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The BOUT++ code is used to simulate edge localized modes (ELMs) in a shifted circle equilibrium. Reduced ideal MHD simulations are first benchmarked against the linear ideal MHD code ELITE, showing good agreement. Diamagnetic drift effects are included finding the expected suppression of high toroidal mode-number modes. Nonlinear simulations are performed, making the assumption that the anomalous kinematic electron viscosity is comparable to the anomalous electron thermal diffusivity. This allows simulations with realistically high Lundquist numbers (S = 108), finding ELM sizes of 5-10% of the pedestal stored thermal energy. Scans show a strong dependence of the ELM size on resistivity at low Lundquist numbers, with higher resistivity leading to more violent eruptions. At high Lundquist numbers relevant to high-performance discharges, ELM size is independent of resistivity as hyper-resistivity becomes the dominant dissipative effect. [ABSTRACT FROM AUTHOR]

The power-law series for the poloidal magnetic flux function, up to the third-order terms, is presented for the case where two nulls of the poloidal magnetic field are separated by a small distance, as in a snowflake divertor. Distinct from the earlier results, no assumptions about the field symmetry are made. Conditions for the realization of an exact snowflake are expressed in terms of the coefficients of the power series. It is shown that, by a proper choice of the coordinate frame in the poloidal plane, one can obtain efficient similarity solutions for the separatrices and flux surfaces in the divertor region: the whole variety of flux surface shapes can be characterized by a single dimensionless parameter. Transition from a snowflake-minus to a snowflake-plus configuration in the case of no particular symmetry is described. The effect of the finite toroidal current density in the divertor region is assessed for the case of no particular symmetry. [ABSTRACT FROM AUTHOR]

Background: Immunotherapies for malignant melanoma are challenged by the resistance developed in a significant proportion of patients. Myeloid-derived suppressor cells (MDSC), with their ability to inhibit antitumor T-cell responses, are a major contributor to immunosuppression and resistance to immune checkpoint therapies in melanoma. Damage-associated molecular patterns S100A8, S100A9, and HMGB1, acting as toll like receptor 4 (TLR4) and receptor for advanced glycation endproducts (RAGE) ligands, are highly expressed in the tumor microenvironment and drive MDSC activation. However, the role of TLR4 and RAGE signaling in the acquisition of MDSC immunosuppressive properties remains to be better defined. Our study investigates how the signaling via TLR4 and RAGE as well as their ligands S100A9 and HMGB1, shape MDSC-mediated immunosuppression in melanoma., Methods: MDSC were isolated from the peripheral blood of patients with advanced melanoma or generated in vitro from healthy donor-derived monocytes. Monocytes were treated with S100A9 or HMGB1 for 72 hours. The immunosuppressive capacity of treated monocytes was assessed in the inhibition of T-cell proliferation assay in the presence or absence of TLR4 and RAGE inhibitors. Plasma levels of S100A8/9 and HMGB1 were quantified by ELISA. Single-cell RNA sequencing (scRNA-seq) was performed on monocytes from patients with melanoma and healthy donors., Results: We showed that exposure to S100A9 and HMGB1 converted healthy donor-derived monocytes into MDSC through TLR4 signaling. Our scRNA-seq data revealed in patient monocytes enriched inflammatory genes, including S100 and those involved in NF-κB and TLR4 signaling, and a reduced major histocompatibility complex II gene expression. Furthermore, elevated plasma S100A8/9 levels correlated with shorter progression-free survival in patients with melanoma., Conclusions: These findings highlight the critical role of TLR4 and, to a lesser extent, RAGE signaling in the conversion of monocytes into MDSC-like cells, underscore the potential of targeting S100A9 to prevent this conversion, and highlight the prognostic value of S100A8/9 as a plasma biomarker in melanoma., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We study the interaction of a dark exciton Bose-Einstein condensate with the nuclei in gallium arsenide/aluminum gallium arsenide coupled quantum wells and find clear evidence for nuclear polarization buildup that accompanies the appearance of the condensate. We show that the nuclei are polarized throughout the mesa area, extending to regions that are far away from the photoexcitation area and persisting for seconds after the excitation is switched off. Photoluminescence measurements in the presence of radio frequency radiation reveal that the hyperfine interaction between the nuclear and electron spins is enhanced by two orders of magnitude. We suggest that this large enhancement manifests the collective nature of the N -exciton condensate, which amplifies the interaction by a factor of [Formula: see text].

The even-denominator fractional quantum Hall (FQH) states ν=5/2 and ν=7/2 have been long predicted to host non-Abelian quasiparticles. Their present energy-carrying neutral modes are hidden from customary conductance measurements and thus motivate thermal transport measurements, which are sensitive to all energy-carrying modes. While past "two-terminal" thermal conductance (k_{2t}T) measurements already proved the non-Abelian nature of the ν=5/2 FQH state, they might have been prone to a lack of thermal equilibration among the counterpropagating edge modes. Here, we report a novel thermal Hall conductance measurement of the ν=5/2 and ν=7/2 states, being insensitive to equilibration among edge modes. We verify the state's non-Abelian nature, with both states supporting a single upstream Majorana edge mode (hence, a particle-hole Pfaffian order). While current numerical works predict a different topological order, this contribution should motivate further theoretical work.

After recognizing its ligand lipopolysaccharide, Toll-like receptor 4 (TLR4) recruits adaptor proteins to the cell membrane, thereby initiating downstream signaling and triggering inflammation. Whether this recruitment of adaptor proteins is dependent solely on protein-protein interactions is unknown. Here, we report that the sphingolipid sphinganine physically interacts with the adaptor proteins MyD88 and TIRAP and promotes MyD88 recruitment in macrophages. Myeloid cell-specific deficiency in serine palmitoyltransferase long chain base subunit 2, which encodes the key enzyme catalyzing sphingolipid biosynthesis, decreases the membrane recruitment of MyD88 and inhibits inflammatory responses in in vitro bone marrow-derived macrophage and in vivo sepsis models. In a melanoma mouse model, serine palmitoyltransferase long chain base subunit 2 deficiency decreases anti-tumor myeloid cell responses and increases tumor growth. Therefore, sphinganine biosynthesis is required for the initiation of TLR4 signal transduction and serves as a checkpoint for macrophage pattern recognition in sepsis and melanoma mouse models., (© 2024. The Author(s).)

