Cancer cell self-built physical barriers promote acquired resistance to immunotherapy [spatial]
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ABSTRACT:
PROVIDER: PRJNA1089514 | ENA |
REPOSITORIES: ENA
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Project description:Drug resistance is the principal challenge of cancer therapies, including recently developed immunotherapy. More and more popular use of immunotherapy, especially treatments with immune checkpoint inhibitors (ICIs), witnesses explosively increasing cases of both primary and acquired immunotherapy resistance. While primary resistance has been extensively studied, mechanisms underlying acquired resistance of immunotherapy are less understood. Here we reported that tumor cells could develop acquired resistance to ICI treatment through self-built collagen-containing physical barriers in non-small cell lung cancer (NSCLC). We found that tumor cells expressed high levels of multiple collagen genes, including COL3A1 and COL6A1, and were fully covered with collagen fibers. COL3A1 formed a castle-like structure of a cluster of tumor cells and prevented the infiltration of T cells, while COL6A1 seemed to be an armor-like structure of each tumor cell and protected them from attack by cytotoxic T cells. Genetic or pharmaceutic disruption of these collagens, by warfarin, a commonly used medicine, significantly reversed the acquired resistance. Thus, our data reveal an unprecedented tumor cell-intrinsic mechanism, mediated by collagen-containing physical barriers, of acquired immunotherapy resistance, which immediately suggests a treatment option for patients.
2025-02-01 | GSE261898 | GEO
Project description:Drug resistance is the principal challenge of cancer therapies, including recently developed immunotherapy. More and more popular use of immunotherapy, especially treatments with immune checkpoint inhibitors (ICIs), witnesses explosively increasing cases of both primary and acquired immunotherapy resistance. While primary resistance has been extensively studied, mechanisms underlying acquired resistance of immunotherapy are less understood. Here we reported that tumor cells could develop acquired resistance to ICI treatment through self-built collagen-containing physical barriers in non-small cell lung cancer (NSCLC). We found that tumor cells expressed high levels of multiple collagen genes, including COL3A1 and COL6A1, and were fully covered with collagen fibers. COL3A1 formed a castle-like structure of a cluster of tumor cells and prevented the infiltration of T cells, while COL6A1 seemed to be an armor-like structure of each tumor cell and protected them from attack by cytotoxic T cells. Genetic or pharmaceutic disruption of these collagens, by warfarin, a commonly used medicine, significantly reversed the acquired resistance. Thus, our data reveal an unprecedented tumor cell-intrinsic mechanism, mediated by collagen-containing physical barriers, of acquired immunotherapy resistance, which immediately suggests a treatment option for patients.
2025-02-01 | GSE261890 | GEO
Project description:Drug resistance is the principal challenge of cancer therapies, including recently developed immunotherapy. More and more popular use of immunotherapy, especially treatments with immune checkpoint inhibitors (ICIs), witnesses explosively increasing cases of both primary and acquired immunotherapy resistance. While primary resistance has been extensively studied, mechanisms underlying acquired resistance of immunotherapy are less understood. Here we reported that tumor cells could develop acquired resistance to ICI treatment through self-built collagen-containing physical barriers in non-small cell lung cancer (NSCLC). We found that tumor cells expressed high levels of multiple collagen genes, including COL3A1 and COL6A1, and were fully covered with collagen fibers. COL3A1 formed a castle-like structure of a cluster of tumor cells and prevented the infiltration of T cells, while COL6A1 seemed to be an armor-like structure of each tumor cell and protected them from attack by cytotoxic T cells. Genetic or pharmaceutic disruption of these collagens, by warfarin, a commonly used medicine, significantly reversed the acquired resistance. Thus, our data reveal an unprecedented tumor cell-intrinsic mechanism, mediated by collagen-containing physical barriers, of acquired immunotherapy resistance, which immediately suggests a treatment option for patients.
