CD58 defines regulatory macrophages within the tumor microenvironment.

CD58 has been implicated in immune suppression and is associated with stemness in various types of cancer. Nonetheless, efficient biomarkers for assessing cancer patient response to immunotherapy are lacking. The present work focused on assessing the immune predictive significance of CD58 for patients with glioma. The expression of CD58 correlates with the clinicopathologic characteristics of patients with glioma, suggesting CD58high cells to signify glioma with tumorigenic potential. The CD58high cells displayed accelerated tumor formation compared to CD58low cells in vivo. Taken together, CD58 could potentially serve as a marker for glioma. CD58high glioma induces macrophage polarization through CXCL5 secretion, where M2 macrophages regulate PD-L1 expression within CD58high glioma via IL-6 production in vitro. Moreover, it was found that combination treatment with CD58 significantly increased the volume of tumors in the xenograft specimens. Evaluating CD58 expression represents a promising approach for identifying patients who can benefit from immunotherapy.

Genetic ablation of adhesion ligands mitigates rejection of allogeneic cellular immunotherapies.

Allogeneic cellular immunotherapies hold promise for broad clinical implementation but face limitations due to potential rejection of donor cells by the host immune system. Silencing of beta-2 microglobulin (B2M) expression is commonly employed to evade T cell-mediated rejection by the host, although the absence of B2M is expected to trigger missing-self responses by host natural killer (NK) cells. Here, we demonstrate that genetic deletion of the adhesion ligands CD54 and CD58 in B2M-deficient chimeric antigen receptor (CAR) T cells and multi-edited induced pluripotent stem cell (iPSC)-derived CAR NK cells reduces their susceptibility to rejection by host NK cells in vitro and in vivo. The absence of adhesion ligands limits rejection in a unidirectional manner in B2M-deficient and B2M-sufficient settings without affecting the antitumor functionality of the engineered donor cells. Thus, these data suggest that genetic ablation of adhesion ligands effectively alleviates rejection by host immune cells, facilitating the implementation of universal immunotherapy.

CD58 Alterations Govern Antitumor Immune Responses by Inducing PDL1 and IDO in Diffuse Large B-Cell Lymphoma.

Recurrent abnormalities in immune surveillance-related genes affect the progression of diffuse large B-cell lymphoma (DLBCL) and modulate the response to therapeutic interventions. CD58 interacts with the CD2 receptor on T cells and NK cells and is recurrently mutated and deleted in DLBCL, suggesting that it may play a role in regulating antitumor immunity. In this study, we comprehensively analyzed the genomic characteristics of CD58 through targeted next-generation sequencing, RNA sequencing (RNA-seq), whole-exome sequencing, and single-cell RNA-seq in patients with newly diagnosed DLBCL. The CD58 mutation rate was 9.1%, and the copy number loss rate was 44.7% among all enrolled patients with DLBCL. Notably, CD58 genetic alterations, along with low CD58 expression, significantly correlated with reduced rates of response to R-CHOP therapy and inferior progression-free survival and overall survival. Single-cell RNA-seq revealed that CD58 expression in tumor cells was negatively correlated with CD8+ T-cell exhaustion/dysfunction status. Insufficient T-cell activation resulting from CD58 alterations could not be attributed solely to CD2 signaling. CD58 inhibited the activity of the JAK2/STAT1 pathway by activating the LYN/CD22/SH2 domain-containing phosphatase 1 (SHP1) axis, thereby limiting PDL1 and IDO expression. Elevated PDL1 and IDO expression in CD58-deficient DLBCL cells led to immune evasion and tumor-intrinsic resistance to chimeric antigen receptor T-cell therapy. Direct activation of CD58-CD2 costimulatory signaling in combination with anti-PDL1 blockade or IDO inhibitor sensitized CD58-deficient DLBCL to chimeric antigen receptor T-cell therapy. Collectively, this work identified the multiple roles of CD58 in regulating antitumor immune responses in DLBCL. Significance: Loss of CD58 mediates immune evasion and therapy resistance in diffuse large B-cell lymphoma by upregulating PDL1 and IDO through LYN/CD22/SHP1 signaling, providing potential targets and therapeutic strategies to improve patient treatment.

