scholarly journals p50 suppresses cytotoxic T lymphocyte effector function to regulate tumor immune escape and response to immunotherapy

2020 ◽  
Vol 8 (2) ◽  
pp. e001365 ◽  
Author(s):  
Chunwan Lu ◽  
John D Klement ◽  
Alyssa D Smith ◽  
Dafeng Yang ◽  
Jennifer L Waller ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Immune Cells ◽  
Expression Profiling ◽  
Immune Escape ◽  
Human Colon ◽  
Tumor Immune Escape ◽  
Human Colorectal Carcinoma

BackgroundNF-κB is a key link between inflammation and cancer. Previous studies of NF-κB have largely focused on tumor cells, and the intrinsic function of NF-κB in T cells in tumor development and response to immunotherapy is largely unknown. We aimed at testing the hypothesis that NF-κB1 (p50) activation in T cells underlies human colon cancer immune escape and human cancer non-response to anti-PD-1 immunotherapy.MethodsWe screened NF-κB activation in human colon carcinoma and used mouse models to determine p50 function in tumor cells and immune cells. RNA-Seq was used to identify p50 target genes. p50 binding to target gene promoters were determined by electrophoresis mobility shift assay and chromatin immunoprecipitation. A p50 activation score was generated from gene expression profiling and used to link p50 activation to T-cell activation and function pre-nivolumab and post-nivolumab immunotherapy in human patients with cancer.Resultsp50 is the dominant form of NF-κB that is highly activated in immune cells in the human colorectal carcinoma microenvironment and neighboring non-neoplastic colon epithelial cells. Tumor cell intrinsic p50 signaling and T-cell intrinsic p50 signaling exert opposing functions in tumor growth control in vivo. Deleting Nfkb1 in tumor cells increased whereas in T cells decreased tumor growth in preclinical mouse models. Gene expression profiling identified Gzmb as a p50 target in T cells. p50 binds directly to a previously uncharacterized κB sequence at the Gzmb promoter in T cells, resulting in repression of Gzmb expression in tumor-infiltrating cytotoxic T lymphocytes (CTLs) to induce a dysfunctional CTL phenotype to promote tumor immune escape. p50 activation is inversely correlated with both GZMB expression and T-cell tumor infiltration in human colorectal carcinoma. Furthermore, nivolumab immunotherapy decreased p50 activation and increased GZMB expression in human patients with melanoma.ConclusionsInflammation activates p50 that binds to the Gzmb promoter to repress granzyme B expression in T cells, resulting in CTL dysfunction to confer tumor immune escape and decreased response to anti-PD-1 immunotherapy.

Differential Gene Expression Profile Identifies Defects and Abnormalities In Infiltrating T Cells In Patients with Follicular Lymphoma at Diagnosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 141-141
Author(s):  
Shahryar Kiaii ◽  
Andrew J. Clear ◽  
Alan G. Ramsay ◽  
Ajanthah Sangaralingam ◽  
John G. Gribben
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Follicular Lymphoma ◽  
Immune Cells ◽  
Peripheral Blood ◽  
Expression Profiling ◽  
Molecular Mechanisms ◽  
Clinical Course ◽  
Cd8 Cells

