An Enriched Multigen Low-Density Array To Predict Outcome in Advanced Hodgkin Lymphoma Paraffin-Embedded Samples.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 383-383
Author(s):  
Beatriz Sanchez-Espiridion ◽  
Abel Sanchez-Aguilera ◽  
Carlos Montalban ◽  
Monica Garcia-Cosio ◽  
Carmen Bellas ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Mapk Pathway ◽  
Unfavorable Outcome ◽  
Gene Set Enrichment Analysis ◽  
Specific Gene ◽  
Low Density ◽  
Tissue Samples ◽  
Increased Risk

Abstract Despite the major advances in the treatment of classical Hodgkin Lymphoma (cHL) patients, around 30% to 40% of cases in advanced stages may relapse or die as result of the disease, and current markers to predict prognosis are rather unreliable. The identification of molecular events and biological processes associated with treatment failure are essential to develop new predictive tools. We used gene expression data from 29 samples of advanced cHL patients and HL-derived cell lines in order to identify transcriptional patterns from both tumoral cells and cell microenvironment. Student t-test was used to detect genes differentially overexpressed in cell lines and in tumor samples, thus creating two databases that report for genes expressed by the tumor HRS cells and genes expressed by the microenvironment. Using Gene Set Enrichment analysis (GSEA) we identified specific gene sets enriched in both databases in patients with favorable and unfavorable outcome, respectively. To validate these pathways we designed a novel Taqman low-density array (LDA) to examine the expression of the most relevant genes in 60 formalin-fixed, paraffin embedded (FFPE) tissue samples, and correlated the results with treatment outcome. Functional pathways related to unfavorable outcome significantly enriched in the HRS cells included the regulation of the G2/M checkpoint of the cell cycle, S phase and G1/S transition, chaperons, histone modification and other signaling pathways with an important representation of the MAPK pathway. On the other hand, genes reporting for specific T-cell populations (T-cytotoxic and T-regulatory cells) and macrophage activation were found to be overexpressed in the microenvironment. The final model presents a balanced representation of these genes, including also genes encoding factors implicated in drug resistance (RRM2, TYMS and TOP2A). RNA extracted from FFPE sections yielded analyzable data for 80% of samples. LDA analysis of the genes included in the model confirmed the feasibility of this approach, and the capacity for identifying cases with increased risk of failure.LDA provides an effective technique for analyzing gene expression in FFPE tissues, and it can be used for clinical prediction in diagnostic samples, using a selection of genes identified after GSEA analysis of the initial molecular signatures. This novel Taqman LDA will be used to develop a new molecular predictor of the outcome of patients with advanced cHL.

Gene expression profiling of microdissected Hodgkin Reed-Sternberg cells correlates with treatment outcome in classical Hodgkin lymphoma

Blood ◽  
2012 ◽  
Vol 120 (17) ◽  
pp. 3530-3540 ◽  
Author(s):  
Christian Steidl ◽  
Arjan Diepstra ◽  
Tang Lee ◽  
Fong Chun Chan ◽  
Pedro Farinha ◽  
...  
Keyword(s):  
Gene Expression ◽  
In Situ Hybridization ◽  
Treatment Failure ◽  
Gene Expression Profiling ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Expression Profiling ◽  
Specific Gene ◽  
Classical Hodgkin Lymphoma

Abstract In classical Hodgkin lymphoma (CHL), 20%-30% of patients experience relapse or progressive disease after initial treatment. The pathogenesis and biology of treatment failure are still poorly understood, in part because the molecular phenotype of the rare malignant Hodgkin Reed-Sternberg (HRS) cells is difficult to study. Here we examined microdissected HRS cells from 29 CHL patients and 5 CHL-derived cell lines by gene expression profiling. We found significant overlap of HL-specific gene expression in primary HRS cells and HL cell lines, but also differences, including surface receptor signaling pathways. Using integrative analysis tools, we identified target genes with expression levels that significantly correlated with genomic copy-number changes in primary HRS cells. Furthermore, we found a macrophage-like signature in HRS cells that significantly correlated with treatment failure. CSF1R is a representative of this signature, and its expression was significantly associated with progression-free and overall survival in an independent set of 132 patients assessed by mRNA in situ hybridization. A combined score of CSF1R in situ hybridization and CD68 immunohistochemistry was an independent predictor for progression-free survival in multivariate analysis. In summary, our data reveal novel insights into the pathobiology of treatment failure and suggest CSF1R as a drug target of at-risk CHL.

