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SummaryTumor-infiltrating regulatory T cells (TI-Tregs) elicit immunosuppressive effects in the tumor microenvironment (TME) leading to accelerated tumor growth and resistance to immunotherapies against solid tumors. Here,we demonstrate that poly-(ADP-ribose)-polymerase-11 (PARP11) is an essential regulator of immunosuppressive activities of TI-Tregs. Expression of PARP11 correlates with TI-Treg cell numbers and poor responses to immune checkpoint blockade (ICB) in human patients with cancer. Tumor-derived factors including adenosine and prostaglandin E2 induce PARP11 in TI-Tregs. Knockout of PARP11 in the cells of the TME or treatment of tumor-bearing mice with selective PARP11 inhibitor ITK7 inactivates TI-Tregs and reinvigorates anti-tumor immune responses. Accordingly,ITK7 decelerates tumor growth and significantly increases the efficacy of anti-tumor immunotherapies including ICB and adoptive transfer of chimeric antigen receptor (CAR) T cells. These results characterize PARP11 as a key driver of TI-Treg activities and a major regulator of immunosuppressive TME and argue for targeting PARP11 to augment anti-cancer immunotherapies. Graphical abstract Highlights•Tumor-derived factors upregulate PARP11 in the tumor-infiltrating Treg cells•PARP11 supports the immunosuppressive properties of Treg cells•Pharmacologic inhibition of PARP11 inactivates intratumoral Treg cells•PARP11 inhibitor augments the efficacy of immunotherapies Basavaraja et al. demonstrate that induction of PARP11 in the intratumoral regulatory T (Treg) cells is required for their regulatory functions and contributes to the immunosuppressive tumor microenvironment. The selective inhibitor of PARP11 ITK7 inactivates tumor Treg cells and improves the efficacy of immunotherapies against tumors. View Publication

IntroductionInnate lymphoid cells (ILCs) are enriched at mucosal surfaces where they respond rapidly to environmental stimuli and contribute to both tissue inflammation and healing. MethodsTo gain insight into the role of ILCs in the pathology and recovery from COVID-19 infection,we employed a multi-omics approach consisting of Abseq and targeted mRNA sequencing to respectively probe the surface marker expression,transcriptional profile and heterogeneity of ILCs in peripheral blood of patients with COVID-19 compared with healthy controls. ResultsWe found that the frequency of ILC1 and ILC2 cells was significantly increased in COVID-19 patients. Moreover,all ILC subsets displayed a significantly higher frequency of CD69-expressing cells,indicating a heightened state of activation. ILC2s from COVID-19 patients had the highest number of significantly differentially expressed (DE) genes. The most notable genes DE in COVID-19 vs healthy participants included a) genes associated with responses to virus infections and b) genes that support ILC self-proliferation,activation and homeostasis. In addition,differential gene regulatory network analysis revealed ILC-specific regulons and their interactions driving the differential gene expression in each ILC. DiscussionOverall,this study provides mechanistic insights into the characteristics of ILC subsets activated during COVID-19 infection. View Publication

Recently developed small-molecule inhibitors of the lysosomal protease dipeptidyl peptidase 1 (DPP1),also known as cathepsin C (CatC),can suppress suppurative inflammation in vivo by blocking the processing of zymogenic (pro-) forms of neutrophil serine proteases (NSPs),including neutrophil elastase,proteinase 3,and cathepsin G. DPP1 also plays an important role in activating granzyme serine proteases that are expressed by cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. Therefore,it is critical to determine whether DPP1 inhibition can also cause off-target suppression of CTL/NK-cell-mediated killing of virus-infected or malignant cells. Herein,we demonstrate that the processing of human granzymes A and B,transitioning from zymogen to active proteases,is not solely dependent on DPP1. Thus,the killing of target cells by primary human CD8+ T cells,NK cells,and gene-engineered anti-CD19 CAR T cells was not blocked in vitro even after prior exposure to high concentrations of the reversible DPP1 inhibitor brensocatib. Consistent with this observation,the turnover of model granzyme A/B peptide substrates in the human CTL/NK cell lysates was not significantly reduced by brensocatib. In contrast,preincubation with brensocatib almost entirely abolished (>90%) both the cytotoxic activity of mouse CD8+ T cells and granzyme substrate turnover. Overall,our finding that the effects of DPP1 inhibition on human cytotoxic lymphocytes are attenuated in comparison to those of mice indicates that granzyme processing/activation pathways differ between mice and humans. Moreover,the in vitro data suggest that human subjects treated with reversible DPP1 inhibitors,such as brensocatib,are unlikely to experience any appreciable deficits in CTL/NK-cell-mediated immunities. View Publication

