapies have been developed to promote anti-tumor immunity. Despite interesting clinical results in hematological malignancies, the development of bispecific ...killer-cell-engager antibody formats directed against tumor cells and stimulating anti-tumor T cell immunity has proved challenging, mostly due to toxicity problems. We report here the generation of trifunctional natural killer (NK) cell engagers (NKCEs), targeting two activating receptors, NKp46 and CD16, on NK cells and a tumor antigen on cancer cells. Trifunctional NKCEs were more potent in vitro than clinical therapeutic antibodies targeting the same tumor antigen. They had similar in vivo pharmacokinetics to full IgG antibodies and no off-target effects and efficiently controlled tumor growth in mouse models of solid and invasive tumors. Trifunctional NKCEs thus constitute a new generation of molecules for fighting cancer.
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•NK cell engagers are multifunctional Abs targeting tumor antigens, NKp46 and CD16•NKCEs bring tumor cells and NK cells together and trigger tumor-cell destruction•NKCEs can show killing potency superior to therapeutic Abs in vitro and in vivo•NKCEs may improve benefit-risk profile for cancer treatment compared to BiTEs
Trifunctional antibodies that engage natural killer cells by binding NKp46 and CD16, in addition to an antigen on cancer cells, show higher potency than current clinically available therapeutic antibodies.
Immune checkpoint inhibitors have revolutionized cancer treatment. However, many cancers are resistant to ICIs, and the targeting of additional inhibitory signals is crucial for limiting tumor ...evasion. The production of adenosine via the sequential activity of CD39 and CD73 ectoenzymes participates to the generation of an immunosuppressive tumor microenvironment. In order to disrupt the adenosine pathway, we generated two antibodies, IPH5201 and IPH5301, targeting human membrane-associated and soluble forms of CD39 and CD73, respectively, and efficiently blocking the hydrolysis of immunogenic ATP into immunosuppressive adenosine. These antibodies promoted antitumor immunity by stimulating dendritic cells and macrophages and by restoring the activation of T cells isolated from cancer patients. In a human CD39 knockin mouse preclinical model, IPH5201 increased the anti-tumor activity of the ATP-inducing chemotherapeutic drug oxaliplatin. These results support the use of anti-CD39 and anti-CD73 monoclonal antibodies and their combination with immune checkpoint inhibitors and chemotherapies in cancer.
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•IPH5201 and IPH5301 block cell-borne and soluble CD39 and CD73, respectively•IPH5201 maintains immunogenic extracellular ATP•When used in combination with chemotherapy, IPH5201 promotes antitumor immunity•Targeting CD39 and CD73 synergistically promotes cancer patient T cell activation
The production of adenosine via CD39 and CD73 ectoenzymes participates in an immunosuppressive tumor microenvironment. Perrot et al. generated two antibodies, IPH5201 and IPH5301, targeting human CD39 and CD73, respectively. In vitro and in vivo data support the use of anti-CD39 and anti-CD73 mAbs in combination cancer therapies.
The hematopoietic growth factor granulocyte colony‐stimulating factor (G‐CSF) has a role in proliferation, differentiation and migration of the myeloid lineage and in mobilizing hematopoietic stem ...and progenitor cells into the bloodstream. However, G‐CSF has been newly characterized as a neurotrophic factor in the brain. We recently uncovered that autonomic nerve development in the tumor microenvironment participates actively in prostate tumorigenesis and metastasis. Here, we found that G‐CSF constrains cancer to grow and progress by, respectively, supporting the survival of sympathetic nerve fibers in 6‐hydroxydopamine‐sympathectomized mice and also, promoting the aberrant outgrowth of parasympathetic nerves in transgenic or xenogeneic prostate tumor models. This provides insight into how neurotrophic growth factors may control tumor neurogenesis and may lead to new antineurogenic therapies for prostate cancer.
What's New?
Granulocyte Colony Stimulating Factor (G‐CSF) is known to mobilize hematopoietic progenitor stem cells in the blood of donors for stem cell transplantations, but its role as a neurotrophic factor is much less well understood. Here the authors show that G‐CSF potentiates tumor growth and metastasis through autonomic nerve development in prostate tumors. This raises concerns regarding the use of G‐CSF in cancer patients and gives insight into the interplay between tumor nerve development and growth factors as a potential new target in cancer therapy.
The repair of toxic double-strand breaks (DSB) is critical for the maintenance of genome integrity. The major mechanisms that cope with DSB are: homologous recombination (HR) and classical or ...alternative nonhomologous end joining (C-NHEJ versus A-EJ). Because these pathways compete for the repair of DSB, the choice of the appropriate repair pathway is pivotal. Among the mechanisms that influence this choice, deoxyribonucleic acid (DNA) end resection plays a critical role by driving cells to HR, while accurate C-NHEJ is suppressed. Furthermore, end resection promotes error-prone A-EJ. Increasing evidence define Poly(ADP-ribose) polymerase 3 (PARP3, also known as ARTD3) as an important player in cellular response to DSB. In this work, we reveal a specific feature of PARP3 that together with Ku80 limits DNA end resection and thereby helps in making the choice between HR and NHEJ pathways. PARP3 interacts with and PARylates Ku70/Ku80. The depletion of PARP3 impairs the recruitment of YFP-Ku80 to laser-induced DNA damage sites and induces an imbalance between BRCA1 and 53BP1. Both events result in compromised accurate C-NHEJ and a concomitant increase in DNA end resection. Nevertheless, HR is significantly reduced upon PARP3 silencing while the enhanced end resection causes mutagenic deletions during A-EJ. As a result, the absence of PARP3 confers hypersensitivity to anti-tumoral drugs generating DSB.
