CD28

Gene Summary

Gene:CD28; CD28 molecule
Aliases: Tp44
Location:2q33.2
Summary:The protein encoded by this gene is essential for T-cell proliferation and survival, cytokine production, and T-helper type-2 development. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jul 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:T-cell-specific surface glycoprotein CD28
Source:NCBIAccessed: 01 September, 2019

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Inducible T-Cell Co-Stimulator Protein
  • CD28 Antigens
  • CTLA-4 Antigen
  • Transfection
  • Genetic Predisposition
  • Flow Cytometry
  • fas Receptor
  • Single Nucleotide Polymorphism
  • Cytokines
  • Gene Expression
  • Immunotherapy, Adoptive
  • Lymphocyte Activation
  • Cultured Cells
  • Transcription
  • CD4-Positive T-Lymphocytes
  • Skin Cancer
  • Phenotype
  • Neoplasm Proteins
  • Case-Control Studies
  • CD Antigens
  • Genotype
  • T-Lymphocytes, Cytotoxic
  • Genetic Vectors
  • Monoclonal Antibodies
  • Breast Cancer
  • Gene Expression Profiling
  • Xenograft Models
  • Telomerase
  • Cancer Gene Expression Regulation
  • T-Lymphocytes
  • CD8-Positive T-Lymphocytes
  • Cell Proliferation
  • Risk Factors
  • PubMed
  • T-Cell Antigen Receptors
  • Chromosome 2
  • Immunophenotyping
  • Cytotoxicity, Immunologic
  • CD3 Complex
  • Th2 Cells
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CD28 (cancer-related)

Xiao Y, Li H, Yang LL, et al.
The Expression Patterns and Associated Clinical Parameters of Human Endogenous Retrovirus-H Long Terminal Repeat-Associating Protein 2 and Transmembrane and Immunoglobulin Domain Containing 2 in Oral Squamous Cell Carcinoma.
Dis Markers. 2019; 2019:5421985 [PubMed] Free Access to Full Article Related Publications
Human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) and transmembrane and immunoglobulin domain containing 2 (TMIGD2) are new immune checkpoint molecules of the B7:CD28 family; however, little research has been performed on these immune checkpoint molecules. In this study, we used oral squamous cells carcinoma (OSCC) tissue microarrays and immunohistochemistry methods to investigate the expression patterns of HHLA2 and TMIGD2 in OSCC. After comparing the HHLA2 and TMIGD2 expression levels in OSCC, dysplasia, and mucosa, we found increased HHLA2 expression in OSCC and dysplasia, while the TMIGD2 expression was decreased in OSCC and dysplasia. Using the Kaplan-Meier method and log-rank test, we found that higher HHLA2 or TMIGD2 expression levels in OSCC indicate poor prognosis. Furthermore, two-tailed Pearson's statistical analysis revealed that the HHLA2 expression levels in OSCC, dysplasia, and mucosa were positively correlated with the T cell immunoglobulin and mucin-domain containing-3 (TIM3), lymphocyte-activation gene 3 (LAG3), B7 homolog 3 protein (B7-H3), B7 homolog 4 protein (B7H4), and V-domain Ig suppressor of T cell activation (VISTA) levels, while the TMIGD2 expression levels in OSCC, dysplasia, and mucosa were inversely correlated with the TIM3, LAG3, and B7H3 levels. Our current study demonstrates that HHLA2 may serve as an immune target for OSCC therapy and that the TMIGD2 expression level in OSCC could forecast patient prognosis.

Zeng Y, Lai N
Association Between the CD28 c.17 +3 T>C Polymorphism (rs3116496) and Cancer Risk: An Updated Meta-Analysis.
Med Sci Monit. 2019; 25:1917-1927 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Numerous studies have been conducted on whether CD28 rs3116496 polymorphism affected cancer susceptibility, and these findings have been controversial. Thus, the purpose of this study was to assess the relationship between rs3116496 and susceptibility to cancer. MATERIAL AND METHODS The research published as of October 25, 2018 were comprehensively searched in PubMed, Embase, Cochrane Library and Chinese Wanfang database, CNKI, CBM. Statistical calculations performed using Stata12.0. RESULTS Overall analyses found that rs3116496 was a risk factor for cancer (C versus T, OR=1.14, 95% CI: 1.01-1.29, PH=0.003), and the heterogeneity was moderate (I²=53.3%). In subgroup analysis results by cancer types, the analysis showed that rs3116496 was a risk factor for breast cancer and leukemia. In the subgroup analysis by ethnicity, rs3116496 was a risk factor for cancer in the Asian population. After PHWE<0.05 was deleted, the analysis showed that rs3116496 might be related to the increased risk of colorectal cancer. CONCLUSIONS Our meta-analysis confirmed that rs3116496 was significantly related to cancer risk, especially in an Asian population, and was strongly correlated with the increased risk of breast cancer, leukemia and colorectal cancer.

