Increasing evidence suggests that asthma is a heterogeneous disorder regulated by distinct molecular mechanisms. In a cross-sectional study of asthmatics of varying severity (n = 51), endobronchial ...tissue gene expression analysis revealed three major patient clusters: TH2-high, TH17-high, and TH2/17-low. TH2-high and TH17-high patterns were mutually exclusive in individual patient samples, and their gene signatures were inversely correlated and differentially regulated by interleukin-13 (IL-13) and IL-17A. To understand this dichotomous pattern of T helper 2 (TH2) and TH17 signatures, we investigated the potential of type 2 cytokine suppression in promoting TH17 responses in a preclinical model of allergen-induced asthma. Neutralization of IL-4 and/or IL-13 resulted in increased TH17 cells and neutrophilic inflammation in the lung. However, neutralization of IL-13 and IL-17 protected mice from eosinophilia, mucus hyperplasia, and airway hyperreactivity and abolished the neutrophilic inflammation, suggesting that combination therapies targeting both pathways may maximize therapeutic efficacy across a patient population comprising both TH2 and TH17 endotypes.
Due to the rapid emergence of antibiotic-resistant bacteria, there is a growing need to discover new antibiotics. To address this challenge, we trained a deep neural network capable of predicting ...molecules with antibacterial activity. We performed predictions on multiple chemical libraries and discovered a molecule from the Drug Repurposing Hub—halicin—that is structurally divergent from conventional antibiotics and displays bactericidal activity against a wide phylogenetic spectrum of pathogens including Mycobacterium tuberculosis and carbapenem-resistant Enterobacteriaceae. Halicin also effectively treated Clostridioides difficile and pan-resistant Acinetobacter baumannii infections in murine models. Additionally, from a discrete set of 23 empirically tested predictions from >107 million molecules curated from the ZINC15 database, our model identified eight antibacterial compounds that are structurally distant from known antibiotics. This work highlights the utility of deep learning approaches to expand our antibiotic arsenal through the discovery of structurally distinct antibacterial molecules.
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•A deep learning model is trained to predict antibiotics based on structure•Halicin is predicted as an antibacterial molecule from the Drug Repurposing Hub•Halicin shows broad-spectrum antibiotic activities in mice•More antibiotics with distinct structures are predicted from the ZINC15 database
A trained deep neural network predicts antibiotic activity in molecules that are structurally different from known antibiotics, among which Halicin exhibits efficacy against broad-spectrum bacterial infections in mice.
The concept of nanoparticle transport through gaps between endothelial cells (inter-endothelial gaps) in the tumour blood vessel is a central paradigm in cancer nanomedicine. The size of these gaps ...was found to be up to 2,000 nm. This justified the development of nanoparticles to treat solid tumours as their size is small enough to extravasate and access the tumour microenvironment. Here we show that these inter-endothelial gaps are not responsible for the transport of nanoparticles into solid tumours. Instead, we found that up to 97% of nanoparticles enter tumours using an active process through endothelial cells. This result is derived from analysis of four different mouse models, three different types of human tumours, mathematical simulation and modelling, and two different types of imaging techniques. These results challenge our current rationale for developing cancer nanomedicine and suggest that understanding these active pathways will unlock strategies to enhance tumour accumulation.
Conventionally, ceramics-based materials, fabricated by high-temperature solid-phase reaction and sintering, are preferred as bone scaffolds in hard-tissue engineering because of their tunable ...biocompatibility and mechanical properties. However, their possible biomedical applications have rarely been considered, especially the cancer phototherapeutic applications in both the first and second near-infrared light (NIR-I and NIR-II) biowindows. In this work, we explore, for the first time as far as we know, a novel kind of 2D niobium carbide (Nb2C), MXene, with highly efficient in vivo photothermal ablation of mouse tumor xenografts in both NIR-I and NIR-II windows. The 2D Nb2C nanosheets (NSs) were fabricated by a facile and scalable two-step liquid exfoliation method combining stepwise delamination and intercalation procedures. The ultrathin, lateral-nanosized Nb2C NSs exhibited extraordinarily high photothermal conversion efficiency (36.4% at NIR-I and 45.65% at NIR-II), as well as high photothermal stability. The Nb2C NSs intrinsically feature unique enzyme-responsive biodegradability to human myeloperoxidase, low phototoxicity, and high biocompatibility. Especially, these surface-engineered Nb2C NSs present highly efficient in vivo photothermal ablation and eradication of tumor in both NIR-I and NIR-II biowindows. This work significantly broadens the application prospects of 2D MXenes by rationally designing their compositions and exploring related physiochemical properties, especially on phototherapy of cancer.
