Browse
Submit Data
Databases
API
Help

Dataset Information

16 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Payload Delivery: Engineering Immune Cells to Disrupt the Tumour Microenvironment.

ABSTRACT: Although chimeric antigen receptor (CAR) T cells have shown impressive clinical success against haematological malignancies such as B cell lymphoma and acute lymphoblastic leukaemia, their efficacy against non-haematological solid malignancies has been largely disappointing. Solid tumours pose many additional challenges for CAR T cells that have severely blunted their potency, including homing to the sites of disease, survival and persistence within the adverse conditions of the tumour microenvironment, and above all, the highly immunosuppressive nature of the tumour milieu. Gene engineering approaches for generating immune cells capable of overcoming these hurdles remain an unmet therapeutic need and ongoing area of research. Recent advances have involved gene constructs for membrane-bound and/or secretable proteins that provide added effector cell function over and above the benefits of classical CAR-mediated cytotoxicity, rendering immune cells not only as direct cytotoxic effectors against tumours, but also as vessels for payload delivery capable of both modulating the tumour microenvironment and orchestrating innate and adaptive anti-tumour immunity. We discuss here the novel concept of engineered immune cells as vessels for payload delivery into the tumour microenvironment, how these cells are better adapted to overcome the challenges faced in a solid tumour, and importantly, the novel gene engineering approaches required to deliver these more complex polycistronic gene constructs.

SUBMITTER: Fowler D

PROVIDER: S-EPMC8657158 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Immune-mediated ECM depletion improves tumour perfusion and payload delivery.

Project description:High extracellular matrix (ECM) content in solid cancers impairs tumour perfusion and thus access of imaging and therapeutic agents. We have devised a new approach to degrade tumour ECM, which improves uptake of circulating compounds. We target the immune-modulating cytokine, tumour necrosis factor alpha (TNFα), to tumours using a newly discovered peptide ligand referred to as CSG. This peptide binds to laminin-nidogen complexes in the ECM of mouse and human carcinomas with little or no peptide detected in normal tissues, and it selectively delivers a recombinant TNFα-CSG fusion protein to tumour ECM in tumour-bearing mice. Intravenously injected TNFα-CSG triggered robust immune cell infiltration in mouse tumours, particularly in the ECM-rich zones. The immune cell influx was accompanied by extensive ECM degradation, reduction in tumour stiffness, dilation of tumour blood vessels, improved perfusion and greater intratumoral uptake of the contrast agents gadoteridol and iron oxide nanoparticles. Suppressed tumour growth and prolonged survival of tumour-bearing mice were observed. These effects were attainable without the usually severe toxic side effects of TNFα.

| S-EPMC6895610 | biostudies-literature

Tuning payload delivery in tumour cylindroids using gold nanoparticles.

Project description:Nanoparticles have great potential as controllable drug delivery vehicles because of their size and modular functionality. Timing and location are important parameters when optimizing nanoparticles for delivery of chemotherapeutics. Here, we show that gold nanoparticles carrying either fluorescein or doxorubicin molecules move and localize differently in an in vitro three-dimensional model of tumour tissue, depending on whether the nanoparticles are positively or negatively charged. Fluorescence microscopy and mathematical modelling show that uptake, not diffusion, is the dominant mechanism in particle delivery. Our results indicate that positive particles may be more effective for drug delivery because they are taken up to a greater extent by proliferating cells. Negative particles, which diffuse more quickly, may perform better when delivering drugs deep into tissues. An understanding of how surface charge can control tissue penetration and drug release may overcome some of the current limitations in drug delivery.

| S-EPMC2881185 | biostudies-literature

The tumour immune microenvironment in oesophageal cancer.

Project description:Oesophageal cancer (OC) is an inflammation-associated malignancy linked to gastro-oesophageal reflux disease, obesity and tobacco use. Knowledge of the microenvironment of oesophageal tumours is relevant to our understanding of the development of OC and its biology, and has major implications for understanding the response to standard therapies and immunotherapies, as well as for uncovering novel targets. In this context, we discuss what is known about the TME in OC from tumour initiation to development and progression, and how this is relevant to therapy sensitivity and resistance in the two major types of OC. We provide an immunological characterisation of the OC TME and discuss its prognostic implications with specific comparison with the Immunoscore and immune-hot, -cold, altered-immunosuppressed and -altered-excluded models. Targeted therapeutics for the TME under pre-clinical and clinical investigation in OCs are also summarised. A deeper understanding of the TME will enable the development of combination approaches to concurrently target the tumour cells and TME delivering precision medicine to OC patients.

| S-EPMC8368180 | biostudies-literature

The tumour microenvironment and immune milieu of cholangiocarcinoma.