Chi VLD, Garaud S, De Silva P, et al.
Age-related changes in the BACH2 and PRDM1 genes in lymphocytes from healthy donors and chronic lymphocytic leukemia patients.
BMC Cancer. 2019; 19(1):81 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Age-related genetic changes in lymphocyte subsets are not currently well documented. BACH2 is a transcription factor that plays an important role in immune-mediated homeostasis by tightly regulating PRDM1 expression in both B-cells and T-cells. BACH2 gene expression is highly sensitive to DNA damage in aged mice. This concept led us to investigate the variation in BACH2 and also PRDM1 expression in major lymphocyte subsets with age.
METHODS: Lymphocyte subsets from 60 healthy donors, aged from 20 to 90 years, and 41 untreated chronic lymphocytic leukemia patients were studied. BACH2 and PRDM1 gene expression was analyzed by real-time quantitative PCR. BACH2 gene expression was correlated with its protein expression. Lymphocyte apoptosis was evaluated after intracellular oxidative stress-inducing etoposide treatment of T and B cells.
RESULTS: Our analysis shows BACH2 mRNA downregulation with age in healthy donor CD4+, CD8+ T-cells and CD19+ B-cells. Decreased BACH2 expression was also correlated with an age-related reduction in CD8 + CD28+ T-cells. We found a strong correlation between age-related BACH2 downregulation and decreased CD4+ T-cell and CD19+ B-cell apoptosis. PRDM1, as expected, was significantly upregulated in CD4+ T-cells, CD8+ T-cells and CD19+ B-cells, and inversely correlated with BACH2. A comparison of untreated chronic lymphocytic leukemia patients with age-matched healthy donors reveals that BACH2 mRNA expression was further reduced in CD4+ T-cells, CD8+ T-cells and leukemic-B cells. PRDM1 gene expression was consequently significantly upregulated in CD4+ and CD8+ T-cells in chronic lymphocytic leukemia patients but not in their leukemic B-cells.
CONCLUSION: Overall, our data suggest that BACH2 and PRDM1 genes are significantly correlated with age in human immune cells and may be involved in immunosenescence.

Iqbal J, Amador C, McKeithan TW, Chan WC
Molecular and Genomic Landscape of Peripheral T-Cell Lymphoma.
Cancer Treat Res. 2019; 176:31-68 [PubMed] Related Publications
Peripheral T-cell lymphoma (PTCL) is an uncommon group of lymphoma covering a diverse spectrum of entities. Little was known regarding the molecular and genomic landscapes of these diseases until recently but the knowledge is still quite spotty with many rarer types of PTCL remain largely unexplored. In this chapter, the recent findings from gene expression profiling (GEP) studies, including profiling data on microRNA, where available, will be presented with emphasis on the implication on molecular diagnosis, prognostication, and the identification of new entities (PTCL-GATA3 and PTCL-TBX21) in the PTCL-NOS group. Recent studies using next-generation sequencing have unraveled the mutational landscape in a number of PTCL entities leading to a marked improvement in the understanding of their pathogenesis and biology. While many mutations are shared among PTCL entities, the frequency varies and certain mutations are quite unique to a specific entity. For example, TET2 is often mutated but this is particularly frequent (70-80%) in angioimmunoblastic T-cell lymphoma (AITL) and IDH2 R172 mutations appear to be unique for AITL. In general, chromatin modifiers and molecular components in the CD28/T-cell receptor signaling pathways are frequently mutated. The major findings will be summarized in this chapter correlating with GEP data and clinical features where appropriate. The mutational landscape of cutaneous T-cell lymphoma, specifically on mycosis fungoides and Sezary syndrome, will also be discussed.

Morimoto Y, Kishida T, Kotani SI, et al.
Interferon-β signal may up-regulate PD-L1 expression through IRF9-dependent and independent pathways in lung cancer cells.
Biochem Biophys Res Commun. 2018; 507(1-4):330-336 [PubMed] Related Publications
The programmed death ligand-1 (PD-L1) (also called B7-H1 and CD274) belonging to the CD28 family of co-stimulatory molecules is ectopically expressed on the surface of various cancer cells. PD-L1 interacts with programmed death-1 (PD-1) on T cells to trigger an inhibitory signal that suppresses anti-tumor T cell responses as an important mechanism of tumor escape from anti-tumor immune response. Recent development of PD-1/PD-L1 blockades has provided novel immunotherapy strategies for cancers including non-small cell lung cancer (NSCLC). Although the therapy is quite effective for some patients with NSCLC, others are resistant to the treatment, so that regulatory mechanisms of PD-L1 in lung cancer cells need to be understood in detail. Here we analyzed effect of interferon-β (IFN-β) that can be produced in cancer microenvironment on PD-L1 expression in lung tumor cells. An addition of IFN-β elevated PD-L1 expression in mouse and human lung cancer cell lines in culture. This phenomenon was totally dependent on JAK signaling molecules, while IRF9 deficiency in murine lung cancer cells partially attenuated the IFN-β-induced increase in PD-L1. mTOR may not be significantly involved in the regulation of PD-L1, whereas PI3-K pathway played differential roles on PD-L1 mRNA and cell-surface PD-L1 expression, in the cells treated with IFN-β. These results strongly suggest that the type I IFN receptor signal elicits an increase in PD-L1 expression in lung cancer cells through IRF9-dependent and independent pathways.

Zhong Q, Zhu YM, Zheng LL, et al.
Chimeric Antigen Receptor-T Cells with 4-1BB Co-Stimulatory Domain Present a Superior Treatment Outcome than Those with CD28 Domain Based on Bioinformatics.
Acta Haematol. 2018; 140(3):131-140 [PubMed] Related Publications
BACKGROUND: The second-generation CD19-chimeric antigen receptor (CAR)-T co-stimulatory domain that is commonly used in clinical practice is CD28 or 4-1BB. Previous studies have shown that the persistence of CAR-T in the 4-1BB co-stimulatory domain appears to be longer.
METHODS: The expression profile data of GSE65856 were obtained from GEO database. After data preprocessing, the differentially expressed genes (DEGs) between the mock CAR versus CD19-28z CAR T cells and mock CAR versus CD19-BBz CAR T cells were identified using the limma package. Subsequently, functional enrichment analysis of DEGs was performed using the DAVID tool. Then, the protein-protein international (PPI) network of these DEGs was visualized by Cytoscape, and the miRNA-target gene-disease regulatory networks were predicted using Webgestal.
RESULTS: A total of 18 common DEGs, 6 CD19-28z specific DEGs and 206 CD19-BBz specific DEGs were identified. Among CD19-28z specific DEGs, down-regulated PAX5 might be an important node in the PPI network and could be targeted by miR-496. In CD19-BBz group, JUN was a hub node in the PPI network and involved in the regulations of miR520D - early growth response gene 3 (EGR3)-JUN and mi-R489-AT-rich interaction domain 5A (ARID5A)-JUN networks.
CONCLUSION: The 4-1BB co-stimulatory domain might play in important role in the treatment of CAR-T via miR-520D-EGR3-JUN and miR489-ARID5A-JUN regulation network, while CD28 had a negative effect on CAR-T treatment.