Loss of the B-lineage–specific gene expression program in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma

Blood ◽  
2003 ◽  
Vol 101 (4) ◽  
pp. 1505-1512 ◽  
Author(s):  
Ines Schwering ◽  
Andreas Bräuninger ◽  
Ulf Klein ◽  
Berit Jungnickel ◽  
Marianne Tinguely ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Expression Profiles ◽  
Specific Gene ◽  
Mrna Levels ◽  
Study Gene Expression ◽  
B Lineage

Hodgkin and Reed-Sternberg (HRS) cells represent the malignant cells in classical Hodgkin lymphoma (HL). Because their immunophenotype cannot be attributed to any normal cell of the hematopoietic lineage, the origin of HRS cells has been controversially discussed, but molecular studies established their derivation from germinal center B cells. In this study, gene expression profiles generated by serial analysis of gene expression (SAGE) and DNA chip microarrays from HL cell lines were compared with those of normal B-cell subsets, focusing here on the expression of B-lineage markers. This analysis revealed decreased mRNA levels for nearly all established B-lineage–specific genes. For 9 of these genes, lack of protein expression was histochemically confirmed. Down-regulation of genes affected multiple components of signaling pathways active in B cells, including B-cell receptor (BCR) signaling. Because several genes down-regulated in HRS cells are positively regulated by the transcriptional activator Pax-5, which is expressed in most HRS cells, we studied HL cell lines for mutations in the Pax-5gene. However, no mutations were found. We propose that the lost B-lineage identity in HRS cells may explain their survival without BCR expression and reflect a fundamental defect in maintaining the B-cell differentiation state in HRS cells, which is likely caused by a novel, yet unknown, pathogenic mechanism.

scholarly journals Methylation of the Cyclin A1 Promoter Correlates with Gene Silencing in Somatic Cell Lines, while Tissue-Specific Expression of Cyclin A1 Is Methylation Independent

2000 ◽  
Vol 20 (9) ◽  
pp. 3316-3329 ◽  
Author(s):  
Carsten Müller ◽  
Carol Readhead ◽  
Sven Diederichs ◽  
Gregory Idos ◽  
Rong Yang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Promoter Methylation ◽  
Cpg Island ◽  
Trichostatin A ◽  
Specific Gene ◽  
Cyclin A1 ◽  
Specific Expression ◽  
Tissue Specific ◽  
Tissue Specific Expression

ABSTRACT Gene expression in mammalian organisms is regulated at multiple levels, including DNA accessibility for transcription factors and chromatin structure. Methylation of CpG dinucleotides is thought to be involved in imprinting and in the pathogenesis of cancer. However, the relevance of methylation for directing tissue-specific gene expression is highly controversial. The cyclin A1 gene is expressed in very few tissues, with high levels restricted to spermatogenesis and leukemic blasts. Here, we show that methylation of the CpG island of the human cyclin A1 promoter was correlated with nonexpression in cell lines, and the methyl-CpG binding protein MeCP2 suppressed transcription from the methylated cyclin A1 promoter. Repression could be relieved by trichostatin A. Silencing of a cyclin A1 promoter-enhanced green fluorescent protein (EGFP) transgene in stable transfected MG63 osteosarcoma cells was also closely associated with de novo promoter methylation. Cyclin A1 could be strongly induced in nonexpressing cell lines by trichostatin A but not by 5-aza-cytidine. The cyclin A1 promoter-EGFP construct directed tissue-specific expression in male germ cells of transgenic mice. Expression in the testes of these mice was independent of promoter methylation, and even strong promoter methylation did not suppress promoter activity. MeCP2 expression was notably absent in EGFP-expressing cells. Transcription from the transgenic cyclin A1 promoter was repressed in most organs outside the testis, even when the promoter was not methylated. These data show the association of methylation with silencing of the cyclin A1 gene in cancer cell lines. However, appropriate tissue-specific repression of the cyclin A1 promoter occurs independently of CpG methylation.