The ability of tumor-derived extracellular vesicles (EVs) to modulate the function of myeloid cells is widely recognized. Hence, a comprehensive understanding of the distinct components associated with EVs and the signals that they deliver to myeloid cells could provide potential approaches to impede the immunosuppression by myeloid-derived suppressor cells (MDSCs). We investigated melanoma EV-associated microRNAs (miRs) using the RET transgenic melanoma mouse model and simulated their transfer to normal myeloid cells by transfecting immature mouse myeloid cells and human monocytes. We observed elevated levels of miR-125a-5p, -125b-5p, and let-7e-5p in mouse melanoma-infiltrating MDSCs. In addition, miR-125a-5p levels in the tumor microenvironment correlated with mouse melanoma progression. The delivery of miR-125a-5p, alone or in combination with let-7e-5p and miR-99b-5p from the same genomic cluster, to normal myeloid cells resulted in their conversion to MDSC-like cells. Our findings indicate that miR-125a-5p could modulate myeloid cell activation in the melanoma microenvironment via a NF-κB-dependent mechanism.

Background: Immunotherapeutic approaches, including immune checkpoint inhibitor (ICI) therapy, are increasingly recognized for their potential. Despite notable successes, patient responses to these treatments vary significantly. The absence of reliable predictive and prognostic biomarkers hampers the ability to foresee outcomes. This meta-analysis aims to evaluate the predictive significance of circulating myeloid-derived suppressor cells (MDSC) in patients with solid tumors undergoing ICI therapy, focusing on progression-free survival (PFS) and overall survival (OS)., Methods: A comprehensive literature search was performed across PubMed and EMBASE from January 2007 to November 2023, utilizing keywords related to MDSC and ICI. We extracted hazard ratios (HRs) and 95% confidence intervals (CIs) directly from the publications or calculated them based on the reported data. A hazard ratio greater than 1 indicated a beneficial effect of low MDSC levels. We assessed heterogeneity and effect size through subgroup analyses., Results: Our search yielded 4,023 articles, of which 17 studies involving 1,035 patients were included. The analysis revealed that patients with lower levels of circulating MDSC experienced significantly improved OS (HR=2.13 [95% CI 1.51-2.99]) and PFS (HR=1.87 [95% CI 1.29-2.72]) in response to ICI therapy. Notably, heterogeneity across these outcomes was primarily attributed to differences in polymorphonuclear MDSC (PMN-MDSC) subpopulations and varying cutoff methodologies used in the studies. The monocytic MDSC (M-MDSC) subpopulation emerged as a consistent and significant prognostic marker across various subgroup analyses, including ethnicity, tumor type, ICI target, sample size, and cutoff methodology., Conclusions: Our findings suggest that standardized assessment of MDSC, particularly M-MDSC, should be integral to ICI therapy strategies. These cells hold the promise of identifying patients at risk of poor response to ICI therapy, enabling tailored treatment approaches. Further research focusing on the standardization of markers and validation of cutoff methods is crucial for integrating MDSC into clinical practice., Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023420095, identifier CRD42023420095., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Möller, Orth, Umansky, Hetjens, Braun, Reißfelder, Hardt and Seyfried.)

Despite its ubiquity in quantum computation and quantum information, a universally applicable definition of quantum entanglement remains elusive. The challenge is further accentuated when entanglement is associated with other key themes, e.g., quantum interference and quantum statistics. Here, we introduce two novel motifs that characterize the interplay of entanglement and quantum statistics: an 'entanglement pointer' and a 'statistics-induced entanglement entropy'. The two provide a quantitative description of the statistics-induced entanglement: (i) they are finite only in the presence of quantum entanglement underlined by quantum statistics and (ii) their explicit form depends on the quantum statistics of the particles (e.g., fermions, bosons, and anyons). We have experimentally implemented these ideas by employing an electronic Hong-Ou-Mandel interferometer fed by two highly diluted electron beams in an integer quantum Hall platform. Performing measurements of auto-correlation and cross-correlation of current fluctuations of the scattered beams (following 'collisions'), we quantify the statistics-induced entanglement by experimentally accessing the entanglement pointer and the statistics-induced entanglement entropy. Our theoretical and experimental approaches pave the way to study entanglement in various correlated platforms, e.g., those involving anyonic Abelian and non-Abelian states., (© 2024. The Author(s).)

Interferometry is a vital tool for studying fundamental features in the quantum Hall effect. For instance, Aharonov-Bohm interference in a quantum Hall interferometer can probe the wave-particle duality of electrons and quasiparticles. Here, we report an unusual Aharonov-Bohm interference of the outermost edge mode in a quantum Hall Fabry-Pérot interferometer, whose Coulomb interactions were suppressed with a grounded drain in the interior bulk of the interferometer. In a descending bulk filling factor from ν_{b}=3 to ν_{b}≈(5/3), the magnetic field periodicity, which corresponded to a single "flux quantum," agreed accurately with the enclosed area of the interferometer. However, in the filling range, ν_{b}≈(5/3) to ν_{b}=1, the field periodicity increased markedly, a priori suggesting a drastic shrinkage of the Aharonov-Bohm area. Moreover, the modulation gate voltage periodicity decreased abruptly at this range. We attribute these unexpected observations to edge reconstruction, leading to area changing with the field and a modified modulation gate-edge capacitance. These reproducible results support future interference experiments with a quantum Hall Fabry-Pérot interferometer.

