Human Blood Specimen Collection to Evaluate Immune Cell Function
Ontology highlight
ABSTRACT:
DISEASE(S): Perioperative Care,Colorectal Cancer,Colorectal Neoplasms
PROVIDER: 2265023 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
Similar Datasets
Project description:The paper describes a model of ADCC.
Created by COPASI 4.26 (Build 213)
This model is described in the article:
A mathematical model of antibody-dependent cellular cytotoxicity (ADCC)
F. Hoffman, D. Gavaghan, J. Osborne, I.P. Barrett, T. You, H. Ghadially, R. Sainson, R.W. Wilkinson, H.M. Byrne
Journal of Theoretical Biology 436 (2018) 39–50
Abstract:
Immunotherapies exploit the immune system to target and kill cancer cells, while sparing healthy tis- sue. Antibody therapies, an important class of immunotherapies, involve the binding to specific antigens on the surface of the tumour cells of antibodies that activate natural killer (NK) cells to kill the tu- mour cells. Preclinical assessment of molecules that may cause antibody-dependent cellular cytotoxicity (ADCC) involves co-culturing cancer cells, NK cells and antibody in vitro for several hours and measuring subsequent levels of tumour cell lysis. Here we develop a mathematical model of such an in vitro ADCC assay, formulated as a system of time-dependent ordinary differential equations and in which NK cells kill cancer cells at a rate which depends on the amount of antibody bound to each cancer cell. Numerical simulations generated using experimentally-based parameter estimates reveal that the system evolves on two timescales: a fast timescale on which antibodies bind to receptors on the surface of the tumour cells, and NK cells form complexes with the cancer cells, and a longer time-scale on which the NK cells kill the cancer cells. We construct approximate model solutions on each timescale, and show that they are in good agreement with numerical simulations of the full system. Our results show how the processes involved in ADCC change as the initial concentration of antibody and NK-cancer cell ratio are varied. We use these results to explain what information about the tumour cell kill rate can be extracted from the cytotoxicity assays.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models .
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide.
Please refer to CC0 Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000802 | BioModels
Project description:Natural killer (NK) cells are important effectors of the innate immune system. Unlike T cells, NK cells do not require antigen-priming, making them an important first-line of defense against malignant cells. Because of the potential for increased cancer risk as a result of astronaut exposure to space radiation, we performed studies to determine whether conditions of microgravity present during spaceflight affects the body’s natural defenses against leukemogenesis. Human NK cells were cultured for 48 hours under normal gravity and simulated microgravity (smG), and cytotoxicity against K-562 (CML) and MOLT-4 (T-ALL) cell lines was measured using standard methodology or under continuous conditions of smG. Even this brief exposure to smG markedly reduced NK cytotoxicity against both leukemic cells using standard assay procedures, and these deleterious effects were even more pronounced in continuous smG. RNA-seq performed on NK cells from two healthy donors provided insight into the mechanism(s) by which smG reduced cytotoxicity. Given our prior report that human HSC exposed to simulated space radiation gave rise to T-ALL in vivo, the reduced cytotoxicity against MOLT-4 is striking and raises the possibility thatmG may add to astronaut risk of leukemogenesis during prolonged missions beyond LEO.
2024-08-22 | GSE255750 | GEO
Project description:Natural Killer cells (NK), a major constituent of innate immune system, have the ability to kill the transformed and infected cells without prior sensitization; can be put to immunotherapeutic use against various malignancies. NK cells discriminate between normal cells and transformed cells via a balance of inhibitory and activating signals induced by interactions between NK cell receptors and target cell ligands. Present study investigates whether expansion of NK cells could augment their anti-myeloma (MM) activity. For NK cell expansion, peripheral blood mononuclear cells from healthy donors and myeloma patients were co-cultured with irradiated K562 cells transfected with 4-1BBL and membrane-bound IL15 (K562-mb15-41BBL). A genome-wide profiling approach was performed to identify gene expression signature in expanded NK (ENK) cells and non-expanded NK cells isolated from healthy donors and myeloma patients. A specific set of genes involved in proliferation, migration, adhesion, cytotoxicity, and activation were up regulated post expansion, also confirmed by flow cytometry. Exp-NK cells killed both allogeneic and autologous primary MM cells more avidly than non-exp-NK cells in vitro. Multiple receptors, particularly NKG2D, natural cytotoxicity receptors, and DNAM-1 contributed to target lysis, via a perforin mediated mechanism. In summary, vigorous expansion and high anti-MM activity both in vitro and in vivo provide the rationale for testing exp-NK cells in a clinical trial for high risk MM. Differential gene expression profile in expanded natural killer (ENK) cells and non-expanded natural killer (NK) cells from healthy donors and myeloma patients Eight healthy donor and eight myeloma patients were used in the study. Non-expanded natural killer (NK) cells were isolated from PBMCs of healthy donors and myeloma patients. Expanded natural killer (ENK) cells were generated from same set of samples as mentioned in expansion protocol. All ENK and NK cells were used for gene expression profiling.