2025-02-01 | GSE261889 | GEO
Project description:Cancer cell self-built physical barriers promote acquired resistance to immunotherapy [scRNAseq]
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Project description:Cancer cell self-built physical barriers promote acquired resistance to immunotherapy [bulk RNAseq]
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Project description:Acquired immunotherapy resistance in PDA
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Project description:Eukaryotic genomes are compacted into loops and topologically associating domains (TADs), which contribute to transcription, recombination and genomic stability. Cohesin extrudes DNA into loops that are thought to lengthen until it encounters CTCF boundaries. Little is known whether loop extrusion is impeded by macromolecular machines. We demonstrate that the replicative helicase MCM is a barrier that restricts loops and TADs in G1 phase. Single-nucleus Hi-C of one-cell embryos revealed that MCM loading reduces CTCF-anchored loops and increases TAD boundary insulation, suggesting loop extrusion is impeded before reaching CTCF. Single-molecule imaging provides evidence that MCM are physical barriers that constrain cohesin translocation in vitro. Simulations are consistent with MCM as abundant, random barriers with low permeability. We conclude that distinct loop extrusion barriers contribute to shaping 3D genomes.
2022-03-07 | GSE155971 | GEO
Project description:Eukaryotic genomes are compacted into loops and topologically associating domains (TADs), which contribute to transcription, recombination and genomic stability. Cohesin extrudes DNA into loops that are thought to lengthen until CTCF boundaries are encountered. Little is known about whether loop extrusion is impeded by DNA-bound macromolecular machines. We demonstrate that the replicative helicase MCM is a barrier that restricts loop extrusion in G1 phase. Single-nucleus Hi-C of one-cell embryos revealed that MCM loading reduces CTCF-anchored loops and decreases TAD boundary insulation, suggesting loop extrusion is impeded before reaching CTCF. Single-molecule imaging shows that MCMs are physical barriers that constrain cohesin translocation in vitro. Simulations are consistent with MCMs as abundant, random barriers. We conclude that distinct loop extrusion barriers contribute to shaping 3D genomes.
2022-03-08 | GSE196300 | GEO
Project description:Immunotherapy has emerged as an unprecedented hope for the treatment of notoriously refractory cancers. Numerous investigational drugs and immunotherapy-including combination regimens are under preclinical and clinical investigation. However, only a small patient subpopulation across different types of cancer responds to the therapy due to the presence of several mechanisms of resistance. There have been extensive efforts to overcome this limitation and to expand the patient population that could be benefited by this state-of-the-art therapeutic modality. Among various causes of the resistance, we here focus on physical stromal barriers that impede the access of immunotherapeutic drug molecules and/or native and engineered immune cells to cancer tissues and cells. Two primary stromal barriers that contribute to the resistance include aberrant tumor vasculatures and excessive extracellular matrix build-ups that restrict extravasation and infiltration, respectively, of molecular and cellular immunotherapeutic agents into tumor tissues. Here, we review the features of these barriers that limit the efficacy of immunotherapy and discuss recent advances that could potentially help immunotherapy overcome the barriers and improve therapeutic outcomes.
| S-EPMC8571040 | biostudies-literature
Project description:Eukaryotic genomes are compacted into loops and topologically associating domains (TADs), which contribute to transcription, recombination and genomic stability. Cohesin extrudes DNA into loops that are thought to lengthen until CTCF boundaries are encountered. Little is known about whether loop extrusion is impeded by DNA-bound machines. Here we show that the minichromosome maintenance (MCM) complex is a barrier that restricts loop extrusion in G1 phase. Single-nucleus Hi-C of mouse zygotes revealed that MCM loading reduces CTCF-anchored loops and decreases TAD boundary insulation, suggesting loop extrusion is impeded before reaching CTCF. This effect extends to HCT116 cells, where MCMs affect the number of CTCF-anchored loops and gene expression. Simulations suggest that MCMs are abundant, randomly positioned, partially permeable barriers. Single-molecule imaging shows that MCMs are physical barriers that frequently constrain cohesin translocation in vitro. Remarkably, chimaeric yeast MCMs harbouring a cohesin-interaction motif from human MCM3 induce cohesin pausing, suggesting that MCMs are “active” barriers with binding sites. These findings raise the possibility that cohesin can arrive by loop extrusion at MCMs, which determine the genomic sites at which sister chromatid cohesion is established. Based on in vivo, in silico and in vitro data, we conclude that distinct loop extrusion barriers shape the 3D genome.
2022-03-08 | GSE196496 | GEO