Anticancer agents continue to dominate the list of newly approved drugs, approximately half of which are immunotherapies. This trend illustrates the considerable promise of cancer treatments that modulate the immune system. However, the immune system is complex and dynamic, and can have both tumour-suppressive and tumour-promoting effects. Understanding the full range of immune modulation in cancer is crucial to identifying more effective treatment strategies. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells that develop in association with chronic inflammation, which is a hallmark of cancer. Indeed, MDSCs accumulate in the tumour microenvironment, where they strongly inhibit anticancer functions of T cells and natural killer cells and exert a variety of other tumour-promoting effects. Emerging evidence indicates that MDSCs also contribute to resistance to cancer treatments, particularly immunotherapies. Conversely, treatment approaches designed to eliminate cancer cells can have important additional effects on MDSC function, which can be either positive or negative. In this Review, we discuss the interplay between MDSCs and various other cell types found in tumours as well as the mechanisms by which MDSCs promote tumour progression. We also discuss the relevance and implications of MDSCs for cancer therapy., (© 2024. Springer Nature Limited.)

The quantum Hall effect is a prototypical realization of a topological state of matter. It emerges from a subtle interplay between topology, interactions and disorder 1-9 . The disorder enables the formation of localized states in the bulk that stabilize the quantum Hall states with respect to the magnetic field and carrier density 3 . Still, the details of the localized states and their contribution to transport remain beyond the reach of most experimental techniques 10-31 . Here we describe an extensive study of the bulk's heat conductance. Using a novel 'multiterminal' short device (on a scale of 10 µm), we separate the longitudinal thermal conductance, [Formula: see text] (owing to the bulk's contribution), from the topological transverse value [Formula: see text] by eliminating the contribution of the edge modes 24 . When the magnetic field is tuned away from the conductance plateau centre, the localized states in the bulk conduct heat efficiently ([Formula: see text]), whereas the bulk remains electrically insulating. Fractional states in the first excited Landau level, such as the [Formula: see text] and [Formula: see text], conduct heat throughout the plateau with a finite [Formula: see text]. We propose a theoretical model that identifies the localized states as the cause of the finite heat conductance, agreeing qualitatively with our experimental findings., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The remarkable Cooper-like pairing phenomenon in the Aharonov-Bohm interference of a Fabry-Perot interferometer-operating in the integer quantum Hall regime-remains baffling. Here, we report the interference of paired electrons employing "interface edge modes." These modes are born at the interface between the bulk of the Fabry-Perot interferometer and an outer gated region tuned to a lower filling factor. Such a configuration allows toggling the spin and the orbital of the Landau level of the edge modes at the interface. We find that electron pairing occurs only when the two modes (the interfering outer and the first inner) belong to the same spinless Landau level.

Treatment with immune checkpoint inhibitors (ICIs) has improved the prognosis of melanoma patients. However, ICIs can cause an overactivation of the immune system followed by diverse immunological side effects known as immune-related adverse events (irAE). Currently, the toxicity of irAE is limiting the usage of ICIs. Here, we studied circulating monocytic myeloid-derived suppressor cells (M-MDSCs) and T cells in course of irAE after the ICI therapy. Our longitudinal study involved 31 melanoma patients with and without adverse events during anti-PD-1 monotherapy or anti-CTLA-4/PD-1 combination therapy. Peripheral blood samples were analyzed before ICI start, during ICI treatment, at the time point of irAE and during immunosuppressive treatment to cure irAE. We observed an enhanced progression-free survival among patients with irAE. In patients with irAE, we found an upregulation of CD69 on CD8 + T cells and a decreased frequency of regulatory T cells (Tregs). Moreover, lower frequencies of Tregs correlated with more severe side effects. Patients treated with immunomodulatory drugs after irAE manifestation tend to show an elevated number of M-MDSCs during an immunosuppressive therapy. We suggest that an activation of CD8 + T cells and the reduction of Treg frequencies could be responsible for the development of irAE., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Despite the remarkable success of immune checkpoint inhibitors (ICIs) in melanoma treatment, resistance to them remains a substantial clinical challenge. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of myeloid cells that can suppress antitumor immune responses mediated by T and natural killer cells and promote tumor growth. They are major contributors to ICI resistance and play a crucial role in creating an immunosuppressive tumor microenvironment. Therefore, targeting MDSCs is considered a promising strategy to improve the therapeutic efficacy of ICIs. This Review describes the mechanism of MDSC-mediated immune suppression, preclinical and clinical studies on MDSC targeting, and potential strategies for inhibiting MDSC functions to improve melanoma immunotherapy.

Multielectron semiconductor quantum dots (QDs) provide a novel platform to study the Coulomb interaction-driven, spatially localized electron states of Wigner molecules (WMs). Although Wigner-molecularization has been confirmed by real-space imaging and coherent spectroscopy, the open system dynamics of the strongly correlated states with the environment are not yet well understood. Here, we demonstrate efficient control of spin transfer between an artificial three-electron WM and the nuclear environment in a GaAs double QD. A Landau-Zener sweep-based polarization sequence and low-lying anticrossings of spin multiplet states enabled by Wigner-molecularization are utilized. Combined with coherent control of spin states, we achieve control of magnitude, polarity, and site dependence of the nuclear field. We demonstrate that the same level of control cannot be achieved in the non-interacting regime. Thus, we confirm the spin structure of a WM, paving the way for active control of correlated electron states for application in mesoscopic environment engineering., (© 2023. The Author(s).)

