Targeting immunosuppressive classical monocytes prevents immunotherapy resistance

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Targeting immunosuppressive Ly6C+ classical monocytes reverses anti-PD-1/CTLA-4 immunotherapy resistance

IntroductionDespite significant clinical advancement with the use of immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC) there are still a major subset of patients that develop adaptive/acquired resistance. Understanding resistance mechanisms to ICB is critical to developing new therapeutic strategies and improving patient survival. The dynamic nature of the tumor microenvironment and the mutational load driving tumor immunogenicity limit the efficacy to ICB. Recent studies indicate that myeloid cells are drivers of ICB resistance. In this study we sought to understand which immune cells were contributing to resistance and if we could modify them in a way to improve response to ICB therapy.ResultsOur results show that combination anti-PD-1/CTLA-4 produces an initial antitumor effect with evidence of an activated immune response. Upon extended treatment with anti-PD-1/CTLA-4 acquired resistance developed with an increase of the immunosuppressive populations, including T-regulatory cells, neutrophils and monocytes. Addition of anti-Ly6C blocking antibody to anti-PD-1/CTLA-4 was capable of completely reversing treatment resistance and restoring CD8 T cell activity in multiple KP lung cancer models and in the autochthonous lung cancer KrasLSL-G12D/p53fl/fl model. We found that there were higher classical Ly6C+ monocytes in anti-PD-1/CTLA-4 combination resistant tumors. B7 blockade illustrated the importance of dendritic cells for treatment efficacy of anti-Ly6C/PD-1/CTLA-4. We further determined that classical Ly6C+ monocytes in anti-PD-1/CTLA-4 resistant tumors are trafficked into the tumor via IFN-γ and the CCL2-CCR2 axis. Mechanistically we found that classical monocytes from ICB resistant tumors were unable to differentiate into antigen presenting cells and instead differentiated into immunosuppressive M2 macrophages or myeloid-derived suppressor cells (MDSC). Classical Ly6C+ monocytes from ICB resistant tumors had a decrease in both Flt3 and PU.1 expression that prevented differentiation into dendritic cells/macrophages.ConclusionsTherapeutically we found that addition of anti-Ly6C to the combination of anti-PD-1/CTLA-4 was capable of complete tumor eradication. Classical Ly6C+ monocytes differentiate into immunosuppressive cells, while blockade of classical monocytes drives dendritic cell differentiation/maturation to reinvigorate the anti-tumor T cell response. These findings support that immunotherapy resistance is associated with infiltrating monocytes and that controlling the differentiation process of monocytes can enhance the therapeutic potential of ICB

TRIM24 promotes mammary tumor development by upregulating metabolic reducing power

Metabolic reprograming is an emerging hallmark of cancer cells. Changes in cellular metabolism can contribute to cancer cell survival and tumor progression. Tripartite motif-containing protein 24 (TRIM24) is an E3 ligase for p53, a nuclear receptor co-regulator, and a histone reader. Over expression of TRIM24 correlates with poor overall survival of breast cancer patients. Previously, our lab created a mouse model that conditionally over-expresses (COE) TRIM24 protein in mammary epithelia (Trim24COE) and develops carcinosarcoma or metaplastic mammary tumors (70% of all Trim24COE tumors), a rare and aggressive triple-negative subtype called metaplastic TNBC in humans (MpBC). RNA-sequencing revealed that Trim24COE mouse mammary tumors have upregulated glycolysis and epithelial-to-mesenchymal transition (EMT). Trim24COE carcinosarcoma cell-derived spheroids showed irregular, poorly differentiated structures that were more invasive compared to spontaneous, control MMTV-cre mammary tumor-derived spheroids. Using 13C6-glucose/glutamine tracing, we found Trim24COE spheroids recapitulated some of the metabolic features of Trim24COE carcinosarcomas like upregulated glycolysis and exhibited aberrantly upregulated antioxidant defenses. We found Trim24COE spheroids exhibited low intracellular and mitochondrial ROS, an increased NADP(H) pool, and were more resistant to oxidative stress. Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and immunoblotting validated that enzymes of one-carbon metabolism and de novo glutathione synthesis pathways were upregulated in Trim24COE spheroids and that upregulation was depended on TRIM24 over expression. NRF2 is a key regulator of cellular antioxidant response and often found over expressed in many different types of cancers. Nrf2 mRNA level and NRF2 protein expression were both upregulated in the Trim24COE spheroids and knocking down TRIM24 significantly decreased Nrf2 expression as well as NRF2-regulated gene expression. Metabolic inhibitors that target enzymes in one-carbon metabolism and de novo glutathione synthesis effectively decreased Trim24COE spheroids viability. The effect of PHGDH inhibitor CBR5884, GLS inhibitors CB839, and GCLC inhibitor was enhanced with TRIM24 knock-down, indicating that TRIM24 plays a critical role in oxidation-reduction (REDOX)-related cell survival. Here, with metabolomic studies, we uncovered the potential metabolic vulnerabilities in Trim24COE MpBC spheroids. TRIM24 over expression led to upregulated production of reducing equivalents which further reduce oxidative stress and increase antioxidant defense in Trim24COE spheroids. Targeting TRIM24 and the corresponding metabolic enzymes in combination could shed light on potential strategies for inhibiting tumor progression of TRIM24-overexpressing MpBC. The work described here supports further investigations of these pathways in MpBC, for which no targeted therapies exist