scholarly journals Differential Regulation of Gene Expression of Alveolar Epithelial Cell Markers in Human Lung Adenocarcinoma-Derived A549 Clones

2015 ◽  
Vol 2015 ◽  
pp. 1-20 ◽  
Author(s):  
Hiroshi Kondo ◽  
Keiko Miyoshi ◽  
Shoji Sakiyama ◽  
Akira Tangoku ◽  
Takafumi Noma
Keyword(s):  
Gene Expression ◽  
Epithelial Cell ◽  
Mapk Pathway ◽  
Alveolar Epithelial Cell ◽  
Marker Gene ◽  
Regulation Of Gene Expression ◽  
Surfactant Protein ◽  
Specific Gene ◽  
Expression Levels ◽  
Alveolar Epithelial

Stem cell therapy appears to be promising for restoring damaged or irreparable lung tissue. However, establishing a simple and reproducible protocol for preparing lung progenitor populations is difficult because the molecular basis for alveolar epithelial cell differentiation is not fully understood. We investigated anin vitrosystem to analyze the regulatory mechanisms of alveolus-specific gene expression using a human alveolar epithelial type II (ATII) cell line, A549. After cloning A549 subpopulations, each clone was classified into five groups according to cell morphology and marker gene expression. Two clones (B7 and H12) were further analyzed. Under serum-free culture conditions,surfactant protein C(SPC), an ATII marker, was upregulated in both H12 and B7.Aquaporin 5(AQP5), an ATI marker, was upregulated in H12 and significantly induced in B7. When the RAS/MAPK pathway was inhibited,SPCandthyroid transcription factor-1(TTF-1) expression levels were enhanced. After treatment with dexamethasone (DEX), 8-bromoadenosine 3′5′-cyclic monophosphate (8-Br-cAMP), 3-isobutyl-1-methylxanthine (IBMX), and keratinocyte growth factor (KGF),surfactant protein BandTTF-1expression levels were enhanced. We found that A549-derived clones have plasticity in gene expression of alveolar epithelial differentiation markers and could be useful in studying ATII maintenance and differentiation.

scholarly journals Controversial T1G3 bladder cancer is the key to revealing the changes in the biological functions of bladder cancer cells

2020 ◽  
Author(s):  
Shen Pan ◽  
Yunhong Zhan ◽  
Xiaonan Chen ◽  
Bin Wu ◽  
Bitian Liu
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Cancer Cells ◽  
Interaction Analysis ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Functional Enrichment ◽  
Specific Gene ◽  
Gene Sets ◽  
Bladder Cancer Cells

Abstract Background T1G3 shows a higher chance of recurrence and progression among early bladder cancer types and the available treatment option is controversial. High recurrence and progression are the problems that need to be explored and solved. Changes in the internal signals of bladder cancer cells and differential genes may be the root cause of these problems. Methods GSE120736, GSE19915, GSE19423, GSE32548 and GSE37815 datasets were obtained from Gene Expression Omnibus (GEO ) to identify differentially expressed genes (DEGs). Bladder cancer transcript data from The Cancer Genome Atlas (TCGA) were clustered into different cell-specific gene sets according to weighted gene co-expression network analysis (WGCNA). Multiple sets of databases were used for gene expression comparison, functional enrichment, and protein interaction analysis, including The Human Protein Atlas, Cancer Dependency Map, Metascape, Gene set enrichment analysis, and DisNor. Results DEGs were obtained through GEO data comparison and intersection. After WGCNA was proven to recognise cell-specific gene sets, candidate DEGs were selected and shown to be specifically expressed in cancer cells. Candidate DEGs were related to mitosis and cell cycle. Further, 12 functional candidate markers were identified from the sequencing data of 30 bladder cancer cell lines. These genes were all up-regulated and previously shown to be closely related to bladder cancer progression. Conclusions Twelve functional genes with specific differential expression in bladder cancer cells were identified. WGCNA can identify the relatively specific expression sets of different cells in bladder cancer with greater tumour heterogeneity, which provides new perspectives for future cancer research.