Correlations of partitioned particles carry essential information about their quantumness 1 . Partitioning full beams of charged particles leads to current fluctuations, with their autocorrelation (namely, shot noise) revealing the particles' charge 2,3 . This is not the case when a highly diluted beam is partitioned. Bosons or fermions will exhibit particle antibunching (owing to their sparsity and discreteness) 4-6 . However, when diluted anyons, such as quasiparticles in fractional quantum Hall states, are partitioned in a narrow constriction, their autocorrelation reveals an essential aspect of their quantum exchange statistics: their braiding phase 7 . Here we describe detailed measurements of weakly partitioned, highly diluted, one-dimension-like edge modes of the one-third filling fractional quantum Hall state. The measured autocorrelation agrees with our theory of braiding anyons in the time domain (instead of braiding in space); with a braiding phase of 2θ = 2π/3, without any fitting parameters. Our work offers a relatively straightforward and simple method to observe the braiding statistics of exotic anyonic states, such as non-abelian states 8 , without resorting to complex interference experiments 9 ., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Although the treatment of advanced melanoma patients with immune checkpoint inhibitors (ICI) significantly increased the therapeutic efficiency, many patients remain resistant to ICI that could be due to immunosuppression mediated by myeloid-derived suppressor cells (MDSC). These cells are enriched and activated in melanoma patients and could be considered as therapeutic targets. Here we studied dynamic changes in immunosuppressive pattern and activity of circulating MDSC from melanoma patients treated with ICI., Experimental Design: MDSC frequency, immunosuppressive markers and function were evaluated in freshly isolated peripheral blood mononuclear cells (PBMC) from 29 melanoma patients receiving ICI. Blood samples were taken prior and during the treatment and analyzed by flow cytometry and bio-plex assay., Results: MDSC frequency was significantly increased before the therapy and through three months of treatment in non-responders as compared to responders. Prior to the ICI therapy, MDSC from non-responders displayed high levels of immunosuppression measured by the inhibition of T cell proliferation assay, whereas MDSC from responding patients failed to inhibit T cells. Patients without visible metastasis were characterized by the absence of MDSC immunosuppressive activity during the ICI treatment. Moreover, non-responders showed significantly higher IL-6 and IL-8 concentrations before therapy and after the first ICI application as compared to responders., Conclusions: Our findings highlight the role of MDSC during melanoma progression and suggest that frequency and immunosuppressive activity of circulating MDSC before and during the ICI treatment of melanoma patients could be used as biomarkers of response to ICI therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Petrova, Groth, Bitsch, Arkhypov, Simon, Hetjens, Müller, Utikal and Umansky.)

A gradual decay in humoral and cellular immune responses over time upon SAR1S-CoV-2 vaccination may cause a lack of protective immunity. We conducted a longitudinal analysis of antibodies, T cells, and monocytes in 25 participants vaccinated with mRNA or ChAdOx1-S up to 12 weeks after the 3 rd (booster) dose with mRNA vaccine. We observed a substantial increase in antibodies and CD8 T cells specific for the spike protein of SARS-CoV-2 after vaccination. Moreover, vaccination induced activated T cells expressing CD69, CD137 and producing IFN-γ and TNF-α. Virus-specific CD8 T cells showed predominantly memory phenotype. Although the level of antibodies and frequency of virus-specific T cells reduced 4-6 months after the 2 nd dose, they were augmented after the 3 rd dose followed by a decrease later. Importantly, T cells generated after the 3 rd vaccination were also reactive against Omicron variant, indicated by a similar level of IFN-γ production after stimulation with Omicron peptides. Breakthrough infection in participants vaccinated with two doses induced more SARS-CoV-2-specific T cells than the booster vaccination. We found an upregulation of PD-L1 expression on monocytes but no accumulation of myeloid cells with MDSC-like immunosuppressive phenotype after the vaccination. Our results indicate that the 3 rd vaccination fosters antibody and T cell immune response independently from vaccine type used for the first two injections. However, such immune response is attenuated over time, suggesting thereby the need for further vaccinations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Özbay Kurt, Lepper, Gerhards, Roemer, Lasser, Arkhypov, Bitsch, Bugert, Altevogt, Gouttefangeas, Neumaier, Utikal and Umansky.)

The topological order of a quantum Hall state is mirrored by the gapless edge modes owing to bulk-edge correspondence. The state at the filling of ν = 5/2, predicted to host non-abelian anyons, supports a variety of edge modes (integer, fractional, neutral). To ensure thermal equilibration between the edge modes and thus accurately determine the state's nature, it is advantageous to isolate the fractional channel (1/2 and neutral modes). In this study, we gapped out the integer modes by interfacing the ν = 5/2 state with integer states ν = 2 and ν = 3 and measured the thermal conductance of the isolated-interface channel. Our measured half-quantized thermal conductance confirms the non-abelian nature of the ν = 5/2 state and its particle-hole Pfaffian topological order. Such an isolated channel may be more amenable to braiding experiments.

Background: Tumor cells modulate host immunity by secreting extracellular vesicles (EV) and soluble factors. Their interactions with myeloid cells lead to the generation of myeloid-derived suppressor cells (MDSC), which inhibit the antitumor function of T and NK cells. We demonstrated previously that EV derived from mouse and human melanoma cells induced immunosuppressive activity via increased expression of programmed cell death ligand 1 (PD-L1) on myeloid cells that was dependent on the heat-shock protein 90α (HSP90α) in EV. Here, we investigated whether soluble HSP90α could convert monocytes into MDSC., Methods: CD14 monocytes were isolated from the peripheral blood of healthy donors, incubated with human recombinant HSP90α (rHSP90α) alone or in the presence of inhibitors of TLR4 signaling and analyzed by flow cytometry. Inhibition of T cell proliferation assay was applied to assess the immunosuppressive function of rHSP90α-treated monocytes. HSP90α levels were measured by ELISA in plasma of patients with advanced melanoma and correlated with clinical outcome., Results: We found that the incubation of monocytes with rHSP90α resulted in a strong upregulation of PD-L1 expression, whereas reactive oxygen species (ROS) and nitric oxide (NO) production as well as the expression of arginase-1, ectoenzymes CD39 and CD73 remained unchanged. The PD-L1 upregulation was blocked by anti-TLR4 antibodies and a nuclear factor-κB inhibitor. rHSP90α-treated monocytes displayed the downregulation of HLA-DR expression and acquired the resistance to apoptosis. Moreover, these monocytes were converted into MDSC as indicated by their capacity to inhibit T cell proliferation, which was mediated by TLR4 signaling as well as PD-L1 and indoleamine 2,3-dioxygenase (IDO) 1 expression. Higher levels of HSP90α in plasma of patients with melanoma correlated with augmented PD-L1 expression on circulating monocytic (M)-MDSC. Patients with melanoma with high levels of HSP90α displayed shorter progression-free survival (PFS) on the treatment with immune checkpoint inhibitors (ICIs)., Conclusion: Our findings demonstrated that soluble rHSP90α increased the resistance of normal human monocytes to apoptosis and converted them into immunosuppressive MDSC via TLR4 signaling that stimulated PD-L1 and IDO-1 expression. Furthermore, patients with melanoma with high concentrations of HSP90α displayed increased PD-L1 expression on M-MDSC and reduced PFS after ICI therapy, suggesting HSP90α as a promising therapeutic target for overcoming immunosuppression in melanoma., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We show that a Bose-Einstein condensate consisting of dark excitons forms in GaAs coupled quantum wells at low temperatures. We find that the condensate extends over hundreds of micrometers, well beyond the optical excitation region, and is limited only by the boundaries of the mesa. We show that the condensate density is determined by spin-flipping collisions among the excitons, which convert dark excitons into bright ones. The suppression of this process at low temperature yields a density buildup, manifested as a temperature-dependent blueshift of the exciton emission line. Measurements under an in-plane magnetic field allow us to preferentially modify the bright exciton density and determine their role in the system dynamics. We find that their interaction with the condensate leads to its depletion. We present a simple rate-equations model, which well reproduces the observed temperature, power, and magnetic-field dependence of the exciton density.