Abstract Abstract 141 Patients with follicular lymphoma (FL) have an extremely variable clinical course. Although clinical parameters can be used to define prognostic subgroups, there is a need to identify robust biomarkers that not only aid in prognosis, but also help define the underlying pathophysiology of the disease. Previous gene expression profiling studies demonstrated that among the most important prognostic markers were the molecular features of nonmalignant tumor-infiltrating immune cells present in the tumor at diagnosis (Sandeep et al. NEJM 2004). To investigate the molecular mechanisms whereby T cells are altered in the FL microenvironment we studied highly purified, sorted infiltrating CD4 and CD8 T cells from previously cryopreserved single cell suspensions of lymph node (LN) biopsies at the time of diagnosis in patients with FL (n=12) and compared them to those isolated from reactive tonsils (n=7) as well as from peripheral blood (PB) (n=10) of age matched healthy individuals. These tumor infiltrating T cells (TILs) have impaired proliferative and cytotoxic responses and impaired capacity to form immunologic synapses with antigen presenting cells. Co-culture of FL cells in contact with healthy allogeneic T cells induces similar T cell functional defects, demonstrating that it is the FL cells that drive the altered T cell function. To investigate the molecular mechanisms for this, we performed global gene expression profiling using Affymetrix U133Plus2 chips of highly purified (>95% purity) CD4 and CD8 cells. For both CD4 and CD8 cells, unsupervised analyses distinguished healthy and FL T cell subsets. Using a fold change cut off > 2 and false discovery rate of 5%, 280 genes were differentially expressed for CD4 and 717 genes for CD8, with109 genes overlapped for both subsets. The gene array data was validated for RNA using Real-Time Quantitative-PCR and for protein by flow cytometry and immunohistochemistry. Pathway analysis indicated disruption in multiple pathways including cytokine signaling, T cell differentiation, cell proliferation and, actin-based motility/cytoskeleton formation. In both CD4 and CD8, among the most downregulated genes in FL TILs were ACTN1 and IL17A, and the most upregulated genes were PMCH and ETV1. Using Tissue Microarray (TMA) we demonstrate that the intensity of expression in TILs in FL was significantly higher for PMCH (p<0.0001) and ETV1 (p<0.0001) than that of reactive tissue. PMCH is not expressed in PB T cells, but its expression is highly induced when healthy peripheral blood T cells are cultured, either in cell contact or in transwell culture, with FL cells. Surprisingly, co-culture of healthy T cells with normal B cells also induced its expression. Taken together, these data indicate that TILs in patients with FL are abnormal in terms of their function and gene expression profile, in keeping with our hypothesis that FL induces changes in immune cells in the tumor microenvironment. We are currently further characterizing the functional consequences of the identified changes in the gene expression in tumor-infiltrating T cells of patients with FL in the biology and progression of disease. As non-malignant immune cells have a major role in the clinical course of patients with FL, understanding the nature and impact of the abnormalities induced in infiltrating T cell's in these patients is vital before any immunotherapeutic strategies can be implemented to attempt to alter the immune microenvironment in FL. Disclosures: Gribben: Roche: Consultancy; Celgene: Consultancy; GSK: Honoraria; Napp: Honoraria.

scholarly journals 793 Targeting engineered interleukin-2 (IL-2) to antigen specific T cells via novel biologic platforms

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A828-A828
Author(s):  
Raymond Moniz ◽  
Ahmet Vakkasoglu ◽  
Zohra Merazga ◽  
Tina Daigneault ◽  
Steve Quayle ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Immune Cells ◽  
Interleukin 2 ◽  
Binding Pocket ◽  
Tumor Escape ◽  
Antigenic Peptides ◽  
T Cell Epitopes ◽  
Cell Repertoire

