The primary mechanisms supporting immunoregulatory polarization of myeloid cells upon infiltration into tumors remain largely unexplored. Elucidation of these signals could enable better strategies ...to restore protective anti-tumor immunity. Here, we investigated the role of the intrinsic activation of the PKR-like endoplasmic reticulum (ER) kinase (PERK) in the immunoinhibitory actions of tumor-associated myeloid-derived suppressor cells (tumor-MDSCs). PERK signaling increased in tumor-MDSCs, and its deletion transformed MDSCs into myeloid cells that activated CD8+ T cell-mediated immunity against cancer. Tumor-MDSCs lacking PERK exhibited disrupted NRF2-driven antioxidant capacity and impaired mitochondrial respiratory homeostasis. Moreover, reduced NRF2 signaling in PERK-deficient MDSCs elicited cytosolic mitochondrial DNA elevation and, consequently, STING-dependent expression of anti-tumor type I interferon. Reactivation of NRF2 signaling, conditional deletion of STING, or blockade of type I interferon receptor I restored the immunoinhibitory potential of PERK-ablated MDSCs. Our findings demonstrate the pivotal role of PERK in tumor-MDSC functionality and unveil strategies to reprogram immunosuppressive myelopoiesis in tumors to boost cancer immunotherapy.
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•Tumor-infiltrating MDSCs demonstrate increased activation of PERK signaling•PERK ablation in MDSCs elicits anti-tumor T cells and synergizes with immunotherapy•Deletion of PERK reprograms tumor MDSC functionality by blunting NRF2 signaling•Reduced NRF2 primes STING-to-type I IFN axis in PERK-null MDSCs via cytosolic mtDNA
The mechanisms underlying the augmented immunoinhibitory activity of myeloid-derived suppressor cells (MDSCs) upon infiltration into tumors remain elusive. Mohamed and colleagues demonstrate that the unfolded protein response (UPR)-related kinase PERK promotes tumor MDSC functionality through stimulation of the transcriptional factor NRF2, which restricts the immunostimulatory axis of cytosolic mitochondrial DNA-STING-type I IFN.
Myeloid-derived suppressor cells (MDSC) represent a primary mechanism of immune evasion in tumors and have emerged as a major obstacle for cancer immunotherapy. The immunoinhibitory activity of MDSC ...is tightly regulated by the tumor microenvironment and occurs through mechanistic mediators that remain unclear. Here, we elucidated the intrinsic interaction between the expression of AMP-activated protein kinase alpha (AMPKα) and the immunoregulatory activity of MDSC in tumors. AMPKα signaling was increased in tumor-MDSC from tumor-bearing mice and patients with ovarian cancer. Transcription of the Ampkα1-coding gene,
, in tumor-MDSC was induced by cancer cell-derived granulocyte-monocyte colony-stimulating factor (GM-CSF) and occurred in a Stat5-dependent manner. Conditional deletion of
in myeloid cells, or therapeutic inhibition of Ampkα in tumor-bearing mice, delayed tumor growth, inhibited the immunosuppressive potential of MDSC, triggered antitumor CD8
T-cell immunity, and boosted the efficacy of T-cell immunotherapy. Complementarily, therapeutic stimulation of AMPKα signaling intrinsically promoted MDSC immunoregulatory activity. In addition,
deletion antagonized the differentiation of monocytic-MDSC (M-MDSC) to macrophages and re-routed M-MDSC, but not granulocytic-MDSC (PMN-MDSC), into cells that elicited direct antitumor cytotoxic effects through nitric oxide synthase 2-mediated actions. Thus, our results demonstrate the primary role of AMPKα1 in the immunosuppressive effects induced by tumor-MDSC and support the therapeutic use of AMPK inhibitors to overcome MDSC-induced T-cell dysfunction in cancer. SIGNIFICANCE: AMPKα1 regulates the immunosuppressive activity and differentiation of tumor-MDSC, suggesting AMPK inhibition as a potential therapeutic strategy to restore protective myelopoiesis in cancer.