We report energy-selective tunneling readout-based Hamiltonian parameter estimation of a two-electron spin qubit in a GaAs quantum dot array. Optimization of readout fidelity enables a single-shot measurement time of 16  μs on average, with adaptive initialization and efficient qubit frequency estimation based on real-time Bayesian inference. For qubit operation in a frequency heralded mode, we observe a 40-fold increase in coherence time without resorting to dynamic nuclear polarization. We also demonstrate active frequency feedback with quantum oscillation visibility, single-shot measurement fidelity, and gate fidelity of 97.7%, 99%, and 99.6%, respectively, showcasing the improvements in the overall capabilities of GaAs-based spin qubits. By pushing the sensitivity of the energy-selective tunneling-based spin to charge conversion to the limit, the technique is useful for advanced quantum control protocols such as error mitigation schemes, where fast qubit parameter calibration with a large signal-to-noise ratio is crucial.

Tumor-associated hypoxia plays an important role in carcinogenesis and metastasis. The expression, activation, and stabilization of hypoxia-inducible transcription factors (HIFs) support malignant cell survival, proliferation, plasticity, and motility. Hypoxia also upregulates the expression of programmed cell death ligand 1 (PD-L1) in malignant and immune regulatory cells. Therefore, the combination of HIF inhibitors and checkpoint inhibitors (CPIs) is promising for boosting antitumor immunity and diminishing malignant cell plasticity and therapy resistance. In this issue of the JCI, Salman et al. report the development of a specific agent that inhibited HIF-1/2-mediated gene expression in tumor cells and suppressed tumor growth. Bailey, Liu, et al. in this issue demonstrate that targeting HIF-1α abrogated PD-L1-mediated immune evasion by suppressing PD-L1 expression on malignant and myeloid regulatory cells, causing tumor rejection. These findings suggest that targeting the HIF/PD-L1 axis with specific HIF inhibitors should improve the safety and efficacy of CPIs for cancer therapy.

Background: Myeloid-derived suppressor cells (MDSCs) represent a negative prognostic factor in malignant melanoma. These cells are generated under chronic inflammatory conditions typical of cancer. The transcription factor signal transducer and activator of transcription 3 (STAT3) orchestrates MDSC accumulation and acquisition of immunosuppressive properties. Here we studied STAT3 inhibition by Napabucasin as a way to block MDSC accumulation and activity and its potential to treat malignant melanoma., Methods: In vitro generated murine MDSC and primary MDSC from melanoma-bearing mice were used to investigate the effects of Napabucasin on MDSC in vitro . The RET transgenic mouse model of malignant melanoma was used to examine Napabucasin therapy efficiency and its underlying mechanisms in vivo . Furthermore, STAT3 activation and its correlation with survival were explored in MDSC from 19 patients with malignant melanoma and human in vitro generated monocytic myeloid-derived suppressor cell (M-MDSC) were used to evaluate the effects of Napabucasin., Results: Napabucasin was able to abrogate the capacity of murine MDSC to suppress CD8 + T-cell proliferation. The STAT3 inhibitor induced apoptosis in murine MDSC, significantly increased expression of molecules associated with antigen processing and presentation, as well as slightly decreased expression of immunosuppressive factors on these cells. RET transgenic mice treated with Napabucasin showed prolonged survival accompanied by a strong accumulation of tumor-infiltrating antigen-presenting cells and activation of CD8 + and CD4 + T cells. Interestingly, patients with malignant melanoma with high expression of activated STAT3 in circulating M-MDSC showed significantly worse progression-free survival (PFS) than patients with low levels of activated STAT3. In addition, Napabucasin was able to abrogate suppressive capacity of human in vitro generated M-MDSC., Conclusion: Our findings demonstrate that STAT3 inhibitor Napabucasin completely abrogated the immunosuppressive capacity of murine MDSC and human M-MDSC and improved melanoma-bearing mouse survival. Moreover, patients with malignant melanoma with high expression levels of activated STAT3 in M-MDSC displayed shorter PFS, indicating its role as a promising therapeutic target in patients with malignant melanoma and a predictive marker for their clinical outcome., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: ADCK2 is a member of the AarF domain-containing kinase family, which consists of five members, and has been shown to play a role in CoQ metabolism. However, ADCKs have also been connected to cancer cell survival, proliferation and motility. In this study, we investigated the role of ADCK2 in melanoma., Methods: The effect of ADCK2 on melanoma cell motility was evaluated by a scratch assay and a transwell invasion assay upon siRNA-mediated knockdown or stable overexpression of ADCK2., Results: We found that high levels of intratumoral ADCK2 and MYL6 are associated with a higher survival rate in melanoma patients. Knocking down ADCK2 resulted in enhanced cell migration of melanoma cells. Moreover, ADCK2-knockdown cells adopted a more dedifferentiated phenotype. A gene expression array revealed that the expression of ADCK2 correlated with the expressions of MYL6 and RAB2A. Knocking down MYL6 in ADCK2-overexpressing cells could abrogate the effect of ADCK2 overexpression and thus confirm the functional connection between ADCK2 and MYL6., Conclusion: ADCK2 affects melanoma cell motility, most probably via MYL6. Our results allow the conclusion that ADCK2 could act as a tumor suppressor in melanoma.