Stacking order modulated anomalous valley Hall effect in antiferromagnetic MXene

The valley index is a promising degree of freedom for information processing in electronic devices. However, the researches on valley polarization are mainly focused on ferromagnetic order, which breaks the time reversal symmetry simultaneously. Here, a novel paradigm for achieving stacking order modulated anomalous valley Hall (AVH) effect is proposed in antiferromagnetic monolayers. The paradigm involves the introduction and reversal of nonuniform potentials by modulating the position of substrate, to break the combined symmetry of spatial inversion and time reversal (PT symmetry) and achieve stacking-dependent valley spin splitting. Based on first-principles calculations, we discover spontaneous valley polarization in antiferromagnetic Cr2CH2 MXene and stacking-dependent valley spin splitting in Cr2CH2/Sc2CO2 heterostructure. Furthermore, switching the ferroelectric polarization of monolayer Sc2CO2 results in a semiconductor-metal transition in Cr2CH2/Sc2CO2, accompanied by the disappearance of valley physics. Our findings provide an alternative way to develop controllable valleytronics devices based on antiferromagnetic monolayers

Enabling blockchain applications over named data networking

Blockchain can be used to ensure trust in a decentralized environment in which no trusted authority is available. Its original idea is to collect transactions in a block, and to chain the blocks together in such a way that attackers cannot forge the chain if the majority of the network is honest. Since its creation in 2008, blockchain technology has been used broadly in Internet to support decentralized payments, cloud computing, publishing, etc. This work focuses on public permissionless blockchain which neither guards against bad actors nor enforces access control. Named data networking (NDN) uses name-based routing and in-networking caching to support efficient content delivery, making it a promising future Internet architecture as well as a great network technology which can improve blockchain data delivery. Therefore, it is a very necessary task to enable deployment of blockchain applications over NDN. However, NDN is not immediately compatible with typical blockchain, since (permissionless) blockchain applications usually require broadcasting transactions and blocks in real time, which is not supported by the “pull” design of NDN. In this work, we propose BoNDN which enables blockchain applications over NDN. Unlike previous work, BoNDN follows the core design of NDN. We treat each type of blockchain data needed to be broadcast individually. Specifically, we rely on Interest broadcasting to support real-time broadcasting of blockchain transactions, which is small in size and can be brought by an Interest packet. In addition, we propose a subscription-push approach to support broadcasting of blockchain blocks, in which each miner performs subscription, and once a block is generated, the subscribed miner will receive the block

Global patterns and controls of the soil microbial biomass response to elevated CO2

Elevated CO2 concentrations (eCO2) have been widely observed to stimulate microbial growth. However, the effect of eCO2 on soil microbial biomass may depend on several factors and their interactions, such as the increase in atmospheric CO2 levels, experimental duration and mean annual precipitation (MAP). We conducted a global meta-analysis from 62 studies that included the responses of soil microbial biomass to eCO2. We found a significant positive eCO2 effect on the bacterial biomass (+9.1 %), fungi (+11 %), arbuscular mycorrhizal fungi (AMF) (+10.2 %) and actinomycetes (ACT) (+16.4 %). The positive effects were mainly observed in studies with low eCO2 levels (≤200 ppm) rather than high levels of eCO2 (>200 ppm), which could be attributable to soil N limitation. It was also found that eCO2 had a significant positive effect on soil microbial biomass in the short term (≤3 y) and under a high MAP (>800 mm). Importantly, we revealed interactive effects between the eCO2 levels, experimental duration on soil microbial biomass. With an increase in eCO2, the total microbial biomass (TMB), bacterial biomass and fungal biomass decreased over the long term (>3 y). These findings indicate the need to incorporate interactions between eCO2 and environmental factors into ecosystem models, to predict future global climate change effects more accurately and their impact on ecosystem functions

High-performance bifunctional oxygen electrocatalyst derived from iron and nickel substituted perfluorosulfonic acid/polytetrafluoroethylene copolymer

Heteroatom-doped carbon materials and 3d transition metals have shown high activity and durability for oxygen reduction reaction (ORR) and oxygen evolution reaction (OER), respectively, but poor bifunctionality. Herein, we use iron and nickel substituted perfluorosulfonic acid/polytetrafluoroethylene copolymer with uniform distribution and conveniently adjustable ratios of metal ions as the pyrolysis precursor to synthesize nitrogen and fluorine co-doped carbon supported FeNi hybrid material. The hybrid material integrates ORR and OER active components together, and exhibits excellent bifunctionality in alkaline medium, demonstrating high performance and cycling durability in rechargeable zinc air battery. (C) 2016 Elsevier Ltd. All rights reserved