Zheng S, Luo X, Dong C, et al.
A B7-CD28 family based signature demonstrates significantly different prognoses and tumor immune landscapes in lung adenocarcinoma.
Int J Cancer. 2018; 143(10):2592-2601 [PubMed] Related Publications
B7 family ligands and CD28 family receptors have complicated interaction for modulating immune functions. They play a central role in response to immunotherapy and outcome of patients with lung adenocarcinoma (LUAD). Thus, we analyzed B7-CD28 family gene expression profiles in LUAD and generated a signature to predict prognosis and immune host status. B7-CD28 family gene expression profiles and clinical data of LUAD from The Cancer Genome Atlas (TCGA) were analyzed. In the training cohort, prognostic association was assessed and then a prognostic signature was built with stepwise multivariable Cox analysis. The signature was validated by Kaplan-Meier and multivariable Cox analysis in several published gene expression datasets and a Fudan University cohort. Expression of immune cell populations and other immunotherapy predictors was further investigated. In TCGA LUAD cohort, eight B7-CD28 family genes had prognostic association with p values <0.05. Stepwise regression generated a gene signature including two genes, CD28 and CD276. Signature high-risk cases had worse overall survival (OS) and disease-free survival (DFS) in three published gene expression datasets and a Fudan University validation cohort. The B7-CD28 family based signature also significantly stratified OS and DFS in important clinical subsets, including stage I-II and EGFR mutant subsets. Signature high- and low-risk tumor had significantly different expressions of PD-L1 and tumor infiltrating leukocytes. The B7-CD28 family based signature demonstrates significantly different prognoses and tumor immune landscapes in LUAD. Whether it could serve as potential biomarkers for immunotherapy needs further investigation.

Donner I, Katainen R, Kaasinen E, et al.
Candidate susceptibility variants in angioimmunoblastic T-cell lymphoma.
Fam Cancer. 2019; 18(1):113-119 [PubMed] Related Publications
Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma with a poor prognosis: the 5-year survival rate is approximately 30%. Somatic driver mutations have been found in TET2, IDH2, DNMT3A, RHOA, FYN, PLCG1, and CD28, whereas germline susceptibility to AITL has to our knowledge not been studied. The homogenous Finnish population is well suited for studies on genetic predisposition. Here, we performed an exome-wide rare variant analysis in 23 AITL patients. No germline mutations were found in the driver genes, implying that they are not frequently involved in genetic AITL predisposition. Potentially pathogenic variants present in at least two patients and showing significant (p < 0.01) enrichment in our sample set were found in ten genes: POLK, PRKCB, ZNF676, PRRC2B, PCDHGB6, GNL3L, TTC36, OTOG, OSGEPL1, and RASSF9. The most significantly enriched variants, causing p.Lys469Ter in a splice variant of POLK and p.Pro588His in PRKCB, are intriguing candidates as Polk deficient mice display a spontaneous mutator phenotype, whereas PRKCB was recently shown to be somatically mutated in 33% of another peripheral T-cell lymphoma, adult T-cell lymphoma. If validated, our findings would provide new insight into the pathogenesis of AITL, as well as tools for early detection in susceptible individuals.

Rolvering C, Zimmer AD, Ginolhac A, et al.
The PD-L1- and IL6-mediated dampening of the IL27/STAT1 anticancer responses are prevented by α-PD-L1 or α-IL6 antibodies.
J Leukoc Biol. 2018; 104(5):969-985 [PubMed] Related Publications
Interleukin-27 (IL27) is a type-I cytokine of the IL6/IL12 family and is predominantly secreted by activated macrophages and dendritic cells. We show that IL27 induces STAT factor phosphorylation in cancerous cell lines of different tissue origin. IL27 leads to STAT1 phosphorylation and recapitulates an IFN-γ-like response in the microarray analyses, with up-regulation of genes involved in antiviral defense, antigen presentation, and immune suppression. Like IFN-γ, IL27 leads to an up-regulation of TAP2 and MHC-I proteins, which mediate increased tumor immune clearance. However, both cytokines also upregulate proteins such as PD-L1 (CD274) and IDO-1, which are associated with immune escape of cancer. Interestingly, differential expression of these genes was observed within the different cell lines and when comparing IL27 to IFN-γ. In coculture experiments of hepatocellular carcinoma (HCC) cells with peripheral blood mononuclear cells, pre-treatment of the HCC cells with IL27 resulted in lowered IL2 production by anti-CD3/-CD28 activated T-lymphocytes. Addition of anti-PD-L1 antibody, however, restored IL2 secretion. The levels of other T