Queen health is crucial to colony survival of social bees. Recently, queen failure has been proposed to be a major driver of managed honey bee colony losses, yet few data exist concerning effects of ...environmental stressors on queens. Here we demonstrate for the first time that exposure to field-realistic concentrations of neonicotinoid pesticides during development can severely affect queens of western honey bees (Apis mellifera). In pesticide-exposed queens, reproductive anatomy (ovaries) and physiology (spermathecal-stored sperm quality and quantity), rather than flight behaviour, were compromised and likely corresponded to reduced queen success (alive and producing worker offspring). This study highlights the detriments of neonicotinoids to queens of environmentally and economically important social bees, and further strengthens the need for stringent risk assessments to safeguard biodiversity and ecosystem services that are vulnerable to these substances.
Abstract
Telomere maintenance is essential to preserve genomic stability and involves telomere-specific proteins, DNA replication and repair proteins. Lamins are key components of the nuclear ...envelope and play numerous roles, including maintenance of the nuclear integrity, regulation of transcription, and DNA replication. Elevated levels of lamin B1, one of the major lamins, have been observed in some human pathologies and several cancers. Yet, the effect of lamin B1 dysregulation on telomere maintenance remains unknown. Here, we unveil that lamin B1 overexpression drives telomere instability through the disruption of the shelterin complex. Indeed, lamin B1 dysregulation leads to an increase in telomere dysfunction-induced foci, telomeric fusions and telomere losses in human cells. Telomere aberrations were preceded by mislocalizations of TRF2 and its binding partner RAP1. Interestingly, we identified new interactions between lamin B1 and these shelterin proteins, which are strongly enhanced at the nuclear periphery upon lamin B1 overexpression. Importantly, chromosomal fusions induced by lamin B1 in excess were rescued by TRF2 overexpression. These data indicated that lamin B1 overexpression triggers telomere instability through a mislocalization of TRF2. Altogether our results point to lamin B1 as a new interacting partner of TRF2, that is involved in telomere stability.
Across the Northern hemisphere, managed honey bee colonies, Apis mellifera, are currently affected by abrupt depopulation during winter and many factors are suspected to be involved, either alone or ...in combination. Parasites and pathogens are considered as principal actors, in particular the ectoparasitic mite Varroa destructor, associated viruses and the microsporidian Nosema ceranae. Here we used long term monitoring of colonies and screening for eleven disease agents and genes involved in bee immunity and physiology to identify predictive markers of honeybee colony losses during winter. The data show that DWV, Nosema ceranae, Varroa destructor and Vitellogenin can be predictive markers for winter colony losses, but their predictive power strongly depends on the season. In particular, the data support that V. destructor is a key player for losses, arguably in line with its specific impact on the health of individual bees and colonies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PARP3 has been shown to be a key driver of TGFβ-induced epithelial-to-mesenchymal transition (EMT) and stemness in breast cancer cells, emerging as an attractive therapeutic target. Nevertheless, the ...therapeutic value of PARP3 inhibition has not yet been assessed. Here we investigated the impact of the absence of PARP3 or its inhibition on the tumorigenicity of BRCA1-proficient versus BRCA1-deficient breast cancer cell lines, focusing on the triple-negative breast cancer subtype (TNBC). We show that PARP3 knockdown exacerbates centrosome amplification and genome instability and reduces survival of BRCA1-deficient TNBC cells. Furthermore, we engineered PARP3
BRCA1-deficient or BRCA1-proficient TNBC cell lines using the CRISPR/nCas9
gene editing technology and demonstrate that the absence of PARP3 selectively suppresses the growth, survival and in vivo tumorigenicity of BRCA1-deficient TNBC cells, mechanistically via effects associated with an altered Rictor/mTORC2 signaling complex resulting from enhanced ubiquitination of Rictor. Accordingly, PARP3 interacts with and ADP-ribosylates GSK3β, a positive regulator of Rictor ubiquitination and degradation. Importantly, these phenotypes were rescued by re-expression of a wild-type PARP3 but not by a catalytic mutant, demonstrating the importance of PARP3's catalytic activity. Accordingly, reduced survival and compromised Rictor/mTORC2 signaling were also observed using a cell-permeable PARP3-specific inhibitor. We conclude that PARP3 and BRCA1 are synthetic lethal and that targeting PARP3's catalytic activity is a promising therapeutic strategy for BRCA1-associated cancers via the Rictor/mTORC2 signaling pathway.
The ADP ribosyl transferase poly(ADP-ribose) polymerase ARTD3(PARP3) is a newly characterized member of the ARTD(PARP) family that catalyzes the reaction of ADP ribosylation, a key posttranslational ...modification of proteins involved in different signaling pathways from DNA damage to energy metabolism and organismal memory. This enzyme shares high structural similarities with the DNA repair enzymes PARP1 and PARP2 and accordingly has been found to catalyse poly(ADP ribose) synthesis. However, relatively little is known about its in vivo cellular properties. By combining biochemical studies with the generation and characterization of loss-of-function human and mouse models, we describe PARP3 as a newcomer in genome integrity and mitotic progression. We report a particular role of PARP3 in cellular response to double-strand breaks, most likely in concert with PARP1. We identify PARP3 as a critical player in the stabilization of the mitotic spindle and in telomere integrity notably by associating and regulating the mitotic components NuMA and tankyrase 1. Both functions open stimulating prospects for specifically targeting PARP3 in cancer therapy.
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