BackgroundA key challenge with IL-2 immunotherapy for cancers is lack of selectivity for anti-tumor immune cells and safety liabilities related to indiscriminate activation of immune cells. The CUE-100 series of Immuno-STATs (ISTs) are designed to selectively activate tumor-specific T cells while avoiding IL-2 toxicities due to systemic activation. CUE-100 series ISTs are rationally engineered Fc fusion proteins comprised of bivalent tumor-peptide-HLA (pHLA) complexes and four affinity-attenuated IL-2 molecules to preferentially engage and activate tumor-specific T cells directly in the patient. Emerging clinical data from our lead candidate CUE-101, which targets HPV-specific T cells in 2L+ R/M HNSCCC, provides PoC for the approach and builds confidence for broad applications in numerous cancers. Building on the CUE-100 series framework, our Neo-STAT (NST) platform contains HLA molecules manufactured with an “empty” peptide-binding pocket, into which diverse tumor-peptides can be chemically conjugated, hence addressing tumor heterogeneity in a cost- and time-efficient manner. Our RDI-STAT (Re-Directed Immuno-STAT) platform further expands the CUE-100 series by redirecting the pre-existing protective viral-specific T cell repertoire to target tumor cells via scFv moieties. RDI-STATs are designed to circumvent potential tumor escape mechanisms linked to HLA loss or defects in antigen-presenting pathways. We present here preclinical data supporting the mechanism of action of these platforms to enhance anti-tumor immune responses.MethodsNSTs were engineered with “empty” HLA-A*0201, into which relevant antigenic peptides were conjugated, and assessed for capacity to expand T cells. RDI-STATs were engineered with TAA-specific scFv and viral-specific pHLA complexes, and assessed for their capacity to induce redirected killing of tumor cells while avoiding systemic activation of all T cells.ResultsThe NST platform demonstrated that different T cell epitopes can be efficiently conjugated into the HLA-binding pocket, and that these molecules activate and expand antigen specific T cells in vitro. RDI-STATs were able to expand anti-viral T cell repertoires and drive anti-viral T cell redirected killing of TAA-expressing cells. In contrast to pan anti-CD3 bispecific molecules, RDI-STATs demonstrated significantly lower induction of pro-inflammatory cytokines.ConclusionsThe IST, NST, and RDI-STAT platforms provide novel opportunities for selective targeting of IL-2 to tumor-relevant T cells while avoiding global immune activation and cytokine release. The scalability and versatility of NSTs highlight the potential to target multiple TAA T cell responses, while RDI-STATs highlight a novel means to harness antiviral immunity against cancer, especially in cases where the tumor may escape immune detection due to loss of HLA.

scholarly journals Arming T Cells with a gp100-Specific TCR and a CSPG4-Specific CAR Using Combined DNA- and RNA-Based Receptor Transfer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 696 ◽  
Author(s):  
Bianca Simon ◽  
Dennis C. Harrer ◽  
Beatrice Schuler-Thurner ◽  
Gerold Schuler ◽  
Ugur Uslu
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Immune Escape ◽  
Cell Receptor ◽  
Adoptive T Cell Therapy ◽  
T Cell Therapy ◽  
Dna And Rna ◽  
Antigen Loss ◽  
Antigen Presenting

Tumor cells can develop immune escape mechanisms to bypass T cell recognition, e.g., antigen loss or downregulation of the antigen presenting machinery, which represents a major challenge in adoptive T cell therapy. To counteract these mechanisms, we transferred not only one, but two receptors into the same T cell to generate T cells expressing two additional receptors (TETARs). We generated these TETARs by lentiviral transduction of a gp100-specific T cell receptor (TCR) and subsequent electroporation of mRNA encoding a second-generation CSPG4-specific chimeric antigen receptor (CAR). Following pilot experiments to optimize the combined DNA- and RNA-based receptor transfer, the functionality of TETARs was compared to T cells either transfected with the TCR only or the CAR only. After transfection, TETARs clearly expressed both introduced receptors on their cell surface. When stimulated with tumor cells expressing either one of the antigens or both, TETARs were able to secrete cytokines and showed cytotoxicity. The confirmation that two antigen-specific receptors can be functionally combined using two different methods to introduce each receptor into the same T cell opens new possibilities and opportunities in cancer immunotherapy. For further evaluation, the use of these TETARs in appropriate animal models will be the next step towards a potential clinical use in cancer patients.

scholarly journals Salmonella Breaks Tumor Immune Tolerance by Downregulating Tumor Programmed Death-Ligand 1 Expression

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 57
Author(s):  
Man-Chin Chen ◽  
Christian Ronquillo Pangilinan ◽  
Che-Hsin Lee
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Cell Infiltration ◽  
Tumor Immune Escape ◽  
Programmed Death Ligand 1 ◽  
T Cell Infiltration ◽  
Programmed Death