Stock S, Hoffmann JM, Schubert ML, et al.
Influence of Retronectin-Mediated T-Cell Activation on Expansion and Phenotype of CD19-Specific Chimeric Antigen Receptor T Cells.
Hum Gene Ther. 2018; 29(10):1167-1182 [PubMed] Related Publications
Enhanced in vivo expansion, long-term persistence of chimeric antigen receptor T (CART) cells, and efficient tumor eradication through these cells are linked to the proportion of less-differentiated cells in the CART cell product. Retronectin is well established as an adjuvant for improved retroviral transduction, while its property to enrich less-differentiated T cells is less known. In order to increase these subsets, this study investigated the effects of retronectin-mediated T-cell activation for CD19-specific CART cell production. Peripheral blood mononuclear cells of healthy donors and untreated chronic lymphocytic leukemia (CLL) patients without or with positive selection for CD3+ T cells were transduced with a CD19.CAR.CD28.CD137zeta third-generation retroviral vector. Activation of peripheral blood mononuclear cells was performed by CD3/CD28, CD3/CD28/retronectin, or CD3/retronectin. Interleukin-7 and -15 were supplemented to all cultures. Retronectin was used in all three activation protocols for retroviral transduction. Expansion was assessed by trypan blue staining. Viability, transduction efficiency, immune phenotype, and cytokine production were longitudinally analyzed by flow cytometry. Cytotoxic capacity of generated CART cells was evaluated using a classical chromium-51 release assay. Retronectin-mediated activation resulted in an enrichment of CD8+ cytotoxic CART cells and less-differentiated naïve-like T cells (CD45RA+CCR7+). Retronectin-activated CART cells showed increased cytotoxic activity. However, activation with retronectin decreased viability, expansion, transduction efficiency, and cytokine production, particularly of CLL patient-derived CART cells. Both retronectin-mediated activation protocols promoted a less-differentiated CART cell phenotype without comprising cytotoxic properties of healthy donor-derived CART cells. However, up-front retronectin resulted in reduced viability and expansion in CLL patients. This effect is probably attributed to the retronectin-mediated activation of B cells with prolonged CLL persistence. Consequently, CART cell expansion and generation failed. In summary, activation with retronectin should be performed with caution and may be limited to patients without a higher percentage of tumor cells in the peripheral blood.

Sahin A, Sanchez C, Bullain S, et al.
Development of third generation anti-EGFRvIII chimeric T cells and EGFRvIII-expressing artificial antigen presenting cells for adoptive cell therapy for glioma.
PLoS One. 2018; 13(7):e0199414 [PubMed] Free Access to Full Article Related Publications
Glioblastoma multiforme (GBM) is the most aggressive and deadly form of adult brain cancer. Despite of many attempts to identify potential therapies for this disease, including promising cancer immunotherapy approaches, it remains incurable. To address the need of improved persistence, expansion, and optimal antitumor activity of T-cells in the glioma milieu, we have developed an EGFRvIII-specific third generation (G3-EGFRvIII) chimeric antigen receptor (CAR) that expresses both co-stimulatory factors CD28 and OX40 (MR1-CD8TM-CD28-OX40-CD3ζ). To enhance ex vivo target specific activation and optimize T-cell culturing conditions, we generated artificial antigen presenting cell lines (aAPC) expressing the extracellular and transmembrane domain of EGFRvIII (EGFRVIIIΔ654) with costimulatory molecules including CD32, CD80 and 4-1BBL (EGFRVIIIΔ654 aAPC and CD32-80-137L-EGFRVIIIΔ654 aAPC). We demonstrate that the highest cell growth was achieved when G3-EGFRvIII CAR T-cells were cocultured with both co-stimulatory aAPCs and with exposure to EGFRvIII (CD32-80-137L-EGFRVIIIΔ654 aAPCs) in culturing periods of three to six weeks. G3-EGFRvIII CAR T-cells showed an increased level of IFN-γ when cocultured with CD32-80-137L-EGFRVIIIΔ654 aAPCs. Evaluation of G3-EGFRvIII CAR T-cells in an orthotropic human glioma xenograft model demonstrated a prolonged survival of G3-EGFRvIII CAR treated mice compared to control mice. Importantly, we observed survival of G3-EGFRvIII CAR T-cells within the tumor as long as 90 days after implantation in low-dose and single administration, accompanied by a marked tumor stroma demolition. These findings suggest that G3-EGFRvIII CAR cocultured with CD32-80-137L-EGFRVIIIΔ654 aAPCs warrants itself as a potential anti-tumor therapy strategy for glioblastoma.

Skerget M, Skopec B, Zadnik V, et al.
CD56 Expression Is an Important Prognostic Factor in Multiple Myeloma Even with Bortezomib Induction.
Acta Haematol. 2018; 139(4):228-234 [PubMed] Related Publications
OBJECTIVES: In this retrospective study, we evaluated the impact of CD56, CD117, and CD28 expression on clinical characteristics and survival in newly diagnosed myeloma patients treated with bortezomib-based induction therapy.
METHODS: We analyzed 110 myeloma patients. Immunophenotype was determined using panels consisting of CD19/CD38/CD45/CD56/CD138 and CD20, CD28, and CD117 were used additionally. All samples were tested for recurrent chromosomal aberrations.
RESULTS: CD56, CD117, and CD28 expression rates were 71, 6, and 68%, respectively. The lack of CD56 expression was associated with light chain myeloma. The lack of CD117 expression was associated with elevated creatinine levels (p = 0.037). We discovered the correlation between CD 28 expression and female gender. The median progression-free survival (PFS) for patients with revised International Staging System stage 2 disease with CD56 expression or the lack of CD56 expression was 20.5 vs. 13.8 months (p = 0.03). In patients undergoing autologous hematopoietic stem cell transplantation (aHSCT), we found no difference in PFS and overall survival regarding the CD56 expression. We found no impact of CD117 and CD28 expression on PFS in patients regarding aHSCT.
CONCLUSIONS: Induction treatment incorporating bortezomib diminishes the negative impact of the lack of CD117 expression and aberrancy of CD28 but does not overcome the negative impact of the lack of CD56 expression.

