参考文献

Activating interferon responses with STING agonists (STINGa) is a current cancer immunotherapy strategy,and therapeutic modalities that enable tumor-targeted delivery via systemic administration could be beneficial. Here we demonstrate that tumor cell-directed STING agonist antibody-drug-conjugates (STINGa ADCs) activate STING in tumor cells and myeloid cells and induce anti-tumor innate immune responses in in vitro,in vivo (in female mice),and ex vivo tumor models. We show that the tumor cell-directed STINGa ADCs are internalized into myeloid cells by Fcγ-receptor-I in a tumor antigen-dependent manner. Systemic administration of STINGa ADCs in mice leads to STING activation in tumors,with increased anti-tumor activity and reduced serum cytokine elevations compared to a free STING agonist. Furthermore,STINGa ADCs induce type III interferons,which contribute to the anti-tumor activity by upregulating type I interferon and other key chemokines/cytokines. These findings reveal an important role for type III interferons in the anti-tumor activity elicited by STING agonism and provide rationale for the clinical development of tumor cell-directed STINGa ADCs. Activation of the STING pathway can promote anti-tumor immunity. Here the authors generate tumor cell-directed STING agonist antibody-drug conjugates that activate STING in tumor and myeloid cells,promoting anti-tumor innate immune responses in preclinical cancer models. View Publication

The progressive decline of CD8 T cell effector function—also known as terminal exhaustion—is a major contributor to immune evasion in cancer. Yet,the molecular mechanisms that drive CD8 T cell dysfunction remain poorly understood. Here,we report that the Kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor erythroid 2-related factor 2 (NRF2) signaling axis,which mediates cellular adaptations to oxidative stress,directly regulates CD8 T cell exhaustion. Transcriptional profiling of dysfunctional CD8 T cells from chronic infection and cancer reveals enrichment of NRF2 activity in terminally exhausted (Texterm) CD8 T cells. Increasing NRF2 activity in CD8 T cells (via conditional deletion of KEAP1) promotes increased glutathione production and antioxidant defense yet accelerates the development of terminally exhausted (PD-1+TIM-3+) CD8 T cells in response to chronic infection or tumor challenge. Mechanistically,we identify PTGIR,a receptor for the circulating eicosanoid prostacyclin,as an NRF2-regulated protein that promotes CD8 T cell dysfunction. Silencing PTGIR expression restores the anti-tumor function of KEAP1-deficient T cells. Moreover,lowering PTGIR expression in CD8 T cells both reduces terminal exhaustion and enhances T cell effector responses (i.e. IFN-γ and granzyme production) to chronic infection and cancer. Together,these results establish the KEAP1-NRF2 axis as a metabolic sensor linking oxidative stress to CD8 T cell dysfunction and identify the prostacyclin receptor PTGIR as an NRF2-regulated immune checkpoint that regulates CD8 T cell fate decisions between effector and exhausted states. One Sentence Summary:The KEAP1-NRF2 pathway is hyperactivated in terminally exhausted CD8 T cells and drives T cell dysfunction via transcriptional regulation of the prostacyclin receptor,Ptgir. 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

BackgroundInterleukin-17 (IL-17) family cytokines promote protective inflammation for pathogen resistance,but also facilitate autoimmunity and tumor development. A direct signal of IL-17 to regulatory T cells (Tregs) has not been reported and may help explain these dichotomous responses.MethodsWe generated a conditional knockout of Il17ra in Tregs by crossing Foxp3-YFP-Cre mice to Il17ra-flox mice (Il17ra ΔTreg mice). Subsequently,we adoptively transferred bone marrow cells from Il17ra ΔTreg mice to a mouse model of sporadic colorectal cancer (Cdx2-Cre +/Apc F/+),to selectively ablate IL-17 direct signaling on Tregs in colorectal cancer. Single cell RNA sequencing and bulk RNA sequencing were performed on purified Tregs from mouse colorectal tumors,and compared to those of human tumor infiltrating Treg cells.ResultsIL-17 Receptor A (IL-17RA) is expressed in Tregs that reside in mouse mesenteric lymph nodes and colon tumors. Ablation of IL-17RA,specifically in Tregs,resulted in increased Th17 cells,and exacerbated tumor development. Mechanistically,tumor-infiltrating Tregs exhibit a unique gene signature that is linked to their activation,maturation,and suppression function,and this signature is in part supported by the direct signaling of IL-17 to Tregs. To study pathways of Treg programming,we found that loss of IL-17RA in tumor Tregs resulted in reduced RNA splicing,and downregulation of several RNA binding proteins that are known to regulate alternative splicing and promote Treg function.ConclusionIL-17 directly signals to Tregs and promotes their maturation and function. This signaling pathway constitutes a negative feedback loop that controls cancer-promoting inflammation in CRC. 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

