Clinical Study on the Efficacy of Autologous Cell Factor Induced Killer Cells in the Treatment of Colorectal Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Cancer,Colorectal Neoplasms
PROVIDER: 4351 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Cytokine Induced Killer (CIK) cells are heterogeneous ex vivo expanded T lymphocytes with mixed T-NK phenotype and endowed with a wide MHC-unrestricted antitumor activity against both solid and hematologic malignancies. CIK cells can be easily ex vivo expanded up to clinical relevant rates from circulating peripheral blood mononuclear cells (PBMC), according to a standard protocol involving timed stimulation with IFN- γ (day 0), Ab-antiCD3 OKT3 (day 1) and IL-2 (from day 1 to the end). Nowadays literature provides scanty information on cytokines, chemokines and growth factors secreted by CIK cells. A comprehensive molecular profiling of CIK cells is needed to complete the knowledge of their biologic and functional features. In this perspective we performed a gene expression profile analysis of basal PBMC and ex vivo expanded CIK cells generated from 3 patients with histologic confirmed Gastrointestinal Stromal Tumors (GIST). The principal component analysis (PCA) shows that the CIK cell samples clustered together and were clearly separated from PBMC ones. First, we checked the mRNA expression levels of secreted proteins and we found a significant upregulation of GM-CSF, IL-5, IL-13, and IFN-γ in CIK cells. Moreover, IL-1Ra, IL-1β, IL-6, IL-10, IL-15, IL-8, Eotaxin and MCP-1 are downregulated in CIK cells if compared to PBMC. Noteworthy, among differentially expressed genes (DEGs) we identified other secreted molecules that are upregulated in patient-derived CIK cells, which can contribute to their tumor killing activity: GZMA, GZMB, GZMK, PRF1, IL-32, and LTA. Furthermore, to better characterize the CIK cell phenotype, we studied the surface antigen expression. As expected, we found the downregulation of several myeloid differentiation markers (CD14, CD9, CD93, CSF2RA, CSF2RB, EPB41L3, Receptors for Fc fragments of immunoglobulins, ITGAX, MCEMP1, and TREM1) and B-cell antigens (CD19, CD24, CD79A, CXCR5, and MS4A1). Moreover, microarray data confirmed the upregulation in CIK cells of well-known surface antigens, like CD3D, CD3G, IL2Ra, IL2RG, CD226/DNAM1, ITGAL/LFA-1, KLRK1/NKG2D, NCR3/NKp30, and TRAIL/TNFSF10. Next, in order to identify differentially expressed pathways during CIK cells maturation, we performed a functional analysis by using Ingenuity Pathway Analysis (IPA) software. Among inactivated functions in CIK cells, we found chemotaxis of myeloid cells, phagocytosis, migration of granulocytes and engulfment of leukocytes. Noteworthy, functional gene categories as proliferation of cells, cell death of lymphocytes, cell death of mononuclear leukocytes, apoptosis of B lymphocytes, and quantity of CD4+ T-lymphocytes resulted activated, in agreement with the selection and expansion of CIK cell precursors induced by in vitro treatment of PBMC. Finally, IPA analysis predicted as activated categories cytotoxicity of lymphocytes, cytotoxicity of cells, and cytotoxicity of natural killer cells. In particular, genes involved in cytotoxic mechanism of CIK cells like NCR3/NKp30, KLRK1/NKG2D, TRAIL/TNFSF10, CD226/DNAM1, CD244, CD69, CD96, GZMA, GZMB, PRF1 are differentially expressed. With this work we highlighted previously unknown secretory properties and provided for the first time a comprehensive molecular characterization of CIK cells, opening the possibility to operate on secretory level to improve CIK cell cytotoxic activity against tumors.