Migrasomes are organelles that are generated by migrating cells. Here we report the key role of neutrophil-derived migrasomes in haemostasis. We found that a large number of neutrophil-derived migrasomes exist in the blood of mice and humans. Compared with neutrophil cell bodies and platelets,these migrasomes adsorb and enrich coagulation factors on the surface. Moreover,they are highly enriched with adhesion molecules,which enable them to preferentially accumulate at sites of injury,where they trigger platelet activation and clot formation. Depletion of neutrophils,or genetic reduction of the number of these migrasomes,significantly decreases platelet plug formation and impairs coagulation. These defects can be rescued by intravenous injection of purified neutrophil-derived migrasomes. Our study reveals neutrophil-derived migrasomes as a previously unrecognized essential component of the haemostasis system,which may shed light on the cause of various coagulation disorders and open therapeutic possibilities. Jiang et al. document an abundance of neutrophil-derived migrasomes in the blood of mice and humans and show that migrasomes are enriched in coagulation factors,accumulate at sites of injury and trigger platelet activation and clot formation. View Publication

SummarySepsis survivors are at high risk for infection-related rehospitalization and mortality for years following the resolution of the acute septic event. These infection-causing microorganisms generally do not cause disease in immunocompetent hosts,suggesting that the post-septic immune response is compromised. Given the importance of CD4 T cells in the development of long-lasting protective immunity,we analyzed their post-septic function. Here we showed that sepsis induced chronic increased and non-specific production of IL-17 by CD4 T cells,resulting in the inability to mount an effective immune response to a secondary pneumonia challenge. Altered cell function was associated with metabolic reprogramming,characterized by mitochondrial dysfunction and increased glycolysis. This metabolic reprogramming began during the acute septic event and persisted long after sepsis had resolved. Our findings reveal cell metabolism as a potential therapeutic target. Given the critical role of cell metabolism in the physiological and pathophysiological processes of immune cells,these findings reveal a potential new therapeutic target to help mitigate sepsis survivors’ susceptibility to secondary infections. Graphical abstract Highlights•Sepsis survivors demonstrate dysfunctional CD4 T cell immunity•Sepsis induces persistent mitochondrial dysfunction in CD4 T cells•Post-septic CD4 T cells are highly glycolytic and exhibit a Th17 phenotype•Sepsis impairs the CD4 T cell recall response Physiology; Molecular biology; Immunology; Components of the immune system View Publication

SummaryEnvironmental lipids are essential for fueling tumor energetics,but whether these exogenous lipids transported into cancer cells facilitate immune escape remains unclear. Here,we find that CD36,a transporter for exogenous lipids,promotes acute myeloid leukemia (AML) immune evasion. We show that,separately from its established role in lipid oxidation,CD36 on AML cells senses oxidized low-density lipoprotein (OxLDL) to prime the TLR4-LYN-MYD88-nuclear factor κB (NF-κB) pathway,and exogenous palmitate transfer via CD36 further potentiates this innate immune pathway by supporting ZDHHC6-mediated MYD88 palmitoylation. Subsequently,NF-κB drives the expression of immunosuppressive genes that inhibit anti-tumor T cell responses. Notably,high-fat-diet or hypomethylating agent decitabine treatment boosts the immunosuppressive potential of AML cells by hijacking CD36-dependent innate immune signaling,leading to a dampened therapeutic effect. This work is of translational interest because lipid restriction by US Food and Drug Administration (FDA)-approved lipid-lowering statin drugs improves the efficacy of decitabine therapy by weakening leukemic CD36-mediated immunosuppression. Graphical abstract Highlights•CD36 on AML cells suppresses T cell proliferation independently of lipid oxidation•OxLDL and palmitate synergize to inhibit T cell activity via CD36 signaling in AML cells•Targeting CD36 signaling with statins improves the efficacy of decitabine therapy in AML Guo et al. find that OxLDL and palmitate uptake by AML cells synergistically upregulates CD36-mediated innate immune signaling to suppress T cell activity. High-fat-diet or decitabine treatment dampened the therapeutic effect by hijacking CD36 signaling. Targeting the CD36 immunosuppressive pathway with statins improves the efficacy of decitabine therapy in AML. View Publication