Meta-analysis of the Selected Genetic Variants in Immune-Related Genes and Multiple Sclerosis Risk.

Previous studies have suggested that certain variants in immune-related genes may participate in the pathogenesis of multiple sclerosis (MS), including rs17824933 in the CD6 gene, rs1883832 in the CD40 gene, rs2300747 in the CD58 gene, rs763361 in the CD226 gene, rs16944 in the IL-1ß gene, rs2243250 in the IL-4 gene, and rs12722489 and rs2104286 in the IL-2Rα gene. However, the results remained inconclusive and conflicting. In view of this, a comprehensive meta-analysis including all eligible studies was conducted to investigate the association between these 8 selected genetic variants and MS risk. Up to June 2023, 64 related studies were finally included in this meta-analysis. The odds ratios (ORs) and corresponding 95% confidence intervals (CIs) calculated by the random-effects model were used to evaluate the strength of association. Publication bias test, sensitivity analyses, and trial sequential analysis (TSA) were conducted to examine the reliability of statistical results. Our results indicated that rs17824933 in the CD6 gene, rs1883832 in the CD40 gene, rs2300747 in the CD58 gene, rs763361 in the CD226 gene, and rs12722489 and rs2104286 in the IL-2Rα gene may serve as the susceptible factors for MS pathogenesis, while rs16944 in the IL-1ß gene and rs2243250 in the IL-4 gene may not be associated with MS risk. However, the present findings need to be confirmed and reinforced in future studies.

Association of CD58 rs12044852 and rs2300747 polymorphisms with the risk of multiple sclerosis: A systematic review and meta-analysis.

OBJECTIVE: Multiple sclerosis is a serious neurodegenerative disorder that causes disability in young adults. Genetic predisposition of multiple sclerosis is well documented and several single nucleotide polymorphisms (SNPs) of the CD58 were found to be associated with this disease. This systematic review and meta-analysis were done with the aim of finding the association between CD58 gene SNPs (rs12044852 and rs2300747) and the risk of multiple sclerosis (MS). METHOD: A comprehensive search was done in PubMed, Google Scholar, Embase, and MSGene.org to find the relevant data. Our search yielded 13 relevant publications which were included for meta-analysis consisting of 5194 cases and 5766 controls. All the statistical analysis was conducted using meta and metafor packages in R studio. The odds ratio (OR) along with 95 % confidence intervals and p values were determined using the fixed effects and random effects model. The I2 test was done to measure heterogeneity. Subgroup analysis was performed along with analysis for publication bias. RESULTS: We found significant association for both rs12044852 (allelic, dominant, over-dominant, heterozygous, and homozygous models) and rs2300747 (allelic, dominant, over-dominant, heterozygous models) with multiple sclerosis. Both the SNPs provided a protective effect for multiple sclerosis. Subgroup analysis indicated that rs12044852 polymorphism provided a protective effect in both Asians and Caucasians. However, for rs2300747, the Asian population showed no statistically significant association with the risk of MS. CONCLUSION: Polymorphism of rs12044852 and rs2300747 of the CD58 gene provided a protective effect for multiple sclerosis. The protective effect is more prominent in Caucasian populations compared to Asians.

Higher Expression of WT1 With Lower CD58 Expression may be Biomarkers for Risk Stratification of Patients With Cytogenetically Normal Acute Myeloid Leukemia.

