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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of mouse NK cells in presence/absence of activated CD8 T cells

ABSTRACT: we compare NK cells in presence of activated CD8 T cells or not. Although both natural killer (NK) cells and CD8 T cells are capable of anti-tumor responses, Recombinase Activating Gene (RAG)-deficient mice, which have a normal component of NK cells, are incapable of rejecting the P815 mastocytoma tumor. We established a model where monoclonal CD8 T cell reactivity was restricted to the tumor antigen (Ag) P1A expressed on the P815 mastocytoma. Reconstitution of the RAG-deficient mice with these (TCRP1A) T cells conferred resistance to tumor growth selectively for the P1A-expressing, but not for a P1A-negative variant of P815. Nevertheless, TCRP1A CD8 T cells were efficient and necessary to promote the NK cell dependent rejection of P1A-negative tumors when both P1A-positive and -negative tumors were present at the same site. Gene expression profiling in NK cells infiltrating the P1A-positive, as compared to the P1A-negative tumor, in mice transferred with TCRP1A CD8 T cells established their acquisition of an activated effector phenotype. Help from CD8 T cells was provided locally, as it did not induce activation of NK cells present in a P1A-negative variant at a distant site, nor the rejection of this variant. These results illustrate a mechanism by which, in the face of immunoselection / editing, the synergy between specific anti-tumor Ag T cells and NK cells can contribute to the elimination of tumor cells whether or not they express the tumor Ag. This mechanism appears ineffective, however, once tumor variants lacking the tumor Ag are separated from the wild-type tumor, as would be the case in tumor metastasis.

INSTRUMENT(S): BAS-5000 [FUJIFILM]

ORGANISM(S): Mus musculus

SUBMITTER: Gregory Verdeil

PROVIDER: E-MEXP-1284 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Transcription profiling of mouse CD8 T cells in response to P1A antigen expressing tumor cells or cells not expressing 1A antigen

Project description:Activation status of CD8 T cells in response to a tumor challenge. Although both natural killer (NK) cells and CD8 T cells are capable of anti-tumor responses, Recombinase Activating Gene (RAG)-deficient mice, which have a normal component of NK cells, are incapable of rejecting the P815 mastocytoma tumor. We established a model where monoclonal CD8 T cell reactivity was restricted to the tumor antigen (Ag) P1A expressed on the P815 mastocytoma. Reconstitution of the RAG-deficient mice with these (TCRP1A) T cells conferred resistance to tumor growth selectively for the P1A-expressing, but not for a P1A-negative variant of P815. Nevertheless, TCRP1A CD8 T cells were efficient and necessary to promote the NK cell dependent rejection of P1A-negative tumors when both P1A-positive and -negative tumors were present at the same site. Gene expression profiling in NK cells infiltrating the P1A-positive, as compared to the P1A-negative tumor, in mice transferred with TCRP1A CD8 T cells established their acquisition of an activated effector phenotype. Help from CD8 T cells was provided locally, as it did not induce activation of NK cells present in a P1A-negative variant at a distant site, nor the rejection of this variant. These results illustrate a mechanism by which, in the face of immunoselection / editing, the synergy between specific anti-tumor Ag T cells and NK cells can contribute to the elimination of tumor cells whether or not they express the tumor Ag. This mechanism appears ineffective, however, once tumor variants lacking the tumor Ag are separated from the wild-type tumor, as would be the case in tumor metastasis.

2007-12-01 | E-MEXP-1285 | biostudies-arrayexpress

Molecular bases for tumor induced exhaustion in CD8 T cells

Project description:The immune system can recognize and respond to tumors. However there are some conditions in which the genetic instability and heterogeneity of tumor cells leads to the development of variants that can escape the immune system. T cells have infiltrated inside many tumors (Tumor Infiltrating Lymphocytes or TILs), but generally these TILs have lost their functional capacity and are unable to eliminate tumor cells. We developed a model of autochthonous melanoma in mice that recapitulates some aspects of inflammatory melanoma in humans. These include a systemic Th2/Th17-oriented chronic inflammation, recruitment of immunosuppressive myeloid cells and acquisition by TILs of an M-bM-^@M-^\exhaustedM-bM-^@M-^] phenotype characterized by expression of receptors for multiple inhibitory molecules. To address the molecular bases for the M-bM-^@M-^\exhaustedM-bM-^@M-^] TILs phenotype, we performed transcriptomic analyses on sorted CD8 or T cells from the induced melanomas. These transcriptomes were compared to those of naM-CM-/ve CD8 T cells and of CD8 T cells immunized with a virus. 10 samples, 3 replicates for controls (untreated and infected with AdP1A), 4 replicates for TILs CD8 from melanoma