A distinctive subtype of t(14;18)-negative nodal follicular non-Hodgkin lymphoma characterized by a predominantly diffuse growth pattern and deletions in the chromosomal region 1p36

Blood ◽  
2009 ◽  
Vol 113 (5) ◽  
pp. 1053-1061 ◽  
Author(s):  
Tiemo Katzenberger ◽  
Jörg Kalla ◽  
Ellen Leich ◽  
Heike Stöcklein ◽  
Elena Hartmann ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Growth Pattern ◽  
Expression Profiles ◽  
Growth Patterns ◽  
Cell Phenotype ◽  
Specific Gene ◽  
Non Hodgkin Lymphoma ◽  
Diffuse Growth

Abstract Follicular lymphoma (FL) is a morphologically and genetically well-characterized B-cell non-Hodgkin lymphoma that can show predominantly follicular, combined follicular and diffuse, or predominantly diffuse growth patterns. Although approximately 85% of FLs harbor the translocation t(14;18)(q32;q21) and consistently display a follicular growth pattern, predominantly diffuse FLs are less well characterized on the phenotypical, molecular, and clinical level. We studied 35 predominantly diffuse FL by immunohistochemistry, classical chromosome banding analysis, fluorescence in situ hybridization (FISH), and gene expression profiling. A total of 28 of 29 analyzable cases lacked t(14;18), and 27 of 29 cases revealed a unifying chromosomal aberration, a deletion in 1p36. Morphologically, 12 FLs were grade 1 and 23 were grade 2, and the immunophenotype with frequent expression of CD10, BCL6, and CD23 was in line with a germinal center B-cell phenotype. The gene expression profiles of 4 predominantly diffuse FLs fell into the spectrum of typical FL, with a unique enrichment of specific gene signatures. Remarkably, patients with diffuse FL frequently presented with low clinical stage and large but localized inguinal tumors. These results suggest that predominantly diffuse FL represent a distinct subtype of t(14;18)-negative nodal FL with a unifying genetic alteration (deletion of 1p36) and characteristic clinical features.

Constitutive FLT3 Activation Results in Specific Changes in Gene Expression in Myeloid Leukemic Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1115-1115
Author(s):  
Kyu-Tae Kim ◽  
Kristin Baird ◽  
Sean Davis ◽  
Mark Levis ◽  
Obdulio Piloto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Microarray Analysis ◽  
Cdna Microarray ◽  
Mapk Pathway ◽  
Cyclin D3 ◽  
Leukemic Cells ◽  
Cdna Microarray Analysis ◽  
Flt3 Inhibitors ◽  
Before And After

Abstract Constitutively activating internal tandem duplication (ITD) mutations of the receptor tyrosine kinase FLT3 play an important role in leukemogenesis. They are the most common genetic alteration in AML and their presence is associated with poor prognosis. To better understand FLT3 signaling in leukemogenesis, we have examined the changes in gene expression induced by FLT3/ITD or constitutively activated wild type FLT3 signaling by cDNA microarray analysis. In order to minimize gene expression changes that might be drug specific and not related to FLT3 inhibition or might be cell-type specific, we used three different FLT3 inhibitors, CEP-701, CEP-5214, and AG1296, and three different constitutively activated FLT3-expressing leukemia-derived cell lines, EOL-1, MOLM-14 and MV4-11. We considered to be FLT3 responsive only those genes whose expression consistently changed in response to FLT3 inhibition by each of the three FLT3 inhibitors in all of the cell lines. RNA for hybridization to the microarrays was harvested from cells both before and after increasing times of FLT3 inhibition to determine genes which decreased or increased in response to FLT3 signaling. In addition, because the inhibitors are all reversible, RNA was also harvested from the cells at increasing times after release from FLT3 inhibition. This enabled us to confirm that, for example, genes whose expression appeared FLT3 dependent and were thus down-regulated by FLT3 inhibition, returned towards normal levels after FLT3 signaling was allowed to resume. Statistical analysis of the microarray results indicated a limited set of genes are highly and consistently affected by FLT3 inhibition and return toward pretreatment levels after release from inhibitor. We confirmed the cDNA microarray data using quantitative real-time PCR. Several of the most significantly affected genes are involved in the Ras/MAPK pathway including DUSP6, DUSP7, MAPK6, TNF, and cMyc. Other sets of genes are involved in JAK/STAT or Wnt signaling pathways including Pim-1, cMyc, Cyclin D3, IL4 receptor, and CISH. These genes are all consistently down-regulated after FLT3 inhibition. These data further confirm the role of constitutively activating FLT3 in mediating multiple signal transduction pathways. We also found several transcriptional factors (RUNX1/AML1, MAFG, XBP1, TGFBI4, and BRD8), several genes involved in receptor-mediated signaling (IL1RAP, CDC42EP3, PLAUR, LY64), and several genes involved in cell proliferation, metabolism, or structure (BCL7A, APTX, GHRH, SET7, ATAD2, CLIC1, CRIP2, MRPL12, VIM) to be consistently differentially expressed. In summary, we have found by cDNA microarray analysis and confirmed by QPCR, a consistent pattern of FLT3 dependent gene expression. The alteration of the gene expression profile in these cells is likely the mechanism of FLT3-mediated leukemogenisis.