Background: Cytogenetics at diagnosis is the most important prognostic factor for adult acute myeloid leukemia (AML), but nearly 50% of AML patients who exhibit cytogenetically normal AML (CN-AML) do not undergo effective risk stratification. Therefore, the development of potential biomarkers to further define risk stratification for CN-AML patients is worth exploring. Methods: Transcriptome data from 163 cases in the GSE12417-GPL96 dataset and 104 CN-AML patient cases in the GSE71014-GPL10558 dataset were downloaded from the Gene Expression Omnibus database for overall survival (OS) analysis and validation. Results: The combination of Wilms tumor 1 (WT1) and cluster of diffraction 58 (CD58) can predict the prognosis of CN-AML patients. High expression of WT1 and low expression of CD58 were associated with poor OS in CN-AML. Notably, when WT1 and CD58 were used to concurrently predict OS, CN-AML patients were divided into three groups: low risk, WT1lowCD58high; intermediate risk, WT1highCD58high or WT1lowCD58low; and high risk, WT1highCD58low. Compared with low-risk patients, intermediate- and high-risk patients had shorter survival time and worse OS. Furthermore, a nomogram model constructed with WT1 and CD58 may personalize and reveal the 1-, 2-, 3-, 4-, and 5-year OS rate of CN-AML patients. Both time-dependent receiver operating characteristics and calibration curves suggested that the nomogram model demonstrated good performance. Conclusion: Higher expression of WT1 with lower CD58 expression may be a potential biomarker for risk stratification of CN-AML patients. Moreover, a nomogram model constructed with WT1 and CD58 may personalize and reveal the 1-, 2-, 3-, 4-, and 5-year OS rates of CN-AML patients.

CD58 Immunobiology at a Glance.

The glycoprotein CD58, also known as lymphocyte-function antigen 3 (LFA-3), is a costimulatory receptor distributed on a broad range of human tissue cells. Its natural ligand CD2 is primarily expressed on the surface of T/NK cells. The CD2-CD58 interaction is an important component of the immunological synapse (IS) that induces activation and proliferation of T/NK cells and triggers a series of intracellular signaling in T/NK cells and target cells, respectively, in addition to promoting cell adhesion and recognition. Furthermore, a soluble form of CD58 (sCD58) is also present in cellular supernatant in vitro and in local tissues in vivo. The sCD58 is involved in T/NK cell-mediated immune responses as an immunosuppressive factor by affecting CD2-CD58 interaction. Altered accumulation of sCD58 may lead to immunosuppression of T/NK cells in the tumor microenvironment, allowing sCD58 as a novel immunotherapeutic target. Recently, the crucial roles of costimulatory molecule CD58 in immunomodulation seem to be reattracting the interests of investigators. In particular, the CD2-CD58 interaction is involved in the regulation of antiviral responses, inflammatory responses in autoimmune diseases, immune rejection of transplantation, and immune evasion of tumor cells. In this review, we provide a comprehensive summary of CD58 immunobiology.

Multimodal pooled Perturb-CITE-seq screens in patient models define mechanisms of cancer immune evasion.

Resistance to immune checkpoint inhibitors (ICIs) is a key challenge in cancer therapy. To elucidate underlying mechanisms, we developed Perturb-CITE-sequencing (Perturb-CITE-seq), enabling pooled clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 perturbations with single-cell transcriptome and protein readouts. In patient-derived melanoma cells and autologous tumor-infiltrating lymphocyte (TIL) co-cultures, we profiled transcriptomes and 20 proteins in ~218,000 cells under ~750 perturbations associated with cancer cell-intrinsic ICI resistance (ICR). We recover known mechanisms of resistance, including defects in the interferon-γ (IFN-γ)-JAK/STAT and antigen-presentation pathways in RNA, protein and perturbation space, and new ones, including loss/downregulation of CD58. Loss of CD58 conferred immune evasion in multiple co-culture models and was downregulated in tumors of melanoma patients with ICR. CD58 protein expression was not induced by IFN-γ signaling, and CD58 loss conferred immune evasion without compromising major histocompatibility complex (MHC) expression, suggesting that it acts orthogonally to known mechanisms of ICR. This work provides a framework for the deciphering of complex mechanisms by large-scale perturbation screens with multimodal, single-cell readouts, and discovers potentially clinically relevant mechanisms of immune evasion.

Rosetting T cells in Hodgkin lymphoma are activated by immunological synapse components HLA class II and CD58.