Liver metastasis, the leading cause of colorectal cancer mortality, exhibits a highly heterogeneous and suppressive immune microenvironment. Here, we sequenced 97 matched samples by using single-cell ...RNA sequencing and spatial transcriptomics. Strikingly, the metastatic microenvironment underwent remarkable spatial reprogramming of immunosuppressive cells such as
M2-like macrophages. We further developed scMetabolism, a computational pipeline for quantifying single-cell metabolism, and observed that those macrophages harbored enhanced metabolic activity. Interestingly, neoadjuvant chemotherapy could block this status and restore the antitumor immune balance in responsive patients, whereas the nonresponsive patients deteriorated into a more suppressive one. Our work described the immune evolution of metastasis and uncovered the black box of how tumors respond to neoadjuvant chemotherapy. SIGNIFICANCE: We present a single-cell and spatial atlas of colorectal liver metastasis and found the highly metabolically activated
M2-like macrophages in metastatic sites. Efficient neoadjuvant chemotherapy can slow down such metabolic activation, raising the possibility to target metabolism pathways in metastasis.
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In vitro cancer cultures, including three-dimensional organoids, typically contain exclusively neoplastic epithelium but require artificial reconstitution to recapitulate the tumor microenvironment ...(TME). The co-culture of primary tumor epithelia with endogenous, syngeneic tumor-infiltrating lymphocytes (TILs) as a cohesive unit has been particularly elusive. Here, an air-liquid interface (ALI) method propagated patient-derived organoids (PDOs) from >100 human biopsies or mouse tumors in syngeneic immunocompetent hosts as tumor epithelia with native embedded immune cells (T, B, NK, macrophages). Robust droplet-based, single-cell simultaneous determination of gene expression and immune repertoire indicated that PDO TILs accurately preserved the original tumor T cell receptor (TCR) spectrum. Crucially, human and murine PDOs successfully modeled immune checkpoint blockade (ICB) with anti-PD-1- and/or anti-PD-L1 expanding and activating tumor antigen-specific TILs and eliciting tumor cytotoxicity. Organoid-based propagation of primary tumor epithelium en bloc with endogenous immune stroma should enable immuno-oncology investigations within the TME and facilitate personalized immunotherapy testing.
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•Air-liquid interface (ALI) patient-derived tumor organoids (PDO) retain immune cells•5′ V(D)J and RNA-seq from the same single cells allows robust immune characterization•T cell receptor repertoire is highly conserved between tumor and PDO•ALI PDOs functionally recapitulate the PD-1/PD-L1-dependent immune checkpoint
The tumor-immune microenvironment is modeled using a patient-derived organoid approach that preserves the original tumor T cell receptor spectrum and successfully models immune checkpoint blockade.
Cytosolic DNA is characteristic of chromosomally unstable metastatic cancer cells, resulting in constitutive activation of the cGAS-STING innate immune pathway. How tumors co-opt inflammatory ...signaling while evading immune surveillance remains unknown. Here, we show that the ectonucleotidase ENPP1 promotes metastasis by selectively degrading extracellular cGAMP, an immune-stimulatory metabolite whose breakdown products include the immune suppressor adenosine. ENPP1 loss suppresses metastasis, restores tumor immune infiltration, and potentiates response to immune checkpoint blockade in a manner dependent on tumor cGAS and host STING. Conversely, overexpression of wild-type ENPP1, but not an enzymatically weakened mutant, promotes migration and metastasis, in part through the generation of extracellular adenosine, and renders otherwise sensitive tumors completely resistant to immunotherapy. In human cancers, ENPP1 expression correlates with reduced immune cell infiltration, increased metastasis, and resistance to anti-PD-1/PD-L1 treatment. Thus, cGAMP hydrolysis by ENPP1 enables chromosomally unstable tumors to transmute cGAS activation into an immune-suppressive pathway. SIGNIFICANCE: Chromosomal instability promotes metastasis by generating chronic tumor inflammation. ENPP1 facilitates metastasis and enables tumor cells to tolerate inflammation by hydrolyzing the immunotransmitter cGAMP, preventing its transfer from cancer cells to immune cells.