2011-03-08 | E-GEOD-27838 | biostudies-arrayexpress
Project description:B-cell lymphoma/leukemia (BCL) 11B represents a major regulator of vital processes in post-thymic lymphocytes as well as of lymphocyte differentiation by blocking NK cell and promoting T cell development and is thus considered a \\"guardian of T cell fate\\". Interestingly, on the one hand, NK cell maturation correlates with increased expression of BCL11B, on the other hand, native or induced T cell populations characterized by multiple NK cell features showed reduced BCL11B expression. Both NK cells or T cells display unique and desired features for cellular therapies. NK cells are able to efficiently lyse cancerous or virally infected cells but can only be poorly expanded in vitro. In contrast, T cell cytotoxic activity is limited by T cell receptor (TCR) but in vitro expansion is easily achievable. We show that from buffy coats of healthy donors isolated and CRISPR/Cas9-mediated BCL11B knock-out CD8+ T cells stimulated with IL-15 acquired remarkable innate characteristics and combine spontaneous and antibody-dependent NK cell cytotoxicity with T cell capability for rapid in vitro expansion. The observed features of the induced innate CD8+ (iiT8) cells make them an interesting and promising tool for cellular therapy.
2022-12-07 | E-MTAB-12064 | biostudies-arrayexpress
Project description:NK cells are lymphocytes that provide a first defense against viral infections and cancer. They act (i) cytotoxic by killing virus-infected and tumorigenic cells and (ii) immune regulatory by releasing cytokines and chemokines. These innate immune cells are commonly further classified as CD56bright and CD56dim NK cells. Former studies confirmed immune regulatory CD56bright NK cells as progenitors of cytotoxic CD56dim NK cells. CD57 was previously described as T cell marker for senescence and terminal differentiation. Recent studies detected CD57+ and CD57- NK cells among the CD56dim NK cell population and suggested a fully mature developmental status for CD57+ NK cells. The recent NK cell maturation model includes CD34+ hematopoietic stem cells (HSC), which develop into CD56bright NK cells, later into CD56dimCD57- and finally into terminally maturated CD56dimCD57+ (1) (2) (3). The molecular mechanisms of human NK cell differentiation and maturation remain unknown to this date. We performed for the first time a proteomic analysis of these distinct developmental stages of human primary NK cells, isolated from overall 10 healthy human blood donors. CD56bright NK cells versusCD56dim and CD56dimCD57- versus CD56dimCD57+ NK cells were analyzed by using quantitative peptide sequencing, which revealed individual protein signatures (3400 proteins) of these different NK cell developmental stages. Notably, our data support the current NK cell differentiation model by highlighting both strong distinctions between CD56dim/bright NK cells and close relationships between CD57+/- NK cells on the proteomic level. Among the most prominent and conserved regulated proteins, we detected myosin IIa, Calvasculin and Calcyclin with very similar expression patterns. We investigated their sub-cellular localization and observed specific recruitment- and accumulation-events at the NK cell immunological synapse (NKIS) after NK activation.