Two-dimensional topological insulators, and in particular quantum Hall states, are characterized by an insulating bulk and a conducting edge. Fractional states may host both downstream (dictated by the magnetic field) and upstream propagating edge modes, which leads to complex transport behavior. Here, we combine two measurement techniques, local noise thermometry and thermal conductance, to study thermal properties of states with counter-propagating edge modes. We find that, while charge equilibration between counter-propagating edge modes is very fast, the equilibration of heat is extremely inefficient, leading to an almost ballistic heat transport over macroscopic distances. Moreover, we observe an emergent quantization of the heat conductance associated with a strong interaction fixed point of the edge modes. Such understanding of the thermal equilibration on edges with counter-propagating modes is a natural route towards extracting the topological order of the exotic 5/2 state., (© 2022. The Author(s).)

Quantum Hall states can harbor exotic quantum phases. The nature of these states is reflected in the gapless edge modes owing to “bulk-edge” correspondence. The most studied putative non-abelian state is the spin-polarized filling factor (ν) = 5/2, which permits different topological orders that can be abelian or non-abelian. We developed a method that interfaces the studied quantum state with another state and used it to identify the topological order of ν = 5/2 state. The interface between two half-planes, one hosting the ν = 5/2 state and the other an integer ν = 3 state, supports a fractional ν = 1/2 charge mode and a neutral Majorana mode. The counterpropagating chirality of the Majorana mode, probed by measuring partition noise, is consistent with the particle-hole Pfaffian (PH-Pf) topological order and rules out the anti-Pfaffian order.

Background: The prognosis of patients with brain metastases (BM) is poor despite advances in our understanding of the underlying pathophysiology. The high incidence of thrombotic complications defines tumor progression and the high mortality rate. We, therefore, postulated that von Willebrand factor (VWF) promotes BM via its ability to induce platelet aggregation and thrombosis., Methods: We measured the abundance of VWF in the blood and intravascular platelet aggregates of patients with BM, and determined the specific contribution of endothelial and platelet-derived VWF using in vitro models and microfluidics. The relevance for the brain metastatic cascade in vivo was demonstrated in ret transgenic mice, which spontaneously develop BM, and by the intracardiac injection of melanoma cells., Results: Higher levels of plasma VWF in patients with BM were associated with enhanced intraluminal VWF fiber formation and platelet aggregation in the metastatic tissue and peritumoral regions. Platelet activation triggered the formation of VWF multimers, promoting platelet aggregation and activation, in turn enhancing tumor invasiveness. The absence of VWF in platelets, or the blocking of platelet activation, abolished platelet aggregation, and reduced tumor cell transmigration. Anticoagulation and platelet inhibition consistently reduced the number of BM in preclinical animal models., Conclusions: Our data indicate that platelet-derived VWF is involved in cerebral clot formation and in metastatic growth of melanoma in the brain. Targeting platelet activation with low-molecular-weight heparins represents a promising therapeutic approach to prevent melanoma BM., (© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Myeloid-derived suppressor cells (MDSC) represent a highly immunosuppressive population that expands in tumor bearing hosts and inhibits both T and NK cell antitumor effector functions. Among MDSC subpopulations, the polymorphonuclear (PMN) one is gaining increasing interest since it is a predominant MDSC subset in most cancer entities and inherits unique properties to facilitate metastatic spread. In addition, further improvement in distinguishing PMN-MDSC from neutrophils has contributed to the design of novel therapeutic approaches. In this review, we summarize the current view on the origin of PMN-MDSC and their relation to classical neutrophils. Furthermore, we outline the metastasis promoting features of these cells and promising strategies of their targeting to improve the efficacy of cancer immunotherapy., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Neutrophils play a key role in cancer biology. In contrast to circulating normal-density neutrophils (NDN), the amount of low-density neutrophils (LDN) significantly increases with tumor progression. The correlation between these neutrophil subpopulations and intratumoral neutrophils (TANs) is still under debate. Using 4T1 (breast) and AB12 (mesothelioma) tumor models, we aimed to elucidate the source of TANs and to assess the mechanisms driving neutrophils' plasticity in cancer. Both NDN and LDN were found to migrate in response to CXCL1 and CXCL2 exposure, and co-infiltrate the tumor site ex vivo and in vivo, although LDN migration into the tumor was higher than NDN. Tumor-derived factors and chemokines, particularly CXCL1, were found to drive neutrophil phenotypical plasticity, inducing NDN to transition towards a low-density state (LD-NDN). LD-NDN appeared to differ from NDN by displaying a phenotypical profile similar to LDN in terms of nuclear morphology, surface receptor markers, decreased phagocytic abilities, and increased ROS production. Interestingly, all three subpopulations displayed comparable cytotoxic abilities towards tumor cells. Our data suggest that TANs originate from both LDN and NDN, and that a portion of LDN derives from NDN undergoing phenotypical changes. NDN plasticity resulted in a change in surface marker expression and functional activity, gaining characteristics of LDN.