Acute and chronic coronary syndromes (ACS and CCS) are leading causes of mortality. Inflammation is considered a key pathogenic driver of these diseases,but the underlying immune states and their clinical implications remain poorly understood. Multiomic factor analysis (MOFA) allows unsupervised data exploration across multiple data types,identifying major axes of variation and associating these with underlying molecular processes. We hypothesized that applying MOFA to multiomic data obtained from blood might uncover hidden sources of variance and provide pathophysiological insights linked to clinical needs. Here we compile a longitudinal multiomic dataset of the systemic immune landscape in both ACS and CCS (n = 62 patients in total,n = 15 women and n = 47 men) and validate this in an external cohort (n = 55 patients in total,n = 11 women and n = 44 men). MOFA reveals multicellular immune signatures characterized by distinct monocyte,natural killer and T cell substates and immune-communication pathways that explain a large proportion of inter-patient variance. We also identify specific factors that reflect disease state or associate with treatment outcome in ACS as measured using left ventricular ejection fraction. Hence,this study provides proof-of-concept evidence for the ability of MOFA to uncover multicellular immune programs in cardiovascular disease,opening new directions for mechanistic,biomarker and therapeutic studies. Multiomic factor analysis of blood multiomic data,including single-cell transcriptomics,for individuals with either acute or chronic coronary syndrome identifies immune cell signatures that correlate with treatment outcomes. View Publication

Haematopoietic stem cell (HSC) transplantation (HSCT) is the only curative treatment for a broad range of haematological malignancies,but the standard of care relies on untargeted chemotherapies and limited possibilities to treat malignant cells after HSCT without affecting the transplanted healthy cells1. Antigen-specific cell-depleting therapies hold the promise of much more targeted elimination of diseased cells,as witnessed in the past decade by the revolution of clinical practice for B cell malignancies2. However,target selection is complex and limited to antigens expressed on subsets of haematopoietic cells,resulting in a fragmented therapy landscape with high development costs2–5. Here we demonstrate that an antibody–drug conjugate (ADC) targeting the pan-haematopoietic marker CD45 enables the antigen-specific depletion of the entire haematopoietic system,including HSCs. Pairing this ADC with the transplantation of human HSCs engineered to be shielded from the CD45-targeting ADC enables the selective eradication of leukaemic cells with preserved haematopoiesis. The combination of CD45-targeting ADCs and engineered HSCs creates an almost universal strategy to replace a diseased haematopoietic system,irrespective of disease aetiology or originating cell type. We propose that this approach could have broad implications beyond haematological malignancies. An antibody–drug conjugate that targets the pan-haematopoietic marker CD45 combined with transplanted stem cells engineered to be shielded from it can eradicate leukaemic cells while preserving haematopoiesis. View Publication

T lymphocyte activation plays a pivotal role in adaptive immune response and alters the spatial organization of nuclear architecture that subsequently impacts transcription activities. Here,using stochastic optical reconstruction microscopy (STORM),we observe dramatic de-condensation of chromatin and the disruption of nuclear envelope at a nanoscale resolution upon T lymphocyte activation. Super-resolution imaging reveals that such alterations in nuclear architecture are accompanied by the release of nuclear DNA into the cytoplasm,correlating with the degree of chromatin decompaction within the nucleus. The authors show that under the influence of metabolism,T lymphocyte activation de-condenses chromatin,disrupts the nuclear envelope,and releases DNA into the cytoplasm. Taken together,this result provides a direct,molecular-scale insight into the alteration in nuclear architecture. It suggests the release of nuclear DNA into the cytoplasm as a general consequence of chromatin decompaction after lymphocyte activation. The authors show that under the influence of metabolism,T lymphocyte activation de-condenses chromatin,disrupts the nuclear envelope,and releases DNA into the cytoplasm. View Publication