2013-01-23 | PRD000666 | Pride
Project description:Natural Killer cells (NK), a major constituent of innate immune system, have the ability to kill the transformed and infected cells without prior sensitization; can be put to immunotherapeutic use against various malignancies. NK cells discriminate between normal cells and transformed cells via a balance of inhibitory and activating signals induced by interactions between NK cell receptors and target cell ligands. Present study investigates whether expansion of NK cells could augment their anti-myeloma (MM) activity. For NK cell expansion, peripheral blood mononuclear cells from healthy donors and myeloma patients were co-cultured with irradiated K562 cells transfected with 4-1BBL and membrane-bound IL15 (K562-mb15-41BBL). A genome-wide profiling approach was performed to identify gene expression signature in expanded NK (ENK) cells and non-expanded NK cells isolated from healthy donors and myeloma patients. A specific set of genes involved in proliferation, migration, adhesion, cytotoxicity, and activation were up regulated post expansion, also confirmed by flow cytometry. Exp-NK cells killed both allogeneic and autologous primary MM cells more avidly than non-exp-NK cells in vitro. Multiple receptors, particularly NKG2D, natural cytotoxicity receptors, and DNAM-1 contributed to target lysis, via a perforin mediated mechanism. In summary, vigorous expansion and high anti-MM activity both in vitro and in vivo provide the rationale for testing exp-NK cells in a clinical trial for high risk MM. Differential gene expression profile in expanded natural killer (ENK) cells and non-expanded natural killer (NK) cells from healthy donors and myeloma patients
2011-03-08 | GSE27838 | GEO
Project description:NK cells may acquire under certain conditions features of adaptive immune cells. As the functional role of memory NK cells in cancer has so far remained elusive, we reasoned whether tumor-priming itself might promote memory NK cell generation. We provide substantial evidence that independent from pro-inflammatory stimulation, tumor-induced memory-like (TIML) NK cells exhibit a heightened, tumor-restricted cytotoxicity which is dependent on a higher/faster perforin but not IFN-γ release. Comparative transcriptome analysis reveals that gene expression patterns differ between TIML- and Cytokine-induced memory-like (CIML)-NK cells.
2016-04-15 | E-MTAB-4606 | biostudies-arrayexpress
Project description:Natural killer (NK) cells are an innate immune cell type that serves at the first level of defense against pathogens and cancer. NK cells have clinical potential; However, multiple current limitations exist that naturally hinder the successful implementation of NK cell therapy against cancer, including their effector function, persistence, and tumor infiltration. To unbiasedly identify genes underlying critical NK cell characteristics against cancer, we perform functional mapping of tumor infiltrating NK (TINK) cells by both in vivo AAV-CRISPR screens and single-cell sequencing. We establish a strategy with AAV-SleepingBeauty(SB)-CRISPR screening leveraging a focused high-density sgRNA library, and perform four independent in vivo tumor infiltration screens of primary NK cells in mouse models of melanoma, breast cancer, pancreatic cancer, and glioblastoma. In parallel, we characterize single-cell transcriptomic landscapes of tumor-infiltrating NK cells, which identifies previously unexplored sub-populations of NK cells with distinct expression profiles, a shift from immature to mature NK (mNK) cells in the tumor microenvironment (TME), and decreased expression of mature marker genes in mNK cells. CALHM2, a calcium homeostasis modulator previously not linked to NK function, emerges as a convergent hit from both CRISPR screen and single-cell data. CALHM2 knockout NK cells show enhancement of in vitro cytotoxicity and in vivo tumor infiltration in both mouse primary NK and human chimeric antigen receptor (CAR)-NK cells. Re-introduction of CALHM2 mRNA reverses CALHM2 knockout phenotype of NK cytotoxicity and degranulation. Importantly, in a solid tumor model that is completely resistant to adoptive cell therapy of unmodified CAR-NK cells, CALHM2 knockout CAR-NK cells show potent in vivo anti-tumor efficacy. Human primary NK cell study with multiple donors reveals that CALHM2 knockout enhances cytotoxicity, degranulation and cytokine production of NK cells. Transcriptomics profiling of human primary NK cells reveal multiple enriched pathways of downstream genes upon CALHM2 knockout in both baseline and stimulated conditions. These data identify endogenous cellular genetic checkpoints that naturally limit NK cell function, and pinpoint CALHM2 as a key factor in which genetic modification can be engineered to enhance NK cell-based immunotherapies.