Straetemans T, Kierkels GJJ, Doorn R, et al.
GMP-Grade Manufacturing of T Cells Engineered to Express a Defined γδTCR.
Front Immunol. 2018; 9:1062 [PubMed] Free Access to Full Article Related Publications
γ9δ2T cells play a critical role in daily cancer immune surveillance by sensing cancer-mediated metabolic changes. However, a major limitation of the therapeutic application of γ9δ2T cells is their diversity and regulation through innate co-receptors. In order to overcome natural obstacles of γ9δ2T cells, we have developed the concept of T cells engineered to express a defined γδT cell receptor (TEGs). This next generation of chimeric antigen receptor engineered T (CAR-T) cells not only allows for targeting of hematological but also of solid tumors and, therefore, overcomes major limitations of many CAR-T and γδT cell strategies. Here, we report on the development of a robust manufacturing procedure of T cells engineered to express the high affinity Vγ9Vδ2T cell receptor (TCR) clone 5 (TEG001). We determined the best concentration of anti-CD3/CD28 activation and expansion beads, optimal virus titer, and cell density for retroviral transduction, and validated a Good Manufacturing Practice (GMP)-grade purification procedure by utilizing the CliniMACS system to deplete non- and poorly-engineered T cells. To the best of our knowledge, we have developed the very first GMP manufacturing procedure in which αβTCR depletion is used as a purification method, thereby delivering untouched clinical grade engineered immune cells. This enrichment method is applicable to any engineered T cell product with a reduced expression of endogenous αβTCRs. We report on release criteria and the stability of TEG001 drug substance and TEG001 drug product. The GMP-grade production procedure is now approved by Dutch authorities and allows TEG001 to be generated in cell numbers sufficient to treat patients within the approved clinical trial NTR6541. NTR6541 will investigate the safety and tolerability of TEG001 in patients with relapsed/refractory acute myeloid leukemia, high-risk myelodysplastic syndrome, and relapsed/refractory multiple myeloma.

Budna J, Kaczmarek M, Kolecka-Bednarczyk A, et al.
Enhanced Suppressive Activity of Regulatory T Cells in the Microenvironment of Malignant Pleural Effusions.
J Immunol Res. 2018; 2018:9876014 [PubMed] Free Access to Full Article Related Publications
Cancer metastatic spread to serous cavity causes malignant pleural effusions (MPEs), indicating dismal prognosis. Tumor microenvironment can implement suppressive activity on host immune responses. Thus, we investigated the prevalence of Tregs and the relationship between them and TGF-

Miyao K, Terakura S, Okuno S, et al.
Introduction of Genetically Modified CD3ζ Improves Proliferation and Persistence of Antigen-Specific CTLs.
Cancer Immunol Res. 2018; 6(6):733-744 [PubMed] Related Publications
The clinical efficacy of T-cell therapies based on T cells transduced with genes encoding tumor-specific T-cell receptors (TCR-T) is related to the

Karabon L, Markiewicz M, Chrobot K, et al.
The Influence of Genetic Variations in the
J Immunol Res. 2018; 2018:3826989 [PubMed] Free Access to Full Article Related Publications
CD86 molecule is the ligand for both costimulatory (CD28) and coinhibitory (CTLA-4) molecules, and it regulates immune response after allogeneic hematopoietic stem cell transplantation (alloHSCT). Therefore, we postulate that

Clauss J, Obenaus M, Miskey C, et al.
Efficient Non-Viral T-Cell Engineering by Sleeping Beauty Minicircles Diminishing DNA Toxicity and miRNAs Silencing the Endogenous T-Cell Receptors.
Hum Gene Ther. 2018; 29(5):569-584 [PubMed] Related Publications
Transposon-based vectors have entered clinical trials as an alternative to viral vectors for genetic engineering of T cells. However, transposon vectors require DNA transfection into T cells, which were found to cause adverse effects. T-cell viability was decreased in a dose-dependent manner, and DNA-transfected T cells showed a delayed response upon T-cell receptor (TCR) stimulation with regard to blast formation, proliferation, and surface expression of CD25 and CD28. Gene expression analysis demonstrated a DNA-dependent induction of a type I interferon response and interferon-β upregulation. By combining Sleeping Beauty transposon minicircle vectors with SB100X transposase-encoding RNA, it was possible to reduce the amount of total DNA required, and stable expression of therapeutic TCRs was achieved in >50% of human T cells without enrichment. The TCR-engineered T cells mediated effective tumor cell killing and cytokine secretion upon antigen-specific stimulation. Additionally, the Sleeping Beauty transposon system was further improved by miRNAs silencing the endogenous TCR chains. These miRNAs increased the surface expression of the transgenic TCR, diminished mispairing with endogenous TCR chains, and enhanced antigen-specific T-cell functionality. This approach facilitates the rapid non-viral generation of highly functional, engineered T cells for immunotherapy.