Comprehensive Analysis of Homeobox Gene Expression in Hodgkin Lymphoma Cell Lines Reveals Similarities to Prostate Carcinoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 966-966
Author(s):  
Stefan Nagel ◽  
Christof Burek ◽  
Hilmar Quentmeier ◽  
Corinna Meyer ◽  
Andreas Rosenwald ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Prostate Carcinoma ◽  
Homeobox Genes ◽  
Homeobox Gene ◽  
Cell Cycle Regulators ◽  
Rt Pcr

Abstract Homeobox genes code for transcription factors with essential regulatory impact on cellular processes during embryogenesis and in the adult. Increasingly, members of the circa 200 gene strong family are emerging as major oncogenic players, prompting our investigation into possible homeobox gene dysregulation in Hodgkin lymphoma (HL) in which no recurrent oncogene involvement has been known. Accordingly, we screened 6 well characterized HL cell lines (HDLM-2, KM-H2, L-1236, L-428, L-540, SUP-HD1) and 3 non-Hodgkin lymphoma (NHL) cell lines (RC-K8, RI-1, SC-1) for homeobox gene expression using Affymetrix U133-2.0 whole-genome oligonucleotide microarrays. Of 15 candidate genes thus shown to reveal HL-specific expression patterns, 5 homeobox genes were shortlisted as potentially key dysregulatory targets in HL after additional RT-PCR expression analysis relative to controls. While 3/5 homeobox genes were upregulated in HL (HOXB9, HOXC8, HLXB9), 2/5 were downregulated (BOB1, PAX5). Furthermore, cloning and sequencing RT-PCR products obtained with degenerate primers recognizing conserved homeobox motifs confirmed the predominant expression of HOXB9 in HL cells. However, fluorescence in situ hybridization (FISH) analysis of the HOXB locus (at 17q21) revealed no cytogenetic aberrations, indicating that its activation is conducted non-chromosomally in HL cells. Surprisingly, known target genes of HOXB9 and HOXC8 remained unperturbed, implying novel downstream effector pathways in HL cells. Antisense oligos directed against HOXB9 and forced expression experiments using cloned full length HOXB9 cDNA indicated its involvement in both proliferation and apoptosis. Cell cycle regulators BTG1, BTG2 and GEMININ have been described to interact with HOXB9 and may represent potential targets deserving investigation. We recently showed that HLXB9 promotes IL6 expression in HL cells in response to a constitutively active PI3K signalling pathway therein (Nagel et al., Leukemia19, 841–6, 2005). Our most recent data indicate that HLXB9 is also expressed in various NHL cell lines including anaplastic, diffuse and mediastinal large cell as well as follicular B-cell lymphomas while expression is notably absent from Burkitt, mantle cell and natural killer T-cell lymphomas reflecting their pathologic classification. Intriguingly, our data highlight unexpected similarities between HL and prostate cancer cells which together uniquely overexpress HOXB9, HOXC8 and HLXB9 (or its close homolog GBX2). Additional genes expressed in prostate carcinoma (HOXB13, PRAC1, PRAC2) were detected in two HL cell lines (KM-H2 and L-428) suggesting further parallels may be revealed. Detection of downregulated B-cell differentiation factors BOB1 and PAX5 in our panel of HL cell lines validated this approach. Both factors were previously implicated in oncogenesis of HL lacking IGH rearrangements and other key B-cell characteristics. In summary, we identified a unique homeobox gene expression pattern involving HOXB9, HOXB13, HOXC8 and HLXB9 in HL cell lines resembling that of prostate carcinoma cells. Overexpressed HOXB9 contributes to proliferation and protects against apoptosis in HL cells potentially via interacting with cell cycle regulators BTG1/2 and/or GEMININ.