2013-12-31 | E-GEOD-42824 | biostudies-arrayexpress

Gene expression in NKR-P1B+ versus Ly49s3+ rat NK cells

Project description:Two major subsets of rat natural killer (NK) cells can be distinguished based on their expression of either the Ly49s3 or the NKR-P1B lectin-like receptor. Ly49s3+ NK cells, but not NKR-P1B+ NK cells, express a wide range of Ly49 receptors. Here, we performed a global gene expression profiling of sorted, single-positive NKR-P1B+ or Ly49s3+ splenic NK cells in order to get an overview of differences in expressed genes between the NKR-P1B+ and Ly49s3+ NK cell subsets. NKR-P1B or Ly49s3 single-positive NK cells were sorted by flow cytometry from NK-enriched mononuclear cells from rat spleens. 9 rats of the PVG.7b strain aged 8-12 weeks were used. Total RNA was harvested by Tri Reagent extraction, and subjected to microarray analysis (Affymetrix Rat Genome 230 2.0 Array).

2010-03-18 | E-GEOD-20935 | biostudies-arrayexpress

Tumor-specific CD4+ T cells eradicate established melanoma

Project description:Adoptive transfer of CD4+ T cells (TRP-1 CD4+ T cells) specific for tyrp-1 (tyrosinase-related protein 1) eradicate established tumors (melanoma) in lymphopenic RAG-/- hosts. In vitro differentiated CD8+ T cells have been the primary focus of immunotherapy of cancer with little focus on CD4+ T cells. Immunotherapy involving in vitro differentiated T cells given after lymphodepleting regimens significantly augments antitumor immunity in animals and human patients with cancer. However, the mechanisms by which lymphopenia augments adoptive cell therapy and the means of properly differentiating T cells in vitro are still emerging. We demonstrate that naïve tumor/self-specific CD4+ T cells naturally differentiated into T helper type 1 (Th1) cytotoxic T cells in vivo and caused the regression of established tumors and depigmentation in lymphopenic hosts. Therapy was independent of vaccination, exogenous cytokine support, CD8+-, B-, NK and NK-T cells. Proper activation of CD4+ T cells in vivo was important for tumor clearance as naïve tumor-specific CD4+ T cells could not completely treat tumor in lymphopenic common gamma chain-deficient (gc-/-) hosts. gc signaling in the tumor-bearing host was important for survival and proper differentiation of adoptively transferred tumor-specific CD4+ T cells. Thus, these data provide a platform for designing immunotherapies that incorporate tumor/self-reactive CD4+ T cells. 2 x 10^5 sorted TRP-1 CD4+ T cells were transferred i.v. into tumor-bearing RAG-/- hosts on day 7-10 after tumor challenge, and ~1 x 10^6 CD4+ T cells were isolated 1 week later by flow sorting from pooled lymph nodes (LN) or spleens. Dye-swaps were performed.

2010-01-14 | E-GEOD-19904 | biostudies-arrayexpress

Proteomic analysis of NK cell-derived extracellular vesicles.

Project description:Natural killer (NK) cells contribute to immunosurveillance and first-line defense in the control of tumor growth and metastasis diffusion. NKEVs are constitutively secreted, are biologically active, reflect the protein and genetic repertoire of their originating cells and exert anti-tumor activity in vitro and in vivo. NKEVs from tumor-conditioned NK cells interact with naïve NK cells promoting their cytotoxic activity. In cancer NK cells exhibit profound defects in degranulation ability, a status probably reflected by their NKEVs. Hence, NKEVs could contribute to improve cancer therapy by interacting with tumor and/or immune cells at the same time sensing the actual NK cell status in cancer patients. Here we investigated the role of NKEVs in stimulating the immune system and developed an immune enzymatic test (NKExoELISA) to sense the systemic NK cell status by measuring plasma NK-derived exosomes through combined capture of exosomes, expressing typical EV (tsg101) and NK cell (CD56) markers. We analyzed by LC-MS/MS the protein content from NKEVs evaluating proteins differentially expressed in exosomes (NKExo), vescicles (NKMV) and total cell extract (Tot extr) from parental NK cells. Proteomic data confirmed the presence of many EV markers and detected several proteins involved in immune response, cell adhesion and complement biological processes.

2020-04-03 | PXD014894 | Pride

Activin A and NK cell function

Project description:Natural killer (NK) cells are innate lymphocytes that play a major role in immunosurveillance against tumor initiation and metastasis spread. Signals and checkpoints that regulate NK cell fitness and function in the tumor microenvironment are not well defined. Transforming grow factor (TGF)- is a recognized suppressor of NK cells that inhibits IL-15 dependent signaling events and induces cellular transdifferentiation, however the role of other SMAD signaling pathways in NK cells is unknown. We used a global, label-free proteomics approach to compare the protein expression profiles of NK cells in the presence of TGF-b or activin-A.