BackgroundT cell immunoglobulin and mucin domain containing−3 (TIM-3) blocking antibodies are currently being evaluated in clinical trials for solid and hematological malignancies. Despite its ...identification on T cells, TIM-3 is predominantly expressed by myeloid cells, including XCR1+ type I conventional dendritic cells (cDC1s). We have recently shown that TIM-3 blockade promotes expression of CXCR3 chemokine ligands by tumor cDCs, but how this drives a CD8+ T cell-dependent response to therapy is unclear.MethodsT cell infiltration, effector function, and spatial localization in relation to XCR1+ cDC1s were evaluated in a murine orthotopic mammary carcinoma model during response to TIM-3 blockade and paclitaxel chemotherapy. Mixed bone marrow chimeras and diphtheria toxin depletion were used to determine the role of specific genes in cDC1s during therapeutic responses.ResultsTIM-3 blockade increased interferon-γ expression by CD8+ T cells without altering immune infiltration. cDC1 expression of CXCL9, but not CXCL10, was required for response to TIM-3 blockade. CXCL9 was also necessary for the increased proximity observed between CD8+ T cells and XCR1+ cDC1s during therapy. Tumor responses were dependent on cDC1 expression of interleukin-12, but not MHCI.ConclusionsTIM-3 blockade increases exposure of intratumoral CD8+ T cells to cDC1-derived cytokines, with implications for the design of therapeutic strategies using antibodies against TIM-3.
Nowadays, space missions face a relentless increase in requirements for on-board computers. Higher computing capacities are needed, while the power consumption, mass and area must be reduced. ...Unfortunately, requirements evolve faster than the ability of manufacturers to develop better space-qualified processors, so techniques that allow designers to use COTS (commercial, off-the-shelf) components are needed. As such, collaborative hardening is a powerful an efficient technique to guarantee the reliability of the safety critical tasks of a satellite. However, the stringent dependability requirements of space missions call for comprehensive on-ground validation of any design using COTS components before it can be used in orbit. In this work, we present the collaborative hardening techniques developed for the OPTOS satellite, and how it was on-ground validated against the effects of radiation. We introduce a methodology for early SEU sensitivity assessment based on fault injection through an autonomous emulation system. Fault injection is performed at system level, not unit level, to validate the safety critical techniques implemented by the collaborative architecture. The experimental results show that, while single units are vulnerable to the effects of radiation, the reliability of the system as a whole is not compromised.
•Collaborative hardware techniques significantly increase distributed systems reliability.•Early and dependable SEU sensitivity assessment at system level through emulation•These two technologies combined facilitate the use of COTS for dependable applications.
Cutaneous T-cell lymphoma (CTCL) is a rare cancer of skin-homing T cells. A subgroup of patients develops large cell transformation with rapid progression to an aggressive lymphoma. Here, we ...investigated the transformed CTCL (tCTCL) tumor ecosystem using integrative multiomics spanning whole-exome sequencing (WES), single-cell RNA sequencing, and immune profiling in a unique cohort of 56 patients. WES of 70 skin biopsies showed high tumor mutation burden, UV signatures that are prognostic for survival, exome-based driver events, and most recurrently mutated pathways in tCTCL. Single-cell profiling of 16 tCTCL skin biopsies identified a core oncogenic program with metabolic reprogramming toward oxidative phosphorylation (OXPHOS), cellular plasticity, upregulation of MYC and E2F activities, and downregulation of MHC I suggestive of immune escape. Pharmacologic perturbation using OXPHOS and MYC inhibitors demonstrated potent antitumor activities, whereas immune profiling provided in situ evidence of intercellular communications between malignant T cells expressing macrophage migration inhibitory factor and macrophages and B cells expressing CD74.
Our study contributes a key resource to the community with the largest collection of tCTCL biopsies that are difficult to obtain. The multiomics data herein provide the first comprehensive compendium of genomic alterations in tCTCL and identify potential prognostic signatures and novel therapeutic targets for an incurable T-cell lymphoma. This article is highlighted in the In This Issue feature, p. 1171.