Immunotherapy is becoming a popular treatment modality in combat against cancer, one of the world’s leading health problems. While tumor cells influence host immunity via expressing immune inhibitory signaling proteins, some bacteria possess immunomodulatory activities that counter the symptoms of tumors. The accumulation of Salmonella in tumor sites influences tumor protein expression, resulting in T cell infiltration. However, the molecular mechanism by which Salmonella activates T cells remains elusive. Many tumors have been reported to have high expressions of programmed death-ligand 1 (PD-L1), which is an important immune checkpoint molecule involved in tumor immune escape. In this study, Salmonella reduced the expression of PD-L1 in tumor cells. The expression levels of phospho-protein kinase B (P-AKT), phospho-mammalian targets of rapamycin (P-mTOR), and the phospho-p70 ribosomal s6 kinase (P-p70s6K) pathway were revealed to be involved in the Salmonella-mediated downregulation of PD-L1. In a tumor-T cell coculture system, Salmonella increased T cell number and reduced T cell apoptosis. Systemic administration of Salmonella reduced the expressions of PD-L-1 in tumor-bearing mice. In addition, tumor growth was significantly inhibited along with an enhanced T cell infiltration following Salmonella treatment. These findings suggest that Salmonella acts upon the immune checkpoint, primarily PD-L1, to incapacitate protumor effects and thereby inhibit tumor growth.

scholarly journals Tumor Antigen-Dependent and Tumor Antigen-Independent Activation of Antitumor Activity in T Cells by a Bispecific Antibody-Modified Tumor Vaccine

2010 ◽  
Vol 2010 ◽  
pp. 1-12 ◽  
Author(s):  
Philippe Fournier ◽  
Volker Schirrmacher
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Cancer Patients ◽  
Tumor Antigen ◽  
Immune Escape ◽  
Tumor Vaccine ◽  
Cell Repertoire ◽  
Tumor Immune Escape

New approaches of therapeutic cancer vaccination are needed to improve the antitumor activity of T cells from cancer patients. We studied over the last years the activation of human T cells for tumor attack. To this end, we combined the personalized therapeutic tumor vaccine ATV-NDV—which is obtained by isolation, shortin vitroculture, irradiation, and infection of patient's tumor cells by Newcastle Disease Virus (NDV)—with bispecific antibodies (bsAbs) binding to this vaccine and introducing anti-CD3 (signal 1) and anti-CD28 (signal 2) antibody activities. This vaccine called ATV-NDV/bsAb showed the unique ability to reactivate a preexisting potentially anergized antitumor memory T cell repertoire. But it also activated naive T cells to have antitumor propertiesin vitroandin vivo. This innovative concept of direct activation of cancer patients' T cells via cognate and noncognate interactions provides potential for inducing strong antitumor activities aiming at overriding T cell anergy and tumor immune escape mechanisms.

scholarly journals High IKZF2 Expression in Malignant T cells Promotes Disease Progression in Cutaneous T cell Lymphoma

2021 ◽  
Author(s):  
Bufang Xu ◽  
Fengjie Liu ◽  
Yumei Gao ◽  
Jingru Sun ◽  
Yingyi Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Disease Progression ◽  
Immune Escape ◽  
Cell Lymphoma ◽  
Malignant Cell ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Tumor Immune Escape ◽  
Malignant T Cells

Cutaneous T cell lymphoma is a generally indolent disease derived from skin-homing mature T cells. However, in advanced stages, CTCL may manifest as aggressive clinical behavior and lead to a poor prognosis. The mechanism of disease progression in CTCL remains unknown. Here, with a large clinical cohort, we identified that IKZF2, an essential transcription factor during T cell development and differentiation, showed stage-dependent overexpression in the malignant T cells in MF lesions. IKZF2 is specifically over-expressed in advanced-stage MF lesions, correlates with poor patient prognosis. Mechanistically, IKZF2 overexpression promotes CTCL progression via inhibiting malignant cell apoptosis and may contribute to tumor immune escape by downregulating MHC-II molecules and up-regulating the production of anti-inflammatory cytokine IL-10 by malignant T cells. These results demonstrate the important role of IKZF2 in high-risk CTCL and pave the way for future targeted therapy.

scholarly journals B7-H5 blockade enhances CD8+ T-cell-mediated antitumor immunity in colorectal cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jiayu Wang ◽  
Hongya Wu ◽  
Yanjun Chen ◽  
Jinghan Zhu ◽  
Linqing Sun ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Inverse Correlation ◽  
Immune Checkpoint Blockade ◽  
Cell Infiltration ◽  
Tumor Immune Escape ◽  
T Cell Infiltration