Metastatic melanoma is an aggressive skin cancer and associated with a poor prognosis. In clinical terms, targeted therapy is one of the most important treatments for patients with BRAF V600E -mutated advanced melanoma. However, the development of resistance to this treatment compromises its therapeutic success. We previously demonstrated that forkhead box D1 (FOXD1) regulates melanoma migration and invasion. Here, we found that FOXD1 was highly expressed in melanoma cells and was associated with a poor survival of patients with metastatic melanoma. Upregulation of FOXD1 expression enhanced melanoma cells' resistance to vemurafenib (BRAF inhibitor [BRAFi]) or vemurafenib and cobimetinib (MEK inhibitor) combination treatment whereas loss of FOXD1 increased the sensitivity to treatment. By comparing gene expression levels between FOXD1 knockdown (KD) and overexpressing (OE) cells, we identified the connective tissue growth factor (CTGF) as a downstream factor of FOXD1. Chromatin immunoprecipitation and luciferase assay demonstrated the direct binding of FOXD1 to the CTGF promoter. Similar to FOXD1, knockdown of CTGF increased the sensitivity of BRAFi-resistant cells to vemurafenib. FOXD1 KD cells treated with recombinant CTGF protein were less sensitive towards vemurafenib compared to untreated FOXD1 KD cells. Based on these findings, we conclude that FOXD1 might be a promising new diagnostic marker and a therapeutic target for the treatment of targeted therapy resistant melanoma., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Group 2 innate lymphoid cells (ILC2s) are essential to maintain tissue homeostasis. In cancer, ILC2s can harbor both pro-tumorigenic and anti-tumorigenic functions, but we know little about their underlying mechanisms or whether they could be clinically relevant or targeted to improve patient outcomes. Here, we found that high ILC2 infiltration in human melanoma was associated with a good clinical prognosis. ILC2s are critical producers of the cytokine granulocyte-macrophage colony-stimulating factor, which coordinates the recruitment and activation of eosinophils to enhance antitumor responses. Tumor-infiltrating ILC2s expressed programmed cell death protein-1, which limited their intratumoral accumulation, proliferation and antitumor effector functions. This inhibition could be overcome in vivo by combining interleukin-33-driven ILC2 activation with programmed cell death protein-1 blockade to significantly increase antitumor responses. Together, our results identified ILC2s as a critical immune cell type involved in melanoma immunity and revealed a potential synergistic approach to harness ILC2 function for antitumor immunotherapies.

Neutrophils-once considered as simple killers of pathogens and unexciting for cancer research-are now acknowledged for their role in the process of tumorigenesis. Neutrophils are recruited to the tumor microenvironment where they turn into tumor-associated neutrophils (TANs), and are able to initiate and promote tumor progression and metastasis. Conversely, anti-tumorigenic properties of neutrophils have been documented, highlighting the versatile nature and high pleiotropic plasticity of these polymorphonuclear leukocytes (PMN-L). Here, we dissect the ambivalent roles of TANs in cancer and focus on selected functional aspects that could be therapeutic targets. Indeed, the critical point of targeting TAN functions lies in the fact that an immunosuppressive state could be induced, resulting in unwanted side effects. A deeper knowledge of the mechanisms linked to diverse TAN functions in different cancer types is necessary to define appropriate therapeutic strategies that are able to induce and maintain an anti-tumor microenvironment.

We report a single-shot-based projective readout of a semiconductor hybrid qubit formed by three electrons in a GaAs double quantum dot. Voltage-controlled adiabatic transitions between the qubit operations and readout conditions allow high-fidelity mapping of quantum states. We show that a large ratio both in relaxation time vs tunneling time (≈50) and singlet-triplet splitting vs thermal energy (≈20) allows energy-selective tunneling-based spin-to-charge conversion with a readout visibility of ≈92.6%. Combined with ac driving, we demonstrate high visibility coherent Rabi and Ramsey oscillations of a hybrid qubit in GaAs. Further, we discuss the generality of the method for use in other materials, including silicon.

Hepatocellular carcinoma (HCC) can have viral or non-viral causes 1-5 . Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need 6,7 . Here we report the progressive accumulation of exhausted, unconventionally activated CD8 + PD1 + T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8 + PD1 + T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8 + PD1 + CXCR6 + , TOX + , and TNF + T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8 + T cells or TNF neutralization, suggesting that CD8 + T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8 + PD1 + T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.

Background: Despite recent improvement in the treatment of malignant melanoma by immune-checkpoint inhibitors, the disease can progress due to an immunosuppressive tumor microenvironment (TME) mainly represented by myeloid-derived suppressor cells (MDSC). However, the relative contribution of the polymorphonuclear (PMN) and monocytic (M) MDSC subsets to melanoma progression is not clear. Here, we compared both subsets regarding their immunosuppressive capacity and recruitment mechanisms. Furthermore, we inhibited PMN-MDSC migration in vivo to determine its effect on tumor progression., Methods: Using the RET transgenic melanoma mouse model, we investigated the immunosuppressive function of MDSC subsets and chemokine receptor expression on these cells. The effect of CXCR2 inhibition on PMN-MDSC migration and tumor progression was studied in RET transgenic mice and in C57BL/6 mice after surgical resection of primary melanomas., Results: Immunosuppressive capacity of intratumoral M- and PMN-MDSC was comparable in melanoma bearing mice. Anti-CXCR2 therapy prolonged survival of these mice and decreased the occurrence of distant metastasis. Furthermore, this therapy reduced the infiltration of melanoma lesions and pre-metastatic sites with PMN-MDSC that was associated with the accumulation of natural killer (NK) cells., Conclusions: We provide evidence for the tumor - promoting properties of PMN-MDSC as well as for the anti-tumor effects upon their targeting in melanoma bearing mice.

The low dose application of chemotherapeutic agents such as paclitaxel was previously shown to initiate anti-tumor activity by neutralizing myeloid-derived suppressor cells (MDSCs) in melanoma mouse models. Here, we investigated immunomodulating effects of low-dose paclitaxel in 9 metastatic melanoma patients resistant to prior treatments. Three patients showed response to therapy (two partial responses and one stable disease). In responding patients, paclitaxel decreased the frequency and immunosuppressive pattern of MDSCs in the peripheral blood and skin metastases. Furthermore, paclitaxel modulated levels of inflammatory mediators in the serum. In addition, responders displayed enhanced frequencies of tumor-infiltrating CD8 + T cells and their activity indicated by the upregulation of CD25 and TCR ζ-chain expression. Our study suggests that low-dose paclitaxel treatment could improve clinical outcome of some advanced melanoma patients by enhancing anti-tumor immunity and might be proposed for combined melanoma immunotherapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Myeloid-derived suppressor cells (MDSC) are known to inhibit functions of T and NK cells. MDSC have been shown to be generated and to accumulate under chronic inflammatory conditions that are typical for cancer. Therefore, it would be highly beneficial to find ways to diminish the number and immunosuppressive functions of these cells in tumor-bearing hosts. Here we describe current protocols to deplete MDSC or induce their maturation in preclinical tumor models that could lead to the attenuation of their immunosuppressive functions.