2023-04-07 | GSE97581 | GEO
Project description:Background. Advanced sarcomas have a severe prognosis, limited therapeutic options, and are seldom sensitive to immunotherapy with checkpoint inhibitors. Novel strategies are urgently needed. Methods. We set up a preclinical approach for testing the combination of chemotherapy (trabectedin) and PARP1 inhibitor (olaparib) to potentiate the HLA-independent cellular immunotherapy with natural killer (NK) or cytokine-induced killer (CIK) lymphocytes. The NK/CIK activators NKG2DLs were studied by qRT-PCR and flow cytometry. Drug-induced transcriptomic events were studied by RNA sequencing and the activation of the cytosolic DNA sensing pathway (cGAS-STING-IRF3-IFNβ) was explored. Focusing on the putative cancer stem cell (CSCs) subpopulation, OCT4 marker was evaluated. IRF3 silencing experiments were done to investigate the role of the cGAS-STING pathway in the control of NKG2DLs. NK/CIK killing activity on both bulk and OCT4-positive cells was tested by viability assay and flow cytometry, respectively. Results. We obtained the enhancement of NK/CIK activity against sarcoma cell lines through an integrated approach based on the combination of trabectedin and olaparib. These drugs upregulated the NKG2DL expression at both mRNA and protein level by inducing the genotoxicity pathway (WP4286) and repressing the cellular response to DNA damage stimulus (GO:0006974). The drug treatment significantly increased the cytosolic DNA content and consequently activated the cGAS-STING-IRF3 pathway and IFNβ production. These molecular events significantly enhanced the antitumor activity of NK and CIK against drug-pretreated sarcoma cells. The OCT4-positive cell fraction was enriched after chemotherapy. Noteworthy, NK/CIK cells efficiently killed both the drug-surviving bulk and CSC subpopulation. Conclusions. Trabectedin+olaparib treatment followed by NK/CIK-based immunotherapy is a promising therapeutic strategy against sarcomas, deserving further investigations.
2025-05-05 | GSE239639 | GEO
Project description:CD3+/CD56+ Natural killer (NK) cell-like T-cells (NKT-like cells) represent <5% of blood lymphocytes, display a cytotoxic phenotype, and can kill various cancers. NKT-like cells can be expanded ex vivo into cytokine-induced killer (CIK) cells, however this therapeutic cell product has had mixed results against hematological malignancies in clinical trials. The aim of this study was to determine if NKT-like cells mobilized during acute cycling exercise could be used to generate more potent anti-tumor CIK cells from healthy donors. An acute exercise bout increased NKT-like cell numbers in blood 2-fold. Single cell RNA sequencing revealed that exercise mobilized NKT-like cells have an upregulation of genes and transcriptomic programs associated with enhanced anti-tumor activity, including cytotoxicity, cytokine responsiveness, and migration. Exercise, however, did not augment the ex vivo expansion of CIK cells or alter their surface phenotypes after 21-days of culture. CIK cells expanded at rest, during exercise (at 60% and 80% VO2max) or after (1h post) were equally capable of killing leukemia, lymphoma, and multiple myeloma target cells with and without cytokine (IL-2) and antibody (OKT3) priming in vitro. We conclude that acute exercise in healthy donors mobilizes NKT-like cells with an upregulation of transcriptomic programs involved in anti-tumor activity, but does not augment the ex vivo expansion of CIK cells.
2022-09-12 | GSE212740 | GEO
Project description:Dr. Christopher Contag lab's aim is to, investigate the molecular interactions that underlie CIK cell homing from the bloodstream to tumor tissue using a combination of gene expression profiling, flow cytometry, and in vivo molecular imaging. Collectively, these proposed experiments will define the repertoire of molecules employed in CIK cell recognition of the tumor vasculature and guide the development of improved CIK cell therapies for use in cancer patients. A promising new direction in cancer therapy is the use of cytokine-induced killer (CIK) cells as broadly active tumoricidal agents. CIK cells derive from blood samples stimulated ex vivo, and these activated immune cells are capable of recognizing and destroying a plethora of tumor targets in vivo. In fact, CIK cells have demonstrated efficacy in clinical trials to treat patients with hepatoma, renal cell cancer, and hematological malignancies. Despite the remarkable clinical promise of this therapy, little is known about the mechanisms that govern CIK cell migration to tumor tissue in vivo. Understanding the trafficking patterns of these potent immune cells is of critical importance to advancing their use in humans. I aim to investigate the molecular interactions that underlie CIK cell homing from the bloodstream to tumor tissue using a combination of gene expression profiling, flow cytometry, and in vivo molecular imaging. Collectively, these proposed experiments will define the repertoire of molecules employed in CIK cell recognition of the tumor vasculature and guide the development of improved CIK cell therapies for use in cancer patients. RNA from three groups (1,2,3) were sent to Microarray Core E. Group one samples: Splenocytes were obtained from BALB/c mice, and the T cells were isolated using a negative isolation kit (magnetic bead separation). For group 2 and 3 samples: The isolated splenocytes were treated with IFN-gamma overnight. The cells were then added to anti-CD3 coated flasks and stimulated with IL-2. Fresh IL-2 was added to the media every 3 days, and the cells were harvested 12 days post-isolation. The RNA was labeled and hybridized to Glyco_v3 arrays.