Project description:Tumour microenvironment is a complex, multicellular functional compartment that, particularly when assembled as an abundant desmoplastic reaction, may profoundly affect the proliferative and invasive abilities of epithelial cancer cells. Tumour microenvironment comprises not only stromal cells, mainly cancer-associated fibroblasts, but also immune cells of both the innate and adaptive system (tumour-associated macrophages, neutrophils, natural killer cells, and T and B lymphocytes), and endothelial cells. This results in an intricate web of mutual communications regulated by an extensively remodelled extracellular matrix, where the tumour cells are centrally engaged. In this regard, cholangiocarcinoma, in particular the intrahepatic variant, has become the focus of mounting interest in the last years, largely because of the lack of effective therapies despite its rising incidence and high mortality rates worldwide. On the other hand, recent studies in pancreatic cancer, which similarly to cholangiocarcinoma, is highly desmoplastic, have argued against a tumour-promoting function of the tumour microenvironment. In this review, we will discuss recent developments concerning the role of each cellular population and their multifaceted interplay with the malignant biliary epithelial counterpart. We ultimately hope to provide the working knowledge on how their manipulation may lead to a therapeutic gain in cholangiocarcinoma.

| S-EPMC10878127 | biostudies-literature

Photoactivated Cyclic Polyphthalaldehyde Microcapsules for Payload Delivery.

Project description:Microcapsules with a cyclic polyphthalaldehyde (cPPA) shell and oil core were fabricated by an emulsification process. The low ceiling temperature cPPA shell was made phototriggerable by incorporating a photoacid generator (PAG). Photoactivation of the PAG created a strong acid which catalyzed cPPA depolymerization, resulting in the release of the core payload, as quantified by 1H NMR. The high molecular weight cPPA (197 kDa) yielded uniform spherical microcapsules. The core diameter was 24.8 times greater than the cPPA shell thickness (2.4 to 21.6 μm). Nonionic bis(cyclohexylsulfonyl)diazomethane (BCSD) and N-hydroxynaphthalimide triflate (HNT) PAGs were used as the PAG in the microcapsule shells. BCSD required dual stimuli of UV radiation and post-exposure baking at 60 °C to activate cPPA depolymerization while room temperature irradiation of HNT resulted in instantaneous core release. A 300 s UV exposure (365 nm, 10.8 J/cm2) of the cPPA/HNT microcapsules resulted in 66.5 ± 9.4% core release. Faster core release was achieved by replacing cPPA with a phthalaldehyde/propanal copolymer. A 30 s UV exposure (365 nm, 1.08 J/cm2) resulted in 82 ± 13% core release for the 75 mol % phthalaldehyde/25 mol % propanal copolymer microcapsules. The photoresponsive shell provides a versatile polymer microcapsule technology for on-demand, controlled release of hydrophobic core payloads.

| S-EPMC11345721 | biostudies-literature

Single-cell spatial landscapes of the lung tumour immune microenvironment.

Project description:Single-cell technologies have revealed the complexity of the tumour immune microenvironment with unparalleled resolution1-9. Most clinical strategies rely on histopathological stratification of tumour subtypes, yet the spatial context of single-cell phenotypes within these stratified subgroups is poorly understood. Here we apply imaging mass cytometry to characterize the tumour and immunological landscape of samples from 416 patients with lung adenocarcinoma across five histological patterns. We resolve more than 1.6 million cells, enabling spatial analysis of immune lineages and activation states with distinct clinical correlates, including survival. Using deep learning, we can predict with high accuracy those patients who will progress after surgery using a single 1-mm2 tumour core, which could be informative for clinical management following surgical resection. Our dataset represents a valuable resource for the non-small cell lung cancer research community and exemplifies the utility of spatial resolution within single-cell analyses. This study also highlights how artificial intelligence can improve our understanding of microenvironmental features that underlie cancer progression and may influence future clinical practice.

| S-EPMC9931585 | biostudies-literature

Engineering the Tumor Immune Microenvironment through Minimally Invasive Interventions.