2024-05-09 | GSE262760 | GEO
Project description:Natural killer (NK) cells are an innate immune cell type that serves at the first level of defense against pathogens and cancer. NK cells have clinical potential; However, multiple current limitations exist that naturally hinder the successful implementation of NK cell therapy against cancer, including their effector function, persistence, and tumor infiltration. To unbiasedly identify genes underlying critical NK cell characteristics against cancer, we perform functional mapping of tumor infiltrating NK (TINK) cells by both in vivo AAV-CRISPR screens and single-cell sequencing. We establish a strategy with AAV-SleepingBeauty(SB)-CRISPR screening leveraging a focused high-density sgRNA library, and perform four independent in vivo tumor infiltration screens of primary NK cells in mouse models of melanoma, breast cancer, pancreatic cancer, and glioblastoma. In parallel, we characterize single-cell transcriptomic landscapes of tumor-infiltrating NK cells, which identifies previously unexplored sub-populations of NK cells with distinct expression profiles, a shift from immature to mature NK (mNK) cells in the tumor microenvironment (TME), and decreased expression of mature marker genes in mNK cells. CALHM2, a calcium homeostasis modulator previously not linked to NK function, emerges as a convergent hit from both CRISPR screen and single-cell data. CALHM2 knockout NK cells show enhancement of in vitro cytotoxicity and in vivo tumor infiltration in both mouse primary NK and human chimeric antigen receptor (CAR)-NK cells. Re-introduction of CALHM2 mRNA reverses CALHM2 knockout phenotype of NK cytotoxicity and degranulation. Importantly, in a solid tumor model that is completely resistant to adoptive cell therapy of unmodified CAR-NK cells, CALHM2 knockout CAR-NK cells show potent in vivo anti-tumor efficacy. Human primary NK cell study with multiple donors reveals that CALHM2 knockout enhances cytotoxicity, degranulation and cytokine production of NK cells. Transcriptomics profiling of human primary NK cells reveal multiple enriched pathways of downstream genes upon CALHM2 knockout in both baseline and stimulated conditions. These data identify endogenous cellular genetic checkpoints that naturally limit NK cell function, and pinpoint CALHM2 as a key factor in which genetic modification can be engineered to enhance NK cell-based immunotherapies.
2024-05-09 | GSE262708 | GEO
Project description:Natural killer (NK) cells are an innate immune cell type that serves at the first level of defense against pathogens and cancer. NK cells have clinical potential; However, multiple current limitations exist that naturally hinder the successful implementation of NK cell therapy against cancer, including their effector function, persistence, and tumor infiltration. To unbiasedly identify genes underlying critical NK cell characteristics against cancer, we perform functional mapping of tumor infiltrating NK (TINK) cells by both in vivo AAV-CRISPR screens and single-cell sequencing. We establish a strategy with AAV-SleepingBeauty(SB)-CRISPR screening leveraging a focused high-density sgRNA library, and perform four independent in vivo tumor infiltration screens of primary NK cells in mouse models of melanoma, breast cancer, pancreatic cancer, and glioblastoma. In parallel, we characterize single-cell transcriptomic landscapes of tumor-infiltrating NK cells, which identifies previously unexplored sub-populations of NK cells with distinct expression profiles, a shift from immature to mature NK (mNK) cells in the tumor microenvironment (TME), and decreased expression of mature marker genes in mNK cells. CALHM2, a calcium homeostasis modulator previously not linked to NK function, emerges as a convergent hit from both CRISPR screen and single-cell data. CALHM2 knockout NK cells show enhancement of in vitro cytotoxicity and in vivo tumor infiltration in both mouse primary NK and human chimeric antigen receptor (CAR)-NK cells. Re-introduction of CALHM2 mRNA reverses CALHM2 knockout phenotype of NK cytotoxicity and degranulation. Importantly, in a solid tumor model that is completely resistant to adoptive cell therapy of unmodified CAR-NK cells, CALHM2 knockout CAR-NK cells show potent in vivo anti-tumor efficacy. Human primary NK cell study with multiple donors reveals that CALHM2 knockout enhances cytotoxicity, degranulation and cytokine production of NK cells. Transcriptomics profiling of human primary NK cells reveal multiple enriched pathways of downstream genes upon CALHM2 knockout in both baseline and stimulated conditions. These data identify endogenous cellular genetic checkpoints that naturally limit NK cell function, and pinpoint CALHM2 as a key factor in which genetic modification can be engineered to enhance NK cell-based immunotherapies.
2024-05-09 | GSE262707 | GEO