Gene expression profile at single cell level of tumor-infiltrating immune cells from mice treated with anti-PD-L1+E.colipBAD28 vs anti-PD-L1+E.colipApyr [CD45positive_TILs_scRNAseq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE250012 | GEO | 2023/12/29
REPOSITORIES: GEO
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Project description:The gut microbiota is essential for many aspects of host physiology, and locally generated secretory IgA (SIgA) modulates its function. Microbiota community determines the efficacy of immune checkpoint blockade (ICB) in cancer immunotherapy. Extracellular ATP (eATP) released by the microbiota restricts the SIgA repertoire by limiting T follicular helper (Tfh) cells activity in the Peyer’s Patches (PPs) via stimulation of ionotropic P2X7 receptor. Here we show that SIgA amplification by oral administration of the ATP hydrolysing enzyme apyrase corrects enteropathic features of ICB and improves the therapeutic outcome.
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Project description:Morphogenesis of epithelial tissues relies on the precise developmental control of cell polarity and architecture. In the early Drosophila embryo, the primarSecretory IgA (SIgA) interaction with commensal bacteria regulates the composition and function of the microbiota, contributing to gut ecosystem homeostasis. However, mechanisms regulating the reciprocal control of microbiota and SIgA are not defined. Bacteria-derived ATP limits T follicular helper (Tfh) cells activity in the Peyer’s patches (Pps) of the small intestine via the P2X7 receptor and thereby SIgA generation. Here we show that inhibition of bacteria derived ATP signaling by delivery of the ATP-degrading enzyme apyrase to the intestine results in the amplification of the SIgA repertoire. The enhanced breadth of SIgA in mice colonized with apyrase-releasing E. Coli conditioned topographical distribution of bacteria and expression of genes involved in metabolic versus immune functions in the intestinal epithelium. SIgA mediated conditioning of bacteria and enterocyte function was also reflected by selective differences in nutrients absorption in mice colonized with apyrase expressing bacteria. Hydrolysis of bacteria derived ATP was particularly helpful in restoring intestinal homeostasis via SIgA in antibiotics induced dysbiosis. Administration of apyrase expressing bacteria attenuated intestinal barrier impairment, glucose metabolism perturbation and susceptibility to infection by enteric pathogens induced by antibiotic treatments. Therefore, microbiota derived ATP regulates SIgA, and amplification of SIgA response by apyrase can be leveraged to restore intestinal fitness in dysbiotic conditions.y epithelium forms during cellularisation, following a tightly controlled genetic programme where specific sets of genes are up-regulated. Some of them, for instance, control membrane invagination between the nuclei anchored at the apical surface of the syncytium.
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Project description:EMT is an early process in metastasis that is associated with up to 90% of cancer-related death. ATP has been known to play some roles in EMT. We previously described that internalization of extracellular ATP (eATP) by cancer cells in vitro and in vivo via macropinocytosis increases intracellular ATP levels, cell proliferation and resistance to anticancer drugs. Recently, we reported eATP also induces EMT and other early metastatic activities independent of TGF-b, a well-known inducer of EMT, in human lung cancer cells. However, exactly how eATP induces EMT at gene expression level is far from understood. In this study, we hypothesize that eATP acts as an inducer and regulator of EMT alternative to TGF-b. Transwell assays revealed that eATP treatment, alone, induced human lung cancer A549 and H1299 cells to invade at rates faster than TGF-b. eATP also induced formation of filopodia-like protrusions faster than TGF-b, and it restored viability of cancer cells treated with TGF-b-neutralizing antibodies. eATP significantly elevated intracellular ATP levels while TGF-b did not. RNA sequencing / western blots revealed that eATP induced changes in expression of genes/proteins involved in EMT similar to but with differences in number and induction time compared with those induced by TGF-b. Metabolomics analysis shows that eATP-induced major metabolic changes are consistent/correlated with those identified at the gene expression level. These differences could be accounted for by the multi-functional and multi-localization properties of eATP and macropinocytosis-internalized eATP, strongly suggesting that eATP is a previously unrecognized master inducer and regulator of EMT.
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Project description:In 2016 and 2017, monoclonal antibodies targeting PD-L1, including atezolizumab, durvalumab, and avelumab, were approved by the FDA for the treatment of multiple advanced cancers. And many other anti-PD-L1 antibodies are under clinical trials. Recently, the crystal structures of PD-L1 in complex with BMS-936559 and avelumab have been determined, revealing details of the antigen-antibody interactions. However, it is still unknown how atezolizumab and durvalumab specifically recognize PD-L1, although this is important for investigating novel binding sites on PD-L1 targeted by other therapeutic antibodies for the design and improvement of anti-PD-L1 agents. Here, we report the crystal structures of PD-L1 in complex with atezolizumab and durvalumab to elucidate the precise epitopes involved and the structural basis for PD-1/PD-L1 blockade by these antibodies. A comprehensive comparison of PD-L1 interactions with anti-PD-L1 antibodies provides a better understanding of the mechanism of PD-L1 blockade as well as new insights into the rational design of improved anti-PD-L1 therapeutics.
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