2020-04-06 | PXD011672 | Pride

Transcription profiling of mouse OTI CD8 T cells transferred to irradiated syngeneic hosts

Project description:A time course of OTI CD8 T cells transferred to irradiated syngeneic hosts (or unirradiated hosts as control).

2007-11-02 | E-GEOD-1921 | biostudies-arrayexpress

Gene expression anaylsis of tumor stimulated human NK cells

Project description:Genome wide expression profiling of human NK cells stimulated with K562 erythroleukemic tumor cells after four hours of NK-tumor co-culture. Responding NK cells were compared to non-responding NK cells, delineated by display of CD107 on the NK cell surface following cytotoxic granule release. We hypothesized that tumor responses would initiate rapid changes in gene expression in the NK cell that would identify new features of the anti-tumor response of NK cells. Results identify NK cell activation responses and induction of TNF superfamily molecules with immunoregulatory activity. Human peripheral blood NK cells were co-cultured with tumor target cell line K562 for 4 hours with GolgiStop (brefeldin) then stained for granule exocytosis marker CD107a / CD107b, and NK cell markers then FACS sorted for responding NK cells (CD107+) and non-responding NK cells (CD107-). Pooled donor sample comprised NK cells from 3 individuals.

2014-03-18 | E-GEOD-55977 | biostudies-arrayexpress

IGR_MESSAI_CCRCC_HIF2

Project description:The aim of the present study was to investigate the potential role of HIF-2a in regulating RCC susceptibility to natural killer (NK) cell-mediated killing. We demonstrated that the RCC cell line 786-O with mutated VHL was resistant to NK-mediated lysis as compared to the VHL corrected cell line (WT7). This resistance was independent of immunological synapse formation and NK ligand expression but was found to be reliant on HIF-2a stabilization in 786-0 cells. In order to elucidate the molecular basis of HIF-2a-induced impairment of NK-mediated killing, we performed global gene analysis using DNA microarray. Three candidate genes (ANGPTL4, ADM and ITPR1) were selected on the basis of their fold change and their involvement in cell death and survival. SiRNA targeting of these genes revealed that only ITPR1 silencing resulted in a significant increase of 786-O susceptibility to NK-mediated lysis. Using gene silencing of HIF2-a and chromatin immunoprecipitation assay, we showed for the first time that ITPR1 was a direct novel target of HIF2-a. Notably, a strong and significant correlation was found between ITPR1and HIF2-a staining in RCC patients. Transcriptional profiling of ITPR1silenced RCC cells indicated that several important genes involved in cell survival and apoptosis were differentially regulated. Using ITPR1 silenced Renca cells, we further found that ITPR1 was involved in the control of tumor progression. Moreover ITPR1 targeting combined with NK depletion significantly enhanced tumor growth as compared to ITPR1 knocked down Renca xenografts. Our data provide insights into the link between HIF-2a, ITPR1-related pathway and natural immunity and suggest a role of the HIF2/ITPR1 axis in regulating RCC cell survival.

2014-01-11 | E-MTAB-1802 | biostudies-arrayexpress

Active STAT5 in CD8 T cells imprints a T-Bet-dependent Tc-1 program with repressed IL-6/ TGFb1 signaling leading to enhanced anti-tumor responses

Project description:CD8 T cells (TCs) expressing active STAT5 (STAT5CA) transcription factors were found to be superior to un-manipulated counterparts in their long-term persistence, capacity to infiltrate a tumor, thrive in its microenvironment and induce its regression. STAT5CA induced sustained expression of genes controlling tissue homing, cytolytic granule composition, Tc-1-associated effector molecules (GranzymeB+/IFNg+/TNFa+/CCL3+ but IL-2-) and potential for secondary responses. Sustained expression of both T-Bet and Eomes transcription factors was correlated with STAT5 binding to their corresponding genes by ChIPSeq analyses. Additionally, STAT5CA-expressing CD8 TCs demonstrated reduced IL-6R/TGFbRII expression and dampened IL-6 and TGFb1 signaling. Altogether, concerted STAT5/T-Bet/Eomes regulation controls homing, recall responses and resistance to Tc-17 polarization in CD8 TCs. TCRP1A CD8 T lymphocytes were activated by their cognate P1A Ag. After 24h, an active form of Stat5 (STAT5CA) was introduced in activated cells. Culture was continued for another 48h to induce their differentiation in effector T cells. These activated T cells were injected in congeneic hosts and recovered 70 days later from hosts' spleen and lymph nodes: TCRP1A eTC-STAT5CA.

2013-09-13 | E-GEOD-41818 | biostudies-arrayexpress

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