2011-04-29 | E-GEOD-28940 | biostudies-arrayexpress
Project description:Dr. Christopher Contag lab's aim is to, investigate the molecular interactions that underlie CIK cell homing from the bloodstream to tumor tissue using a combination of gene expression profiling, flow cytometry, and in vivo molecular imaging. Collectively, these proposed experiments will define the repertoire of molecules employed in CIK cell recognition of the tumor vasculature and guide the development of improved CIK cell therapies for use in cancer patients. A promising new direction in cancer therapy is the use of cytokine-induced killer (CIK) cells as broadly active tumoricidal agents. CIK cells derive from blood samples stimulated ex vivo, and these activated immune cells are capable of recognizing and destroying a plethora of tumor targets in vivo. In fact, CIK cells have demonstrated efficacy in clinical trials to treat patients with hepatoma, renal cell cancer, and hematological malignancies. Despite the remarkable clinical promise of this therapy, little is known about the mechanisms that govern CIK cell migration to tumor tissue in vivo. Understanding the trafficking patterns of these potent immune cells is of critical importance to advancing their use in humans. I aim to investigate the molecular interactions that underlie CIK cell homing from the bloodstream to tumor tissue using a combination of gene expression profiling, flow cytometry, and in vivo molecular imaging. Collectively, these proposed experiments will define the repertoire of molecules employed in CIK cell recognition of the tumor vasculature and guide the development of improved CIK cell therapies for use in cancer patients.
2011-04-29 | GSE28940 | GEO
Project description:Surgical resection is the major clinical intervention for Stage III colorectal cancer (CRC) currently. However, as much as 30.8% of the patients who had ever taken curative resection came out of recurrence eventually. Therefore, to facilitate formulating effective treatment plans, there is an intense demand for Stage III CRC post-surgical prognostic biomarkers. In this study, we identified total 146 differentially expressed proteins (DEPs) associated with poor prognosis in Stage III CRC patients with TMT-based quantitative mass spectrometry (MS). In these DEPs, the protein expression level of R-Ras and Transgelin were tested with immunohistochemistry (IHC) of 192 individual specimens. Further Kaplan-Meier analysis revealed that the level of R-Ras and Transgelin is associated with patients’ 5-year overall survival (OS) and disease-free survival (DFS) significantly, and multivariate Cox-regression analyses revealed that R-Ras and Transgelin are independent prognostic factors for OS and DFS respectively. In conclusion, our study presents that R-Ras and Transgelin are potential post-surgical prognostic biomarkers of Stage III CRC.
2016-06-20 | PXD002903 | Pride
Project description:Despite recent different molecular classifications for colorectal cancer (CRC) have been proposed, CRCs are currently diagnosed based their histology [Hamilton] and just a few biomarkers are used to determine the most suitable treatment. It is for this reason important to correlate molecular profiling with histological features. This issue is especially critical in the serrated pathway for colorectal carcinogenesis since it is not as clearly discerned as the conventional adenoma-carcinoma. Furthermore, making the immune surveillance awake against tumor is now considered as a breakthrough in cancer treatment and the serrated pathological pathway comprises two CRC subtypes with typical weak (SAC) and abundant (hMSI-H) immune responses. Therefore, it is crucial to characterize the biology of these tumors since no previous studies have compared their molecular signatures.
2018-06-27 | GSE116305 | GEO
Project description:This is a phase II Randomized comparison clinical trial of activated CIK armed with anti-CD3-MUC1 bispecific antibody for advanced colorectal cancer. And the aim of this research is to study the clinical efficacy and safety of activated CIK armed with anti-CD3-MUC1 bispecific antibody for colorectal cancer.
| 2272861 | ecrin-mdr-crc
Project description:Neuroblastoma is an embryonic malignancy originating from early nerve cells. Neuroblastoma retains plasticity, interconverting between the mesenchymal (MES) and adrenergic (ADRN) states, which are controlled by different sets of transcription factors forming the core regulatory circuit (CRC). However, their functional roles and cooperative mechanisms in neuroblastoma pathogenesis are poorly understood. Here, we demonstrate that overexpression of ASCL1 in MES neuroblastoma cells opens closed chromatin at the promoters of key ADRN genes, accompanied by epigenetic activation and establishment of enhancer-promoter interactions, thereby initiating subtype switching. ASCL1 inhibits the TGFb-SMAD2/3 pathway but activates the BMP-SMAD1-ID3/4 pathway, serving as negative feedback to balance the function of ASCL1-TCF12 dimers. ASCL1 and other ADRN CRC members potentiate each other’s activity, increasing the expression of the original targets and inducing a new set of genes, thereby promoting conversion to ADRN neuroblastoma. Thus, via its pioneer factor function, ASCL1 serves as a master regulator that characterizes ADRN neuroblastoma.
2023-12-08 | PXD037670 | Pride