A unique feature of Hodgkin lymphoma (HL) is the presence of CD4+ T cells that surround, protect, and promote survival of tumor cells. The adhesion molecules involved in this so-called T-cell rosetting are important components of the immunological synapse (IS). However, it is unknown whether this synapse is fully assembled and leads to T-cell activation by enabling interaction between the T-cell receptor (TCR) and human leukocyte antigen class II (HLA-II). We established a novel rosetting model by coculturing HLA-II-matched peripheral blood mononuclear cells with HL cell lines and showed IS formation with activation of rosetting T cells. HLA-II downregulation by class II transactivator knockout did not affect the extent of rosetting, but almost completely abrogated T-cell activation. Intriguingly, the level of CD58 expression correlated with the extent of rosette formation, and CD58 knockout or CD2 blockade reduced both rosette formation and T-cell activation. The extension of our findings to primary HL tissue by immunohistochemistry and proximity ligation assays showed interaction of CD2 with CD58 and of TCR-associated CD4 with HLA-II. In conclusion, T-cell rosetting in HL is established by formation of the IS, and activation of rosetting T cells critically depends on the interaction of both TCR-HLA-II and CD2-CD58.

Replication analysis of variants associated with multiple sclerosis risk.

Multiple Sclerosis (MS) is a complex chronic neurodegenerative disorder resulting from an autoimmune reaction against myelin. So far, many genetic variants have been reported to associate with MS risk however their association is inconsistent across different populations. Here we investigated the association of the most consistently reported genetic MS risk variants in the Kuwaiti MS population in a case-control study designs. Of the 94 reported MS risk variants four variants showed MS risk association in Arabs exome analysis (EVI5 rs11808092 p = 0.0002; TNFRSF1A rs1800693 p = 0.00003; MTHFR rs1801131 p = 0.038; and CD58 rs1414273 p = 0.00007). Replication analysis in Kuwaiti MS cases and healthy controls confirmed EVI5 rs11808092A (OR: 1.6, 95%CI: 1.19-2.16, p = 0.002) and MTHFR rs1801131G (OR: 1.79, 95%CI: 1.3-2.36, p = 0.001) as MS risk genetic factors, while TNFRSF1A rs1800693C had a marginal MS risk association (OR: 1.36, 95%CI: 1.04-1.78, p = 0.025) in the Kuwaiti population. CD58 rs1414273 did not sustain risk association (p = 0.37). In conclusion, EVI5 rs11808092A, TNFRSF1A rs1800693C and MTHFR rs1801131G are MS risk factors in the Kuwaiti population. Further investigations into their roles in MS pathogenesis and progression are merited.

EZH2 inhibitors restore epigenetically silenced CD58 expression in B-cell lymphomas.

Loss of CD58 is a common mechanism for tumor immune evasion in lymphoid malignancies. CD58 loss is known to occur due to both genetic and non-genetic causes; therefore, we hypothesized that restoring CD58 expression in lymphoma cells may be an effective treatment approach. To explore the potential for restoring CD58 expression, we first screened 11 B-cell lymphoma lines and found that 3 had decreased CD58 expression. Among these, CD58 was genetically damaged in two lines but not in the third line. Using the cell line with downregulated CD58 without a genetic abnormality, we performed epigenetic library screening and found that two EZH2 inhibitors, EPZ6438 and GSK126, specifically enhanced CD58 expression. By examining the effect of three EZH2 inhibitors with different selectivity profiles in different B-cell lines, EZH2 inhibition was shown to have a common activity in upregulating CD58 expression. Restoring the expression of CD58 in lymphoma cells using an EZH2 inhibitor was shown to enhance interferon-γ production of T and NK cells against lymphoma cells. H3K27 was shown to be highly trimethylated in the CD58 promoter region, and EZH2 inhibition induced its demethylation and activated transcription of the CD58 gene. These results indicated that EZH2 is involved in the epigenetic silencing of CD58 in lymphoma cells as a mechanism for tumor immune escape, and EZH2 inhibitors are able to restore epigenetically suppressed CD58 expression. Our findings provide a molecular basis for the combination of an EZH2 inhibitor and immunotherapy for lymphoma treatment.

Association of CD58 Polymorphisms and its Protein Expression with the Development and Prognosis of Autoimmune Thyroid Diseases.