Cherian MA, Olson S, Sundaramoorthi H, et al.
An activating mutation of interferon regulatory factor 4 (IRF4) in adult T-cell leukemia.
J Biol Chem. 2018; 293(18):6844-6858 [PubMed] Free Access to Full Article Related Publications
The human T-cell leukemia virus-1 (HTLV-1) oncoprotein Tax drives cell proliferation and resistance to apoptosis early in the pathogenesis of adult T-cell leukemia (ATL). Subsequently, probably as a result of specific immunoediting, Tax expression is down-regulated and functionally replaced by somatic driver mutations of the host genome. Both amplification and point mutations of interferon regulatory factor 4 (IRF4) have been previously detected in ATL., K59R is the most common single-nucleotide variation of IRF4 and is found exclusively in ATL. High-throughput whole-exome sequencing revealed recurrent activating genetic alterations in the T-cell receptor, CD28, and NF-κB pathways. We found that IRF4, which is transcriptionally activated downstream of these pathways, is frequently mutated in ATL. IRF4 RNA, protein, and IRF4 transcriptional targets are uniformly elevated in HTLV-1-transformed cells and ATL cell lines, and IRF4 was bound to genomic regulatory DNA of many of these transcriptional targets in HTLV-1-transformed cell lines. We further noted that the K59R IRF4 mutant is expressed at higher levels in the nucleus than WT IRF4 and is transcriptionally more active. Expression of both WT and the K59R mutant of IRF4 from a constitutive promoter in retrovirally transduced murine bone marrow cells increased the abundance of T lymphocytes but not myeloid cells or B lymphocytes in mice. IRF4 may represent a therapeutic target in ATL because ATL cells select for a mutant of IRF4 with higher nuclear expression and transcriptional activity, and overexpression of IRF4 induces the expansion of T lymphocytes

Mao Y, Wang C, Meng F, et al.
Polymorphisms in the ICOS/CD28-ICOSL pathway are related to capecitabine-based chemotherapy response in advanced colon cancer patients.
Mol Immunol. 2018; 96:78-82 [PubMed] Related Publications
Polymorphisms within a gene's 3'-UTR may modulate posttranscriptional regulation of gene expression, and may explain individual sensitivity of chemotherapy. To investigate the correlation between single nucleotide polymorphisms (SNPs) in 3'-UTRs of B7/CD28 family genes and the response of capecitabine-based chemotherapy in colon cancer, 16 SNPs were identified in 274 advanced colon cancer patients. Statistical analysis indicated that ICOS rs1559931, rs4404254, and rs4675379 were in complete linkage disequilibrium and significantly associated with chemotherapy response. Heterozygous patients with rs1559931 G/A (31.34% vs 48.29%; P = 0.016), rs4404254 T/C (30.43% vs 48.77%; P = 0.011), or rs4675379 G/C (28.13% vs 49.04%; P = 0.004) genotypes showed poorer response to chemotherapy compared to wildtype patients. Moreover, three SNPs, including ICOSL rs15927, ICOSL rs3804033 and CD28 rs3181113, were significantly associated with the occurrence of side effects of chemotherapy. In addition, patients with ICOSL rs15927 G/G (78.26%), ICOSL rs3804033 G/G (76.00%), or CD28 rs3181113 T/T (82.05%) were more prone to enduring adverse events compared to patients bearing other polymorphisms. Taken together, our findings demonstrated that polymorphisms in the 3'-UTRs of genes in the ICOS/CD28-ICOSL pathway may influence the efficacy and occurrence of adverse events of capecitabine-based chemotherapy in advanced colon cancer patients.

Pituch KC, Miska J, Krenciute G, et al.
Adoptive Transfer of IL13Rα2-Specific Chimeric Antigen Receptor T Cells Creates a Pro-inflammatory Environment in Glioblastoma.
Mol Ther. 2018; 26(4):986-995 [PubMed] Free Access to Full Article Related Publications
In order to fully harness the potential of immunotherapy with chimeric antigen receptor (CAR)-modified T cells, pre-clinical studies must be conducted in immunocompetent animal models that closely mimic the immunosuppressive malignant glioma (MG) microenvironment. Thus, the goal of this project was to study the in vivo fate of T cells expressing CARs specific for the MG antigen IL13Rα2 (IL13Rα2-CARs) in immunocompetent MG models. Murine T cells expressing IL13Rα2-CARs with a CD28.ζ (IL13Rα2-CAR.CD28.ζ) or truncated signaling domain (IL13Rα2-CAR.Δ) were generated by retroviral transduction, and their effector function was evaluated both in vitro and in vivo. IL13Rα2-CAR.CD28.ζ T cells' specificity toward IL13Rα2 was confirmed through cytokine production and cytolytic activity. In vivo, a single intratumoral injection of IL13Rα2-CAR.CD28.ζ T cells significantly extended the survival of IL13Rα2-expressing GL261 and SMA560 glioma-bearing mice; long-term survivors were resistant to re-challenge with IL13Rα2-negative and IL13Rα2-positive tumors. IL13Rα2-CAR.CD28.ζ T cells proliferated, produced cytokines (IFNγ, TNF-α), and promoted a phenotypically pro-inflammatory glioma microenvironment by inducing a significant increase in the number of CD4

Bae J, Hideshima T, Tai YT, et al.
Histone deacetylase (HDAC) inhibitor ACY241 enhances anti-tumor activities of antigen-specific central memory cytotoxic T lymphocytes against multiple myeloma and solid tumors.
Leukemia. 2018; 32(9):1932-1947 [PubMed] Free Access to Full Article Related Publications
Histone deacetylases (HDAC) are therapeutic targets in multiple cancers. ACY241, an HDAC6 selective inhibitor, has shown anti-multiple myeloma (MM) activity in combination with immunomodulatory drugs and proteasome inhibitors. Here we show ACY241 significantly reduces the frequency of CD138