AbstractNegative immune checkpoint blockade immunotherapy has shown potential for multiple malignancies including colorectal cancer (CRC). B7-H5, a novel negative immune checkpoint regulator, is highly expressed in tumor tissues and promotes tumor immune escape. However, the clinical significance of B7-H5 expression in CRC and the role of B7-H5 in the tumor microenvironment (TME) has not been fully clarified. In this study, we observed that high B7-H5 expression in CRC tissues was significantly correlated with the lymph node involvement, AJCC stage, and survival of CRC patients. A significant inverse correlation was also observed between B7-H5 expression and CD8+ T-cell infiltration in CRC tissues. Kaplan−Meier analysis showed that patients with high B7-H5 expression and low CD8+ T-cell infiltration had the worst prognosis in our cohort of CRC patients. Remarkably, both high B7-H5 expression and low CD8+ T infiltration were risk factors for overall survival. Additionally, B7-H5 blockade using a B7-H5 monoclonal antibody (B7-H5 mAb) effectively suppressed the growth of MC38 colon cancer tumors by enhancing the infiltration and Granzyme B production of CD8+ T cells. Importantly, the depletion of CD8+ T cells obviously abolished the antitumor effect of B7-H5 blockade in the MC38 tumors. In sum, our findings suggest that B7-H5 may be a valuably prognostic marker for CRC and a potential target for CRC immunotherapy.

scholarly journals Inhibition of Arginase 1 Liberates Potent T Cell Immunostimulatory Activity of Human Neutrophil Granulocytes

2021 ◽  
Vol 11 ◽  
Author(s):  
Verena Vonwirth ◽  
Yagmur Bülbül ◽  
Anke Werner ◽  
Hakim Echchannaoui ◽  
Johannes Windschmitt ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Immune Escape ◽  
Suppressor Cells ◽  
T Cell Proliferation ◽  
Neutrophil Granulocytes ◽  
Tumor Immune Escape ◽  
Cell Functions ◽  
Arginase 1

Myeloid cell arginase-mediated arginine depletion with consecutive inhibition of T cell functions is a key component of tumor immune escape. Both, granulocytic myeloid-derived suppressor cells (G-MDSC) and conventional mature human polymorphonuclear neutrophil granulocytes (PMN) express high levels of arginase 1 and can act as suppressor cells of adaptive anti-cancer immunity. Here we demonstrate that pharmacological inhibition of PMN-derived arginase 1 not only prevents the suppression of T cell functions but rather leads to a strong hyperactivation of T cells. Human PMN were incubated in cell culture medium in the absence or presence of an arginase inhibitor. T cells from healthy donors were then activated either polyclonally or in an antigen-specific manner in the supernatants of the PMN cultures at different PMN-T cell ratios. T cell proliferation was completely suppressed in these supernatants in the absence of an arginase inhibitor. Arginase inhibition led to a strong hyperinduction of T cell proliferation, which exceeded control activation conditions up to 25-fold. The hyperinduction was correlated with higher PMN-T cell ratios and was only apparent when PMN arginase activity was blocked sufficiently. The T cell stimulatory factor was liberated very early by PMN and was present in the &lt; 3 kDa fraction of the PMN supernatants. Increased T cell production of specific proinflammatory cytokines by PMN supernatant in the presence of arginase inhibitor was apparent. Upon arginase inhibition, downregulation of important T cell membrane activation and costimulation proteins was completely prevented or de novo induction accelerated. Antigen-specific T cell cytotoxicity against tumor cells was enhanced by PMN supernatant itself and could be further increased by PMN arginase blockade. Finally, we analyzed anergic T cells from multiple myeloma patients and noticed a complete reversal of anergy and the induction of strong proliferation upon T cell activation in PMN supernatants by arginase inhibition. In summary, we discovered a potent PMN-mediated hyperactivation of human T cells, which is apparent only when PMN arginase-mediated arginine depletion is concurrently inhibited. Our findings are clearly relevant for the analysis and prevention of human tumor immune escape in conjunction with the application of arginase inhibitors already being developed clinically.

scholarly journals Endogenous T cells prevent tumor immune escape following adoptive T cell therapy