The prognosis of autoimmune thyroid diseases (AITDs), including Graves' disease (GD) and Hashimoto's disease (HD), varies among patients. The interaction of CD58 and its ligand (CD2) promotes the differentiation of regulatory T cells and suppresses the immune response. To clarify the association of CD58 expression with the pathogenesis and prognosis of AITDs, we genotyped polymorphisms in the CD58 gene including rs12044852A/C (SNP1), rs2300747A/G (SNP2), rs1335532C/T (SNP3), rs1016140G/T (SNP4), rs1414275C/T (SNP5) and rs11588376C/T (SNP6). The CD58 SNPs were genotyped in 177 GD patients, 193 HD patients and 116 healthy volunteers (control subjects). We used the Polymerase chain reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method for the genotyping of SNP1 and SNPs3-6 and the TaqMan® SNP genotyping assay for the genotyping of SNP2. The frequencies of the AA genotype in SNP1 tend to be high in all patients with AITDs than in control subjects, although it was not significant. The GG genotype of SNP2, the CC genotype of SNP3, the TT genotype of SNP4, the CC genotype of SNP5 and the CC genotype of SNP6 were all significantly more frequent in patients with AITDs than in control subjects. The proportion of CD58+ cells in monocytes was significantly lower in healthy individuals with each of these risk genotypes of AITDs and lower in GD and HD patients than that in healthy controls. In conclusion, CD58 SNPs are involved in AITD susceptibility through the reduction in CD58 expression, which probably suppresses regulatory T cells.

High-resolution melting curve analysis of polymorphisms within CD58, CD226, HLA-G genes and association with multiple sclerosis susceptibility in a subset of Iranian population: a case-control study.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system with unknown etiology, which typically is manifested in early to middle adulthood. Recently, genome-wide association studies have identified susceptibility of immune-related genes to be involved in MS predisposition. The goal of the current study was to investigate the association of single nucleotide polymorphisms (SNP) with the immunologically related genes responsible for the disease, composed of CD58 (rs2300747 A>G), CD226 (rs763361 C>T), and HLA-G (rs1611715 A>C), with MS susceptibility. In this case-control study, a total of 200 patients suffering from relapsing-remitting multiple sclerosis and 200 healthy individuals were recruited. DNA was extracted from blood and then all subjects were genotyped for the polymorphism within mentioned genes by high-resolution melting (HRM) real-time PCR method. Statistical analyses were performed using SPSS software (version 20; SPSS, Chicago, IL, USA). Our finding showed that there are significant differences in genotype and allele frequencies between two groups regarding rs763361 (P = 0.035, OR 0.64, CI 95% for C allele) and rs1611715 (P = 0.038, OR 1.57, CI 95% for AA genotype) polymorphisms within CD226 and HLA-G genes, respectively. Concerning rs2300747 polymorphism on CD58 gene, no significant differences were found between cases and controls. In general, results from the current study indicate that CD226 and HLA-G, but not CD58 genetic polymorphisms are associated with increased risk of MS in Isfahan population similar to European populations. However, to elucidate how these SNPs contribute to MS pathogenesis, functional studies are needed.

Analysis of chosen SNVs in GPC5, CD58 and IRF8 genes in multiple sclerosis patients.

PURPOSE: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system with a neurodegenerative compound. Heterogenetic background of autoimmunity pathway components has been suggested in the MS pathogenesis. The main aim of our study was to evaluate the association between selected polymorphisms of theCD58, IRF8 and GPC5 genes and treatment effectiveness in a group of relapsing-remitting MS patients. This is the first study of MS patients from Podlaskie Region in the Polish population. MATERIALS AND METHODS: The study group comprised 174 relapsing-remitting MS patients diagnosed under 40 years of age. Genotyping was performed using ready to use TaqMan assays. RESULTS: We demonstrate a strong association of the polymorphisms with sex, age of onset and response to the treatment applied. A significant correlation was observed in the presence of allele T of rs10492503 polymorphism inGPC5 gene with sex and age of MS onset. Logistic regression analysis revealed an increased risk of the interaction of rs17445836 in IRF8 gene with male sex and the type of treatment (OR = 3.80, p < 0.05), and a decreased risk in the interaction of female sex with disease progress according to the EDSS scale (OR=-2.33, p < 0.05). CONCLUSIONS: The analysis of the correlation between different alleles, genotypes and clinical status confirmed the interaction between the genetic factors of age of onset and response to therapy. The study suggests that genetic variants inGPC5, CD58 and IRF8 genes may be of clinical interest in MS as predictors of age of onset and response to therapy.

A genetic variant associated with multiple sclerosis inversely affects the expression of CD58 and microRNA-548ac from the same gene.

