scholarly journals New insights in the biology of Hodgkin lymphoma

Hematology ◽  
2012 ◽  
Vol 2012 (1) ◽  
pp. 328-334 ◽  
Author(s):  
Ralf Küppers
Keyword(s):  
T Cells ◽  
B Cells ◽  
Signaling Pathways ◽  
Hodgkin Lymphoma ◽  
Tumor Cells ◽  
Cytotoxic T Cells ◽  
Cell Gene Expression ◽  
Expression Program ◽  
Multiple Signaling ◽  
Cell Gene

Abstract The Hodgkin and Reed/Sternberg (HRS) tumor cells of classical Hodgkin lymphoma (HL) and the lymphocyte-predominant tumor cells of nodular lymphocyte–predominant HL are both derived from germinal center B cells. HRS cells, however, have largely lost their B-cell gene-expression program and coexpress genes typical of various types of hematopoietic cells. Multiple signaling pathways show a deregulated activity in HRS cells. The genetic lesions involved in the pathogenesis of HL are only partly known, but numerous members and regulators of the NF-κB and JAK/STAT signaling pathways are affected, suggesting an important role for these pathways in HL pathogenesis. Some genetic lesions involve epigenetic regulators, and there is emerging evidence that HRS cells have undergone extensive epigenetic alterations compared with normal B cells. HRS and lymphocyte-predominant cells are usually rare in the lymphoma tissue, and interactions with other cells in the microenvironment are likely critical for HL pathophysiology. T cells represent a main population of infiltrating cells, and it appears that HRS cells both inhibit cytotoxic T cells efficiently and also receive survival signals from Th cells in direct contact with them.

scholarly journals Molecular biology of Hodgkin lymphoma

Leukemia ◽  
2021 ◽  
Vol 35 (4) ◽  
pp. 968-981
Author(s):  
Marc A. Weniger ◽  
Ralf Küppers
Keyword(s):  
B Cells ◽  
B Cell ◽  
Signaling Pathways ◽  
Hodgkin Lymphoma ◽  
Tumor Cells ◽  
Bacterial Antigen ◽  
Cellular Interactions ◽  
Constitutive Activation ◽  
Expression Program ◽  
Hodgkin Cells

AbstractClassical Hodgkin lymphoma (cHL) is unique among lymphoid malignancies in several key biological features. (i) The Hodgkin and Reed-Sternberg (HRS) tumor cells are rare among an extensive and complex microenvironment. (ii) They derive from B cells, but have largely lost the B-cell typical gene expression program. (iii) Their specific origin appears to be pre-apoptotic germinal center (GC) B cells. (iv) They consistently develop bi- or multinucleated Reed-Sternberg cells from mononuclear Hodgkin cells. (v) They show constitutive activation of numerous signaling pathways. Recent studies have begun to uncover the basis of these specific features of cHL: HRS cells actively orchestrate their complex microenvironment and attract many distinct subsets of immune cells into the affected tissues, to support their survival and proliferation, and to create an immunosuppressive environment. Reed-Sternberg cells are generated by incomplete cytokinesis and refusion of Hodgkin cells. Epstein-Barr virus (EBV) plays a major role in the rescue of crippled GC B cells from apoptosis and hence is a main player in early steps of lymphomagenesis of EBV+ cHL cases. The analysis of the landscape of genetic lesions in HRS cells so far did not reveal any highly recurrent HRS cell-specific lesions, but major roles of genetic lesions in members of the NF-κB and JAK/STAT pathways and of factors of immune evasion. It is perhaps the combination of the genetic lesions and the peculiar cellular origin of HRS cells that are disease defining. A combination of such genetic lesions and multiple cellular interactions with cells in the microenvironment causes the constitutive activation of many signaling pathways, often interacting in complex fashions. In nodular lymphocyte predominant Hodgkin lymphoma, the GC B cell-derived tumor cells have largely retained their typical GC B-cell expression program and follicular microenvironment. For IgD-positive cases, bacterial antigen triggering has recently been implicated in early stages of its pathogenesis.