PD-1/PD-1-Ligand Interaction Contributes to Immunosuppressive Microenvironment of Hodgkin Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 379-379
Author(s):  
Ryo Yamamoto ◽  
Momoko Nishikori ◽  
Toshio Kitawaki ◽  
Tomomi Sakai ◽  
Masakatsu Hishizawa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Signaling System ◽  
Peripheral T Cells ◽  
Ifn Γ ◽  
Immunosuppressive Microenvironment

Abstract Programmed death-1 (PD-1), a member of the CD28 costimulatory receptor superfamily, inhibits T cell activity by providing a second signal to T cells in conjunction with signaling through the T-cell receptor. PD-1/PD-1 ligand (PD-L) signaling system is indicated to be involved in the functional impairment of T cells such as in chronic viral infection or tumor immune evasion. We hypothesized that this signaling system is also involved in the pathogenesis of Hodgkin lymphoma (HL). We examined expression of B7-H1 and B7-DC, two known PD-Ls, in lymphoid cell lines using RT-PCR and flow cytometry. They were expressed in HL and several T-cell lines, whereas most B-NHL lines lacked their expression. Immunohistochemical staining of HL tissues demonstrated that PD-Ls were also expressed in primary H/RS cells. As gene expression of B7-H1 and B7-DC was increased in Epstein-Barr virus (EBV)-transformed lymphoblastoid B-cell lines, we examined the effect of EBV latent membrane proteins on their gene regulation. By luciferase reporter assay, both LMP1 and LMP2A were shown to enhance promoter activity of B7-H1 and B7-DC genes. This finding implies that in cases of EBV-positive HL, latent membrane proteins may help H/RS cells escape from host immune surveillance by upregulating PD-L gene expression. We next analyzed PD-1 expression of tumor-infiltrating T cells of HL tissue samples by flow cytometry, and found that PD-1+ cells were elevated markedly in these cells. As HL patients are well recognized as having defective cellular immunity, we compared PD-1 expression level in peripheral blood T cells of HL patients with those of healthy volunteers and B-NHL patients. PD-1 was significantly elevated in peripheral T cells of HL patients compared to the other two groups. PD-1+ T cells were highest in patients with active disease, and tended to decline along with treatment. Although regulatory T cells are reported to play a part in the pathogenesis of HL, FOXP3+ T cells were not significantly elevated in peripheral T cells of HL patients, and PD-1+ T cells did not overlap with these regulatory population. To elucidate whether the PD-1/PD-L signaling pathway is functional in the immunosuppressive microenvironment of HL, we finally examined the effect of blockade of this pathway. After culturing bulk HL tumor cells with anti-PD-L blocking antibodies, IFN-γ production was measured by ELISA. Blockade of PD-Ls augmented IFN-γ production of HL-infiltrating T cells. We concluded that anti-tumor activity of HL-infiltrating T cells was inhibited via the PD-1/PD-L pathway, and this inhibition could be successfully relieved by PD-L blockade. Taken together, our observations indicate that “T-cell exhaustion” is essential to the pathogenesis of HL, and tumor-infiltrating T cells around H/RS cells seem to be kept in balance by this inhibitory signaling. Our findings provide a potentially effective and clinically applicable strategy for the immunotherapy of HL.

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