Li S, Tao Z, Xu Y, et al.
CD33-Specific Chimeric Antigen Receptor T Cells with Different Co-Stimulators Showed Potent Anti-Leukemia Efficacy and Different Phenotype.
Hum Gene Ther. 2018; 29(5):626-639 [PubMed] Related Publications
Acute myeloid leukemia (AML) is a kind of a malignant hematologic tumor caused by uncontrolled repopulation of myeloid hematopoietic stem cells (HSCs). Current therapeutic effects for AML patients are unsatisfactory. In particular, relapsed and refractory AML still have a poor prognosis. T cells modified by chimeric antigen receptor (CAR) was an immunotherapeutic strategy for malignancies, which has a broad developing prospect. Most AML cells overexpress the myeloid antigen CD33. Therefore, CD33-specific CAR-T cells with different co-stimulators (CD28, 4-1BB, or both, referred to as CD33 28z.CAR-T cells, CD33 BBz.CAR-T cells, or CD33 28BBz.CAR-T cells, respectively) were developed to evaluate their efficacy against AML. The effectiveness of three types of CD33 CAR-T cells against AML was verified by specific killing effect to AML cells and prolonged survival of a xenograft mouse model. In terms of CAR-T cell efficacy, especially when transfused into human bodies, the persistence of T cells is also an important index, as it is closely associated with the long-term effect of CAR-T cells. Therefore, the characteristics of three types of CD33 CAR-T cells related to the persistence of T cells were examined. It was found that during expansion, CD33 BBz.CAR-T cells had an increased central memory compartment, while CD33 28z.CAR-T cells were predominantly effector memory T cells. In addition, CD33 28z.CAR-T cells were more inclined to become exhausted. The study suggests that incorporation of 4-1BB in CARs may endow T cells with long-lasting survival ability, thus improving the long-term anti-leukemia effect of CAR-T cells, especially when transfused to the human body.

Ma H, Davarifar A, Amengual JE
The Future of Combination Therapies for Peripheral T Cell Lymphoma (PTCL).
Curr Hematol Malig Rep. 2018; 13(1):13-24 [PubMed] Related Publications
PURPOSE OF REVIEW: Peripheral T cell lymphoma is a rare heterogeneous group of diseases which are characterized by poor outcomes to treatment and short overall survival. In the past decade, several new therapies targeting T cell biology have been approved in the relapsed setting. These new therapies, such as pralatrexate, romidepsin, belinostat, and brentuximab vedotin, have begun to make their way into practice. Despite these advances, outcomes have not changed dramatically. In recent years, efforts have been made to incorporate these new therapies into combination strategies to treat this challenging disease entity. Herein we will review some of the latest developments.
RECENT FINDINGS: With the new WHO classification, discrete entities of PTCL are now being identified by molecular and phenotypic markers. This new classification is critical to our ability to define disease entities which may respond to certain classes of targeted therapy. Some such mutations include genes controlling epigenetics (TET2, IDH2, DNMT3A, RHOA, CD28). As such, epigenetic therapies such as histone deacetylase (HDAC) inhibitors have become the platform to which other novel therapies or chemotherapy has been added. Early phase clinical studies have demonstrated that combination therapy with romidepsin plus other agents known to have activity in T cell lymphoma have enhanced clinical benefit for this group of diseases. In addition, the antibody drug conjugate, brentuximab vedotin has been shown to have potent activity in T cell lymphomas expressing CD30. This drug is being studied as well with other targeted therapies and chemotherapy in an effort to improve response rates and progression-free survival. Although T cell lymphomas remain a highly challenging group of diseases to treat, new efforts to leverage drugs that discretely target the biology that drives T cell lymphomagenesis in combination provide hope that improved outcomes may be realized in the near future.

Fujisawa M, Chiba S, Sakata-Yanagimoto M
Recent Progress in the Understanding of Angioimmunoblastic T-cell Lymphoma.
J Clin Exp Hematop. 2017; 57(3):109-119 [PubMed] Free Access to Full Article Related Publications
Angioimmunoblastic T-cell lymphoma (AITL) has been classified as a subtype of mature T-cell neoplasms. The recent revision of the WHO classification proposed a new category of nodal T-cell lymphoma with follicular helper T (TFH)-cell phenotype, which was classified into three diseases: AITL, follicular T-cell lymphoma, and nodal peripheral T-cell lymphoma with TFH phenotype. These lymphomas are defined by the expression of TFH-related antigens, CD279/PD-1, CD10, BCL6, CXCL13, ICOS, SAP, and CXCR5. Although recurrent mutations in TET2, IDH2, DNMT3A, RHOA, and CD28, as well as gene fusions, such as ITK-SYK and CTLA4-CD28, were not diagnostic criteria, they may be considered as novel criteria in the near future. Notably, premalignant mutations, tumor-specific mutations, and mutations specific to tumor-infiltrating B cells were identified in AITL. Thus, multi-step and multi-lineage genetic events may lead to the development of AITL.

Xu Z, Chang CC, Li M, et al.
ILT3.Fc-CD166 Interaction Induces Inactivation of p70 S6 Kinase and Inhibits Tumor Cell Growth.
J Immunol. 2018; 200(3):1207-1219 [PubMed] Related Publications
The blockade of immune checkpoints by anti-receptor and/or anti-ligand mAb is one of the most promising approaches to cancer immunotherapy. The interaction between Ig-like transcript 3 (ILT3), a marker of tolerogenic dendritic cells, also known as LILRB4/LIR5/CD85k, and its still unidentified ligand on the surface of activated human T cells is potentially important for immune checkpoint blockade. To identify the ILT3 ligand, we generated mAb by immunizing mice with Jurkat acute T cell leukemia, which binds ILT3.Fc to its membrane. Flow cytometry, mass spectrometry, and Biacore studies demonstrated that the ILT3 ligand is a CD166/activated leukocyte cell adhesion molecule. Knockdown of CD166 in primary human T cells by nucleofection abolished the capacity of ILT3.Fc to inhibit CD4