The current evolution of the space missions demands to increase the computing capacities of the on-board computer while reducing its power consumption. This requirement evolves faster than the ...ability of the manufacturers to develop better space-qualified processors. To meet the strong requirements, the National Institute of Aerospace Technology has developed a distributed on-board computer based on commercial off-the-shelf (COTS). This computer, named OPTOS, provides enhanced computational capacities with respect to what computers of other small satellites typically provide. To maintain the reliability needed to perform typical critical activities such as real-time maintenance or current surveillance, authors have conceived a set of collaborative hardening techniques, taking advantage of the distributed architecture of the OPTOS On-Board Computer. The 3-year mission data analysis shows the feasibility of the collaborative hardening techniques implemented, despite using SEU sensitive devices. The authors describe the processes and tools used to analyse the data and clearly expose the functional errors found at unit level, while the system remains unfaulty and reliable thanks to the collaborative techniques.
The Radiation and Dust Sensor is one of six sensors of the Mars Environmental Dynamics Analyzer onboard the Perseverance rover from the Mars 2020 NASA mission. Its primary goal is to characterize the ...airbone dust in the Mars atmosphere, inferring its concentration, shape and optical properties. Thanks to its geometry, the sensor will be capable of studying dust-lifting processes with a high temporal resolution and high spatial coverage. Thanks to its multiwavelength design, it will characterize the solar spectrum from Mars' surface. The present work describes the sensor design from the scientific and technical requirements, the qualification processes to demonstrate its endurance on Mars' surface, the calibration activities to demonstrate its performance, and its validation campaign in a representative Mars analog. As a result of this process, we obtained a very compact sensor, fully digital, with a mass below 1 kg and exceptional power consumption and data budget features.
Objectives. Low blood pressure (BP) has been proposed as a risk factor of death in elderly patients. However, this association could be partially accounted for by the deleterious effects of ...BP-lowering drugs. We analyzed whether these drugs are associated to an increased risk of death in elderly patients taking multiple potential confounders into account. Design. This is a prospective cohort study. Setting and Participants. Probabilistic sample of 772 community-dwelling patients aged >65 years living in Spain, who were appointed for an initial clinical visit and followed up through telephone calls 4, 6, 9, 12, and 60 months afterwards. Methods. At baseline visit, BP was measured using standardized methods, and BP medications and risk factors of death in elderly patients (BMI, oxygen saturation, toxic habits, comorbidity, muscular strength, and functional and cognitive capacity) were collected. During the follow-up, the vital status of patients and the date of death were ascertained. Results. During a median 5-year follow-up, 226 all-cause deaths occurred among the 686 participants included in the analysis. In a Cox regression model that included all the BP drug classes, diuretics and nitrites were significantly associated with mortality (p<0.005). Within diuretics, furosemide was found to be responsible for the association of the group. In multivariable Cox regression models adjusted for BP and the rest of the mortality risk factors, furosemide remained as the only BP drug that was independently associated with mortality (hazard ratio 2.34; p<0.01). Conclusions. Furosemide was prospectively associated with increased mortality in older people. If confirmed, this drug should be taken into account by prescribers and considered a confounder in BP studies.
In this paper, class-E power amplifiers (PAs) and rectifiers, operating at UHF band, are properly integrated in efficient AC-to-RF and RF-to-AC converters for their use in 50/60 Hz wireless power ...transmission (WPT). Slightly modifying a center-tap full-wave rectifier, it is proved that a 915 MHz frequency carrier may be high-level amplitude modulated by each of the semi-cycles of the utility waveform. Assuming those components are transmitted by means of orthogonal antenna polarizations, the high-fidelity recovery of both semi-sinusoids in the remote position is also demonstrated, to be stepped-up and combined at the Δ port of an additional center-tap transformer. GaN HEMT packaged devices were selected for the designed PAs, while Schottky diodes for the rectifiers, resulting in average efficiency figures of 83.3% and 75.4%, respectively.
The National Institute of Aerospace Technology (INTA) has specialized in the development of miniaturized instrumentation for Mars exploration during the last decade. The validation and comparison ...with reference instrumentation of these devices under representative scenarios is crucial, and it requires specific infrastructure to be able to manage field campaigns all around the world. The present work describes the I-BOX, a portable and embedded system that allows to develop short and long-term campaigns under extreme environmental conditions and with low maintenance.
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