Myeloid-derived suppressor cells (MDSC) are generated during tumor progression and suppress the anti-tumor functions of T and natural killer (NK) cells. Their enrichment is associated with a bad prognosis and a worse outcome of immunotherapy in cancer patients. The cytokine interleukin (IL)-6 was found to be a crucial regulator of MDSC accumulation and activation as well as a factor, stimulating tumor cell proliferation, survival, invasiveness and metastasis. Accordingly, IL-6 can serve as a negative prognostic marker in cancer. On the other hand, this cytokine is also involved in T cell activation. This review discusses the pleiotropic effects of IL-6 on immune cell populations that are critical for tumor development, such as MDSC and T cells, and summarizes the data on targeting IL-6 or IL-6 receptor (IL-6R) for tumor immunotherapy to block MDSC-mediated immunosuppression in cancer patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Studies of energy flow in quantum systems complement the information provided by common conductance measurements. The quantum limit of heat flow in one-dimensional ballistic modes was predicted, and experimentally demonstrated, to have a universal value for bosons, fermions, and fractionally charged anyons. A fraction of this value is expected in non-Abelian states; harboring counterpropagating edge modes. In such exotic states, thermal-energy relaxation along the edge is expected, and can shed light on their topological nature. Here, we introduce a novel experimental setup that enables a direct observation of thermal-energy relaxation in chiral 1D edge modes in the quantum Hall effect. Edge modes, emanating from a heated reservoir, are partitioned by a quantum point contact (QPC) constriction, which is located at some distance along their path. The resulting low frequency noise, measured downstream, allows determination of the "effective temperature" of the edge mode at the location of the QPC. An expected, prominent energy relaxation was found in hole-conjugate states. However, relaxation was also observed in particlelike states, where heat is expected to be conserved. We developed a model, consisting of distance-dependent energy loss, which agrees with the observations; however, we cannot exclude energy redistribution mechanisms, which are not accompanied with energy loss.

Melanoma is an aggressive form of skin cancer that is often characterized by activating mutations in the Mitogen-Activated Protein (MAP) kinase pathway, causing hyperproliferation of the cancer cells. Thus, inhibitors targeting this pathway were developed. These inhibitors are initially very effective, but the occurrence of resistance eventually leads to a failure of the therapy and is the major obstacle for clinical success. Therefore, investigating the mechanisms causing resistance and discovering ways to overcome them is essential for the success of therapy. Here, we observed that treatment of melanoma cells with the B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF) inhibitor vemurafenib caused an increased cell surface expression and activation of human epidermal growth factor receptor 3 (HER3) by shed ligands. HER3 promoted the activation of signal transducer and activator of transcription 3 (STAT3) resulting in upregulation of the STAT3 target gene SRY-Box Transcription Factor 2 ( SOX2 ) and survival of the cancer cells. Pharmacological blocking of HER led to a diminished STAT3 activation and increased sensitivity toward vemurafenib. Moreover, HER blocking sensitized vemurafenib-resistant cells to drug treatment. We conclude that the inhibition of the STAT3 upstream regulator HER might help to overcome melanoma therapy resistance toward targeted therapies.

The transcription factor SOX2 is essential for embryonic development and plays a crucial role in maintaining the stemness of embryonic cells and various adult stem cell populations. On the other hand, dysregulation of SOX2 expression is associated with a multitude of cancer types and it has been shown that SOX2 positively affects cancer cell traits such as the capacity to proliferate, migrate, invade and metastasize. Moreover, there is growing evidence that SOX2 mediates resistance towards established cancer therapies and that it is expressed in cancer stem cells. These findings indicate that studying the role of SOX2 in the context of cancer progression could lead to the development of new therapeutic options. In this review, the current knowledge about the role of SOX2 in development, maintenance of stemness, cancer progression and the resistance towards cancer therapies is summarized., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The realization of integrated quantum circuits requires precise on-chip control of charge carriers. Aiming at the coherent coupling of distant nanostructures at zero magnetic field, here we study the ballistic electron transport through two quantum point contacts (QPCs) in series in a three terminal configuration. We enhance the coupling between the QPCs by electrostatic focusing using a field effect lens. To study the emission and collection properties of QPCs in detail we combine the electrostatic focusing with magnetic deflection. Comparing our measurements with quantum mechanical and classical calculations we discuss generic features of the quantum circuit and demonstrate how the coherent and ballistic dynamics depend on the details of the QPC confinement potentials.

Background: Myeloid-derived suppressor cells (MDSC) are a functional myeloid cell subset that includes myeloid cells with immune suppressive properties. The presence of MDSC has been reported in the peripheral blood of patients with several malignant and non-malignant diseases. So far, direct comparison of MDSC across different diseases and Centers is hindered by technical pitfalls and a lack of standardized methodology. To overcome this issue, we formed a network through the COST Action Mye-EUNITER (www.mye-euniter.eu) with the goal to standardize and facilitate the comparative analysis of human circulating MDSC in cancer, inflammation and infection. In this manuscript, we present the results of the multicenter study Mye-EUNITER MDSC Monitoring Initiative, that involved 13 laboratories and compared circulating MDSC subsets across multiple diseases, using a common protocol for the isolation, identification and characterization of these cells., Methods: We developed, tested, executed and optimized a standard operating procedure for the isolation and immunophenotyping of MDSC using blood from healthy donors. We applied this procedure to the blood of almost 400 patients and controls with different solid tumors and non-malignant diseases. The latter included viral infections such as HIV and hepatitis B virus, but also psoriasis and cardiovascular disorders., Results: We observed that the frequency of MDSC in healthy donors varied substantially between centers and was influenced by technical aspects such as the anticoagulant and separation method used. Expansion of polymorphonuclear (PMN)-MDSC exceeded the expansion of monocytic MDSC (M-MDSC) in five out of six solid tumors. PMN-MDSC expansion was more pronounced in cancer compared with infection and inflammation. Programmed death-ligand 1 was primarily expressed in M-MDSC and e-MDSC and was not upregulated as a consequence of disease. LOX-1 expression was confined to PMN-MDSC., Conclusions: This study provides improved technical protocols and workflows for the multi-center analysis of circulating human MDSC subsets. Application of these workflows revealed a predominant expansion of PMN-MDSC in solid tumors that exceeds expansion in chronic infection and inflammation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)