Genome-wide association studies have identified more than 200 genetic variants to be associated with an increased risk of developing multiple sclerosis (MS). Still, little is known about the causal molecular mechanisms that underlie the genetic contribution to disease susceptibility. In this study, we investigated the role of the single-nucleotide polymorphism (SNP) rs1414273, which is located within the microRNA-548ac stem-loop sequence in the first intron of the CD58 gene. We conducted an expression quantitative trait locus (eQTL) analysis based on public RNA-sequencing and microarray data of blood-derived cells of more than 1000 subjects. Additionally, CD58 transcripts and mature hsa-miR-548ac molecules were measured using real-time PCR in peripheral blood samples of 32 MS patients. Cell culture experiments were performed to evaluate the efficiency of Drosha-mediated stem-loop processing dependent on genotype and to determine the target genes of this underexplored microRNA. Across different global populations and data sets, carriers of the MS risk allele showed reduced CD58 mRNA levels but increased hsa-miR-548ac levels. We provide evidence that the SNP rs1414273 might alter Drosha cleavage activity, thereby provoking partial uncoupling of CD58 gene expression and microRNA-548ac production from the shared primary transcript in immune cells. Moreover, the microRNA was found to regulate genes, which participate in inflammatory processes and in controlling the balance of protein folding and degradation. We thus uncovered new regulatory implications of the MS-associated haplotype of the CD58 gene locus, and we remind that paradoxical findings can be encountered in the analysis of eQTLs upon data aggregation. Our study illustrates that a better understanding of RNA processing events might help to establish the functional nature of genetic variants, which predispose to inflammatory and neurological diseases.

Alu insertion variants alter mRNA splicing.

RNA splicing is a highly regulated process dependent on sequences near splice sites. Insertions of Alu retrotransposons can disrupt splice sites or bind splicing regulators. We hypothesized that some common inherited polymorphic Alu insertions are responsible for splicing QTLs (sQTL). We focused on intronic Alu variants mapping within 100 bp of an alternatively used exon and screened for those that alter splicing. We identify five loci, 21.7% of those assayed, where the polymorphic Alu alters splicing. While in most cases the Alu promotes exon skipping, at one locus the Alu increases exon inclusion. Of particular interest is an Alu polymorphism in the CD58 gene. Reduced CD58 expression is associated with risk for developing multiple sclerosis. We show that the Alu insertion promotes skipping of CD58 exon 3 and results in a frameshifted transcript, indicating that the Alu may be the causative variant for increased MS risk at this locus. Using RT-PCR analysis at the endogenous locus, we confirm that the Alu variant is a sQTL for CD58. In summary, altered splicing efficiency is a common functional consequence of Alu polymorphisms including at least one instance where the variant is implicated in disease risk. This work broadens our understanding of splicing regulatory sequences around exons.

Protective C allele of the single-nucleotide polymorphism rs1335532 is associated with strong binding of Ascl2 transcription factor and elevated CD58 expression in B-cells.

CD58 is expressed on the surface of antigen-presenting cells, including B-cells, and provides co-stimulation to regulatory T-cells (Treg) through CD2 receptor binding. Tregs appear to be essential suppressors of tissue-specific autoimmune responses. Thereby, CD58 plays protective role in multiple sclerosis (MS) and CD58 was identified among several loci associated with MS susceptibility. Minor (C) variant of the single-nucleotide polymorphism (SNP) rs1335532 is associated with lower MS risk according to genome-wide association studies (GWAS) and its presence correlates with higher CD58 mRNA levels in MS patients. We found that genomic region containing rs1335532 has enhancer properties and can significantly boost the CD58 promoter activity in lymphoblast cells. Using bioinformatics and pull-down assay we found that the protective (C) rs1335532 allele created functional binding site for ASCL2 transcription factor, a target of the Wnt signaling pathway. Both in B-lymphoblastoid cell lines and in primary B-cells, as well as in a monocytic cell line, activation of Wnt signaling resulted in an increased CD58 promoter activity in the presence of the protective but not the risk allele of rs1335532, whereas ASCL2 knockdown abrogated this effect. In summary, our results suggest that ASCL2 mediates the protective function of rs1335532 minor (C) allele in MS.