Hutten TJA, Norde WJ, Woestenenk R, et al.
Increased Coexpression of PD-1, TIGIT, and KLRG-1 on Tumor-Reactive CD8
Biol Blood Marrow Transplant. 2018; 24(4):666-677 [PubMed] Related Publications
Allogeneic stem cell transplantation (allo-SCT) can be a curative treatment for patients with a hematologic malignancy due to alloreactive T cell responses recognizing minor histocompatibility antigens (MiHA). Yet tumor immune escape mechanisms can cause failure of T cell immunity, leading to relapse. Tumor cells display low expression of costimulatory molecules and can up-regulate coinhibitory molecules that inhibit T cell functionality on ligation with their counter-receptors on the tumor-reactive T cells. The aim of this explorative study was to evaluate immune checkpoint expression profiles on T cell subsets and on cytomegalovirus (CMV)- and/or MiHA-reactive CD8

Yan Y, Zhang X
The association between
Biosci Rep. 2017; 37(6) [PubMed] Free Access to Full Article Related Publications
T-lymphocyte activation plays an important role in suppressing the development of human cancers including breast cancer (BC). Cluster of differentiation 28 (CD28) is the primary T-cell costimulatory molecule and enhances T-cell activation and proliferation. To examine the role of CD28 gene polymorphism in BC, we conducted a case-control study involving 312 BC patients and 312 controls in a Chinese Han population. Bioinformatics analyses were conducted to analyze the expression level of CD28 and its association with overall survival (OS) of BC. Genotyping was performed using a custom-by-design 48-Plex single nucleotide polymorphism (SNP) Scan™ Kit. Our results indicated that CD28 mRNA level was down-regulated in the BC patients, whereas high expression of CD28 showed better OS for BC. In addition, an increased risk of BC was associated with the rs3116496 CC genotype of

Scarpa M, Kotsafti A, Fassan M, et al.
Immunonutrition before esophagectomy: Impact on immune surveillance mechanisms.
Tumour Biol. 2017; 39(10):1010428317728683 [PubMed] Related Publications
Preoperative oral immunonutrition was demonstrated to improve immune response and to decrease the infection rate in patients with cancer. This study aimed to assess how immunonutrition could influence the immune cell response in the mucosal microenvironment of esophageal adenocarcinoma. Therefore, A prospective cohort of consecutive patients undergoing esophagectomy for esophageal adenocarcinoma was enrolled. A subgroup of them was given preoperative oral immunonutrition with Oral Impact® and was compared to those who received no preoperative supplementation. Mucosal samples from healthy esophagus were obtained at esophagectomy. Histology, immunohistochemistry, gene expression analysis, and cytofluorimetry were performed. Markers of activation of antigen-presenting cells (CD80, CD86, and HLA-I), innate immunity (TLR4 and MyD88), and cytotoxic lymphocyte infiltration and activation (CD8, CD38, CD69, and CD107) were measured. In all, 50 patients received preoperative Oral Impact® and 129 patients received no nutritional support. CD80, CD86, MyD88, and CD69 messenger RNA expression was significantly increased in patients receiving immunonutrition compared to controls. In the subgroup of patients with stages I-II cancer, the rate of epithelial cells expressing CD80 and HLA-ABC was significantly higher in those receiving immunonutrition compared to controls as well as CD8+ CD28+ cell rate. Immunonutrition administration before surgery was significantly associated to increased degranulating CD8 and natural killer cells (CD107+) infiltrating the healthy esophageal mucosa. All the comparisons were adjusted for cancer stage and preoperative therapy. In conclusion, in healthy esophageal mucosa of patients undergoing esophagectomy, a 5-day course of immunonutrition enhances expression of antigen-presenting cells activity and increased CD8+ T cell activation and degranulating activity. Further studies are warranted to understand the clinical implication in terms of cancer recurrence.

Hickey JW, Vicente FP, Howard GP, et al.
Biologically Inspired Design of Nanoparticle Artificial Antigen-Presenting Cells for Immunomodulation.
Nano Lett. 2017; 17(11):7045-7054 [PubMed] Free Access to Full Article Related Publications
Particles engineered to engage and interact with cell surface ligands and to modulate cells can be harnessed to explore basic biological questions as well as to devise cellular therapies. Biology has inspired the design of these particles, such as artificial antigen-presenting cells (aAPCs) for use in immunotherapy. While much has been learned about mimicking antigen presenting cell biology, as we decrease the size of aAPCs to the nanometer scale, we need to extend biomimetic design to include considerations of T cell biology-including T-cell receptor (TCR) organization. Here we describe the first quantitative analysis of particle size effect on aAPCs with both Signals 1 and 2 based on T cell biology. We show that aAPCs, larger than 300 nm, activate T cells more efficiently than smaller aAPCs, 50 nm. The 50 nm aAPCs require saturating doses or require artificial magnetic clustering to activate T cells. Increasing ligand density alone on the 50 nm aAPCs did not increase their ability to stimulate CD8+ T cells, confirming the size-dependent phenomenon. These data support the need for multireceptor ligation and activation of T-cell receptor (TCR) nanoclusters of similar sizes to 300 nm aAPCs. Quantitative analysis and modeling of a nanoparticle system provides insight into engineering constraints of aAPCs for T cell immunotherapy applications and offers a case study for other cell-modulating particles.

Kreuzinger C, Geroldinger A, Smeets D, et al.
A Complex Network of Tumor Microenvironment in Human High-Grade Serous Ovarian Cancer.
Clin Cancer Res. 2017; 23(24):7621-7632 [PubMed] Related Publications

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Cite this page: Cotterill SJ. CD28, Cancer Genetics Web: http://www.cancer-genetics.org/CD28.htm Accessed:

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