2019 ◽  
Vol 129 (12) ◽  
pp. 5400-5410 ◽  
Author(s):  
Scott R. Walsh ◽  
Boris Simovic ◽  
Lan Chen ◽  
Donald Bastin ◽  
Andrew Nguyen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Immune Escape ◽  
Adoptive T Cell Therapy ◽  
Tumor Immune Escape ◽  
T Cell Therapy

Gene Expression Profiling Identifies Oncogenic Molecular Pathways in T-Lymphoma Induction by SL3-3 Retrovirus Insertional Mutagenesis in Inbred NMRI Mice.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3010-3010
Author(s):  
Karen Dybkaer ◽  
Karina D. Sørensen ◽  
Jörg Schmidt ◽  
Francesco d’Amore ◽  
Finn S. Pedersen
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Murine Model ◽  
Expression Profiling ◽  
Insertional Mutagenesis ◽  
S Phase ◽  
Molecular Pathways ◽  
Integration Sites ◽  
Thymic Tumors

Abstract The non-oncogene bearing retrovirus SL3-3 murine leukemia virus (MLV) induces T-cell lymphomas with a remarkably consistent immunophenotype when injected into newborn inbred NMRI (NMRI-i) mice, making it, at present, the most homogeneous murine model of MLV induced T-lymphomas1. The oncogenic effects of SL3-3 are caused by proviral insertional mutagenesis of the host genome in or near genes of major importance for lymphoma/leukemia development. Determination of SL3-3 integration sites in the NMRI-i genome therefore provides an efficient whole genome screening method for identifying genes involved in murine and potentially also human T-cell lymphomagenic processes. Here, the impact of integration sites on latency, tumor immunophenotype, clonality, and gene expression profiles reflecting the affected molecular pathways involved in the carcinogenesis was analyzed. So far, a total of 22 retroviral integration sites were identified in thymic (14) and mesenteric lymph node tumors (8) from 10 SL3-3-infected NMRI-i mice. The majority of tumors were CD3+CD4+CD8− (2 thymus tumors were CD3+CD4+CD8+) and TCRβ clonality was demonstrated for all tumors by Southern analysis. Gene expression profiling using 60-mer oligonucleotide microarrays representing 10.000 different genes was performed in triplicate for 3 thymic tumors and a pool of 3 normal thymuses from uninfected NMRI-i mice. Unsupervised clustering of microarray data, two tailed student t-tests and significance analysis of microarrays (SAM) showed the T-cell thymus tumors to be more closely related to each other than to normal thymus tissues. The most common integration sites identified in thymic T-cell tumors were in or close to growth factor independence-1 (Gfi-1) and G1/S-specific cyclin D3 (CCND3), both involved in regulation of cell cycle progression in T cells. The two thymic tumors with CCND3 integrations contained homogenous CD3+CD4+CD8− single positive populations. The transcript levels determined by microarray of CCND3 were for both tumors 2-fold higher that what was observed in normal thymuses. D cyclins and cyclin-dependent kinases (CDKs) regulate the G1/S checkpoint and the interaction partner of CCND3, CDK6 was also up-regulated as compared to the normal thymus tissue. Similar expression features for CCND3 and CDK6 were observed for the third thymus tumor with, at present, unknown integration sites. Thus, for tumors with CCND3 integrations a promoted S phase entry leading irreversibly to cell division in the tumor cells can be suggested as further supported by the observation of decreased expression levels of the negative regulator of CDK2, p27KIP1 and increased expression of mRNA encoding G1 to S phase transition 2 (Gspt2). Notably, CCND3 is required for T-cell receptor (TCR) dependent expansion of transformed murine T-lymphocytes. Among other genes with a differential up-regulated expression in T-cell derived thymus tumors with SL3-3 integration in CCND3 were members of the TCR signaling cascade (Zap70, Fyn, VAV2, VAV3 and RAC2) and oncognes (Rel and Ect2) illustrating some of the transformation processes occurring in the malignant T-cells. In summary, this murine model of T-lymphomas enables a specific coupling of common integrations sites, like CCND3 or Gfi-1 to their effects on downstream molecular pathways.

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