SUMMARY Circular RNAs (circRNAs) are stable RNAs present in cell-free RNA,which may comprise cellular debris and pathogen genomes. Here we investigate the phenomenon and mechanism of cellular uptake and intracellular fate of exogenous circRNAs. Human myeloid cells and B cells selectively internalize extracellular circRNAs. Macrophage uptake of circRNA is rapid,energy-dependent,and saturable. CircRNA uptake can lead to translation of encoded sequences and antigen presentation. The route of internalization influences immune activation after circRNA uptake,with distinct gene expression programs depending on the route of RNA delivery. Genome-scale CRISPR screens and chemical inhibitor studies nominate macrophage scavenger receptor MSR1,toll-like receptors,and mTOR signaling as key regulators of receptor-mediated phagocytosis of circRNAs,a dominant pathway to internalize circRNAs in parallel to macropinocytosis. These results suggest that cell-free circRNA serves as an “eat me” signal and danger-associated molecular pattern,indicating orderly pathways of recognition and disposal. eTOC Blurb: Amaya et. al. explores how cells take up extracellular circular RNAs (CircRNAs) and their impact on immune signaling. Macrophages readily internalize circRNAs,and this study identifies the specific receptors and signaling pathways governing circRNA internalization,highlighting their role as signaling molecules for immune recognition and disposal. Graphical Abstract View Publication

SummaryAerobic exercise training (AET) has emerged as a strategy to reduce cancer mortality,however,the mechanisms explaining AET on tumor development remain unclear. Tumors escape immune detection by generating immunosuppressive microenvironments and impaired T cell function,which is associated with T cell mitochondrial loss. AET improves mitochondrial content and function,thus we tested whether AET would modulate mitochondrial metabolism in tumor-infiltrating lymphocytes (TIL). Balb/c mice were subjected to a treadmill AET protocol prior to CT26 colon carcinoma cells injection and until tumor harvest. Tissue hypoxia,TIL infiltration and effector function,and mitochondrial content,morphology and function were evaluated. AET reduced tumor growth,improved survival,and decreased tumor hypoxia. An increased CD8+ TIL infiltration,IFN-γ and ATP production promoted by AET was correlated with reduced mitochondrial loss in these cells. Collectively,AET decreases tumor growth partially by increasing CD8+ TIL effector function through an improvement in their mitochondrial content and function. Graphical abstract Highlights•Exercise training reduces tumor growth and improves survival in colorectal cancer•Trained mice present tumors with less hypoxia and higher CD8+ T cells infiltration•The production of IFNγ by CD8+ TIL is increased in exercise-trained mice•CD8+ TIL from trained mice show higher mitochondrial density and function Natural sciences; Biological sciences; Biochemistry; Physiology; Immunology; Systems biology; Cancer systems biology View Publication

AbstractDespite the success of antiretroviral therapy,human immunodeficiency virus (HIV) cannot be cured because of a reservoir of latently infected cells that evades therapy. To understand the mechanisms of HIV latency,we employed an integrated single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin with sequencing (scATAC-seq) approach to simultaneously profile the transcriptomic and epigenomic characteristics of ∼ 125,000 latently infected primary CD4+ T cells after reactivation using three different latency reversing agents. Differentially expressed genes and differentially accessible motifs were used to examine transcriptional pathways and transcription factor (TF) activities across the cell population. We identified cellular transcripts and TFs whose expression/activity was correlated with viral reactivation and demonstrated that a machine learning model trained on these data was 75%–79% accurate at predicting viral reactivation. Finally,we validated the role of two candidate HIV-regulating factors,FOXP1 and GATA3,in viral transcription. These data demonstrate the power of integrated multimodal single-cell analysis to uncover novel relationships between host cell factors and HIV latency. View Publication

Comparative genomics has revealed the rapid expansion of multiple gene families involved in immunity. Members within each gene family often evolved distinct roles in immunity. However,less is known about the evolution of their epigenome and cis-regulation. Here we systematically profile the epigenome of the recently expanded murine Ly49 gene family that mainly encode either inhibitory or activating surface receptors on natural killer cells. We identify a set of cis-regulatory elements (CREs) for activating Ly49 genes. In addition,we show that in mice,inhibitory and activating Ly49 genes are regulated by two separate sets of proximal CREs,likely resulting from lineage-specific losses of CRE activity. Furthermore,we find that some Ly49 genes are cross-regulated by the CREs of other Ly49 genes,suggesting that the Ly49 family has begun to evolve a concerted cis-regulatory mechanism. Collectively,we demonstrate the different modes of cis-regulatory evolution for a rapidly expanding gene family. The Ly49 gene family mainly encodes inhibitory or activating surface receptors on natural killer cells. Here the authors show that in mice,inhibitory and activating Ly49 genes are regulated by two distinct sets of cis-regulatory elements,and that different Ly49 genes can be cross-regulated. View Publication