Project description:The tumor microenvironment (TME) is a unique landscape that poses several physical, biochemical, and immune barriers to anti-cancer therapies. The rapidly evolving field of immuno-engineering provides new opportunities to dismantle the tumor immune microenvironment by efficient tumor destruction. Systemic delivery of such treatments can often have limited local effects, leading to unwanted offsite effects such as systemic toxicity and tumor resistance. Interventional radiologists use contemporary image-guided techniques to locally deliver these therapies to modulate the immunosuppressive TME, further accelerating tumor death and invoking a better anti-tumor response. These involve local therapies such as intratumoral drug delivery, nanorobots, nanoparticles, and implantable microdevices. Physical therapies such as photodynamic therapy, electroporation, hyperthermia, hypothermia, ultrasound therapy, histotripsy, and radiotherapy are also available for local tumor destruction. While the interventional radiologist can only locally manipulate the TME, there are systemic offsite recruitments of the immune response. This is known as the abscopal effect, which leads to more significant anti-tumoral downstream effects. Local delivery of modern immunoengineering methods such as locoregional CAR-T therapy combined with immune checkpoint inhibitors efficaciously modulates the immunosuppressive TME. This review highlights the various advances and technologies available now to change the TME and revolutionize oncology from a minimally invasive viewpoint.

| S-EPMC9818918 | biostudies-literature

Bispecific digoxigenin-binding antibodies for targeted payload delivery.

Project description:Bispecific antibodies that bind cell-surface targets as well as digoxigenin (Dig) were generated for targeted payload delivery. Targeting moieties are IgGs that bind the tumor antigens Her2, IGF1R, CD22, or LeY. A Dig-binding single-chain Fv was attached in disulfide-stabilized form to C termini of CH3 domains of targeting antibodies. Bispecific molecules were expressed in mammalian cells and purified in the same manner as unmodified IgGs. They are stable without aggregation propensity and retain binding specificity/affinity to cell-surface antigens and Dig. Digoxigeninylated payloads were generated that retain full functionality and can be complexed to bispecific antibodies in a defined 21 ratio. Payloads include small compounds (Dig-Cy5, Dig-Doxorubicin) and proteins (Dig-GFP). Complexed payloads are targeted by the bispecifics to cancer cells and because these complexes are stable in serum, they can be applied for targeted delivery. Because Dig bispecifics also effectively capture digoxigeninylated compounds under physiological conditions, separate administration of uncharged Dig bispecifics followed by application of Dig payload is sufficient to achieve antibody-mediated targeting in vitro and in vivo.

| S-EPMC3100918 | biostudies-literature

Reshaping the tumour immune microenvironment in solid tumours via tumour cell and immune cell DNA methylation: from mechanisms to therapeutics.

Project description:In recent years, the tumour microenvironment (TME) of solid tumours has attracted more and more attention from researchers, especially those non-tumour components such as immune cells. Infiltration of various immune cells causes tumour immune microenvironment (TIME) heterogeneity, and results in different therapeutic effects. Accumulating evidence showed that DNA methylation plays a crucial role in remodelling TIME and is associated with the response towards immune checkpoint inhibitors (ICIs). During carcinogenesis, DNA methylation profoundly changes, specifically, there is a global loss of DNA methylation and increased DNA methylation at the promoters of suppressor genes. Immune cell differentiation is disturbed, and exclusion of immune cells from the TME occurs at least in part due to DNA methylation reprogramming. Therefore, pharmaceutical interventions targeting DNA methylation are promising. DNA methyltransferase inhibitors (DNMTis) enhance antitumor immunity by inducing transcription of transposable elements and consequent viral mimicry. DNMTis upregulate the expression of tumour antigens, mediate immune cells recruitment and reactivate exhausted immune cells. In preclinical studies, DNMTis have shown synergistic effect when combined with immunotherapies, suggesting new strategies to treat refractory solid tumours.

| S-EPMC10307880 | biostudies-literature

Heterogeneity and evolution of tumour immune microenvironment in metastatic gastroesophageal adenocarcinoma.

Project description:BackgroundTumour immune microenvironment heterogeneity is prevalent in numerous cancers and can negatively impact immunotherapy response. Immune heterogeneity and evolution in gastroesophageal adenocarcinoma (GEA) have not been studied in the past.MethodsTogether with a multi-region sampling of normal, primary and metastatic tissues, we performed whole exome sequencing, TCR sequencing as well as immune cell infiltration estimation through deconvolution of gene expression signals.ResultsWe discovered high TCR repertoire and immune cell infiltration heterogeneity among metastatic sites, while they were homogeneous among primary and normal samples. Metastatic sites shared high levels of abundant TCR clonotypes with blood, indicating immune surveillance via blood. Metastatic sites also had low levels of tumour-eliminating immune cells and were undergoing heavy immunomodulation compared to normal and primary tumour tissues. There was co-evolution of neo-antigen and TCR repertoire, but only in patients with late diverging mutational evolution. Co-evolution of TCR repertoire and immune cell infiltration was seen in all except one patient.ConclusionsOur findings revealed immune heterogeneity and co-evolution in GEA, which may inform immunotherapy decision-making.

| S-EPMC9587966 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data