Low responsiveness to a hepatitis B virus vaccine in a Chinese population lacks association with ITGAL, CD58, TNFSF15, CCL15, TGFB3, and BCL6 gene variants.

It is known that multiple genetic variants can affect immune responses to the hepatitis B virus (HBV) vaccine. A case-control study was undertaken to examine the possible association of low responsiveness to the HBV vaccine in a Chinese population with genetic polymorphisms in integrin subunit alpha L, CD58, tumor necrosis factor superfamily member 15, C-C motif chemokine ligand 15, transforming growth factor beta 3, and B-cell lymphoma 6 protein. The copy numbers of these six genes were detected in 129 low responders, 129 middle responders and 129 high responders to HBV vaccination. There were no significant differences in the copy numbers of these six genes between the groups. Thus, these findings indicated that the copy number variations of these genes may not be the reason for the low responsiveness to the HBV vaccine in a Chinese population.

Costimulatory Function of Cd58/Cd2 Interaction in Adaptive Humoral Immunity in a Zebrafish Model.

CD58 and CD2 have long been known as a pair of reciprocal adhesion molecules involved in the immune modulations of CD8+ T and NK-mediated cellular immunity in humans and several other mammals. However, the functional roles of CD58 and CD2 in CD4+ T-mediated adaptive humoral immunity remain poorly defined. Moreover, the current functional observations of CD58 and CD2 were mainly acquired from in vitro assays, and in vivo investigation is greatly limited due to the absence of a Cd58 homology in murine models. In this study, we identified cd58 and cd2 homologs from the model species zebrafish (Danio rerio). These two molecules share conserved structural features to their mammalian counterparts. Functionally, cd58 and cd2 were significantly upregulated on antigen-presenting cells and Cd4+ T cells upon antigen stimulation. Blockade or knockdown of Cd58 and Cd2 dramatically impaired the activation of antigen-specific Cd4+ T and mIgM+ B cells, followed by the inhibition of antibody production and host defense against bacterial infections. These results indicate that CD58/CD2 interaction was required for the full activation of CD4+ T-mediated adaptive humoral immunity. The interaction of Cd58 with Cd2 was confirmed by co-immunoprecipitation and functional competitive assays by introducing a soluble Cd2 protein. This study highlights a new costimulatory mechanism underlying the regulatory network of adaptive immunity and makes zebrafish an attractive model organism for the investigation of CD58/CD2-mediated immunology and disorders. It also provides a cross-species understanding of the evolutionary history of costimulatory signals from fish to mammals as a whole.

Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the Transcription Factor Brachyury.

Purpose: The transcription factor brachyury has been shown in preclinical studies to be a driver of the epithelial-to-mesenchymal transition (EMT) and resistance to therapy of human tumor cells. This study describes the characterization of a Modified Vaccinia Ankara (MVA) vector-based vaccine expressing the transgenes for brachyury and three human costimulatory molecules (B7.1, ICAM-1, and LFA-3, designated TRICOM) and a phase I study with this vaccine.Experimental Design: Human dendritic cells (DC) were infected with MVA-brachyury-TRICOM to define their ability to activate brachyury-specific T cells. A dose-escalation phase I study (NCT02179515) was conducted in advanced cancer patients (n = 38) to define safety and to identify brachyury-specific T-cell responses.Results: MVA-brachyury-TRICOM-infected human DCs activated CD8+ and CD4+ T cells specific against the self-antigen brachyury in vitro No dose-limiting toxicities were observed due to vaccine in cancer patients at any of the three dose levels. One transient grade 3 adverse event (AE) possibly related to vaccine (diarrhea) resolved without intervention and did not recur with subsequent vaccine. All other AEs related to vaccine were transient and ≤grade 2. Brachyury-specific T-cell responses were observed at all dose levels and in most patients.Conclusions: The MVA-brachyury-TRICOM vaccine directed against a transcription factor known to mediate EMT can be administered safely in patients with advanced cancer and can activate brachyury-specific T cells in vitro and in patients. Further studies of this vaccine in combination therapies are warranted and planned. Clin Cancer Res; 23(22); 6833-45. ©2017 AACR.