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Limiting metabolic competition in the tumour microenvironment may increase the effectiveness of immunotherapy. Owing to its crucial role in the glucose metabolism of activated T cells, CD28 ...signalling has been proposed as a metabolic biosensor of T cells
. By contrast, the engagement of CTLA-4 has been shown to downregulate T cell glycolysis
. Here we investigate the effect of CTLA-4 blockade on the metabolic fitness of intra-tumour T cells in relation to the glycolytic capacity of tumour cells. We found that CTLA-4 blockade promotes metabolic fitness and the infiltration of immune cells, especially in glycolysis-low tumours. Accordingly, treatment with anti-CTLA-4 antibodies improved the therapeutic outcomes of mice bearing glycolysis-defective tumours. Notably, tumour-specific CD8
T cell responses correlated with phenotypic and functional destabilization of tumour-infiltrating regulatory T (T
) cells towards IFNγ- and TNF-producing cells in glycolysis-defective tumours. By mimicking the highly and poorly glycolytic tumour microenvironments in vitro, we show that the effect of CTLA-4 blockade on the destabilization of T
cells is dependent on T
cell glycolysis and CD28 signalling. These findings indicate that decreasing tumour competition for glucose may facilitate the therapeutic activity of CTLA-4 blockade, thus supporting its combination with inhibitors of tumour glycolysis. Moreover, these results reveal a mechanism by which anti-CTLA-4 treatment interferes with T
cell function in the presence of glucose.
Tumor hypoxia has proven to be the major bottleneck of photodynamic therapy (PDT) to clinical transformation. Different from traditional O
delivery approaches, here we describe an innovative binary ...photodynamic O
-economizer (PDOE) tactic to reverse hypoxia-driven resistance by designing a superoxide radical (O
) generator targeting mitochondria respiration, termed SORgenTAM. This PDOE system is able to block intracellular O
consumption and down-regulate HIF-1α expression, which successfully rescues cancer cells from becoming hypoxic and relieves the intrinsic hypoxia burden of tumors in vivo, thereby sparing sufficient endogenous O
for the PDT process. Photosensitization mechanism studies demonstrate that SORgenTAM has an ideal intersystem crossing rate and triplet excited state lifetime for generating O
through type-I photochemistry, and the generated O
can further trigger a biocascade to reduce the PDT's demand for O
in an O
-recycble manner. Furthermore, SORgenTAM also serves to activate the AMPK metabolism signaling pathway to inhibit cell repair and promote cell death. Consequently, using this two-step O
-economical strategy, under relatively low light dose irradiation, excellent therapeutic responses toward hypoxic tumors are achieved. This study offers a conceptual while practical paradigm for overcoming the pitfalls of phototherapeutics.
Conspectus Nanomedicine holds significant potential to improve the efficacy of cancer immunotherapy. Thus far, nanomedicines, i.e., 1–100(0) nm sized drug delivery systems, have been primarily used ...to improve the balance between the efficacy and toxicity of conjugated or entrapped chemotherapeutic drugs. The clinical performance of cancer nanomedicines has been somewhat disappointing, which is arguably mostly due to the lack of tools and technologies for patient stratification. Conversely, the clinical progress made with immunotherapy has been spectacular, achieving complete cures and inducing long-term survival in advanced-stage patients. Unfortunately, however, immunotherapy only works well in relatively small subsets of patients. Increasing amounts of preclinical and clinical data demonstrate that combining nanomedicine with immunotherapy can boost therapeutic outcomes, by turning “cold” nonimmunoresponsive tumors and metastases into “hot” immunoresponsive lesions. Nano-immunotherapy can be realized via three different approaches, in which nanomedicines are used (1) to target cancer cells, (2) to target the tumor immune microenvironment, and (3) to target the peripheral immune system. When targeting cancer cells, nanomedicines typically aim to induce immunogenic cell death, thereby triggering the release of tumor antigens and danger-associated molecular patterns, such as calreticulin translocation, high mobility group box 1 protein and adenosine triphosphate. The latter serve as adjuvants to alert antigen-presenting cells to take up, process and present the former, thereby promoting the generation of CD8+ cytotoxic T cells. Nanomedicines targeting the tumor immune microenvironment potentiate cancer immunotherapy by inhibiting immunosuppressive cells, such as M2-like tumor-associated macrophages, as well as by reducing the expression of immunosuppressive molecules, such as transforming growth factor beta. In addition, nanomedicines can be employed to promote the activity of antigen-presenting cells and cytotoxic T cells in the tumor immune microenvironment. Nanomedicines targeting the peripheral immune system aim to enhance antigen presentation and cytotoxic T cell production in secondary lymphoid organs, such as lymph nodes and spleen, as well as to engineer and strengthen peripheral effector immune cell populations, thereby promoting anticancer immunity. While the majority of immunomodulatory nanomedicines are in preclinical development, exciting results have already been reported in initial clinical trials. To ensure efficient translation of nano-immunotherapy constructs and concepts, we have to consider biomarkers in their clinical development, to make sure that the right nanomedicine formulation is combined with the right immunotherapy in the right patient. In this context, we have to learn from currently ongoing efforts in nano-biomarker identification as well as from partially already established immuno-biomarker initiatives, such as the Immunoscore and the cancer immunogram. Together, these protocols will help to capture the nano-immuno status in individual patients, enabling the identification and use of individualized and improved nanomedicine-based treatments to boost the performance of cancer immunotherapy.
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