Nodular lymphocyte-predominant Hodgkin lymphoma with nodules resembling T-cell/histiocyte-rich B-cell lymphoma: differential diagnosis between nodular lymphocyte-predominant Hodgkin lymphoma and T-cell/histiocyte-rich B-cell lymphoma

Blood ◽  
2003 ◽  
Vol 102 (10) ◽  
pp. 3753-3758 ◽  
Author(s):  
Ludmila Boudová ◽  
Emina Torlakovic ◽  
Jan Delabie ◽  
Peter Reimer ◽  
Beate Pfistner ◽  
...  
Keyword(s):  
T Cells ◽  
Differential Diagnosis ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Tumor Cells ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
World Health

AbstractNodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) and T-cell/histiocyte-rich B-cell lymphoma (T/HRBCL) are distinct tumors and are treated differently. They are linked by a morphologic and probably a biologic continuum, which renders the differential diagnosis difficult. To develop criteria to distinguish the entities along the morphologic continuum, we correlated the lymph node architecture and immunophenotype of both tumor cells and reactive components of 235 neoplasms in the spectrum of NLPHL and T/HRBCL with clinical data. Two hundred and eighteen cases fitted the World Health Organization (WHO) criteria of NLPHL (139) or T/HRBCL (79). While tumor cells in both entities were immunophenotypically similar, background composition differed: in NLPHL small B cells and CD3+CD4+CD57+ T cells were common, whereas in T/HRBCL, CD8+ cytotoxic T cells and histiocytes dominated. Follicular dendritic cells (FDCs) formed expanded meshworks in NLPHL, whereas they were absent in T/HRBCL. Seventeen cases represented a gray zone: within FDC meshworks, neoplastic B cells resided in a background depleted of small B cells but rich in T cells and histiocytes. Tumor cells either were loosely scattered or formed clusters, thus resembling areas of either T/HRBCL or inflammatory diffuse large BCL (DLBCL) within the nodules. Patients with these NLPHLs with T-cell/histiocyte-rich nodules presented at a high stage and with B symptoms, as in T/HRBCL, but had an excellent survival, as in NLPHL. This morphologic pattern suggests a biologic continuum between NLPHL and T/HRBCL. (Blood. 2003;102:3753-3758)

scholarly journals 46 Proximity between cytotoxic antigen-experienced T cells and tumor cells is associated with improved clinical outcomes in early-stage NSCLC

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A53-A53
Author(s):  
Qianyun Luo ◽  
Edwin Parra ◽  
Marcelo Negrao ◽  
Neal Akhave ◽  
Erin Bayley ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Tumor Cells ◽  
Clinical Outcomes ◽  
Early Stage ◽  
Cytotoxic T Cells ◽  
Small Cell ◽  
Small Cell Lung ◽  
Early Stage Nsclc ◽  
Nsclc Patients

BackgroundWhile the development of immunotherapies has improved the treatment of non-small cell lung cancer (NSCLC), most patients still fail to respond. Immune cell densities have been utilized to predict clinical responses but have largely failed to do so. However, the spatial distribution and interaction of these cells at the tissue level have been less studied. Here, we performed spatial analysis of the cells within the tumor immune microenvironment in order to evaluate their relationship with clinical outcomes in early-stage NSCLC.MethodsMultiplex immunofluorescence was performed on 123 early-stage NSCLC patients from the ICON (Immunogenomic profiling of non-small cell lung cancer) cohort including Cytokeratin (CK), CD3, CD8, CD45RO, FoxP3, CD68, CD20, CD57, Granzyme B (GzmB), PD-1, and PD-L1. Area under the curve (AUC) was calculated using Ripley’s L function, which evaluates the degree of spatial proximity of two cell populations, with a high AUC indicating clustering and low AUC indicating scattering. Findings were integrated with clinical parameters.ResultsAdenocarcinomas demonstrated CD3+PD1+ T cells were closer to CK+ tumor cells (n=60, p=0.035), and B cells were closer to cytotoxic T cells (n=43, p=0.03) than in squamous cell carcinoma. Higher AUC was observed between CD3+PD1+ T cells (n=56, p=0.035), with cytotoxic antigen-experienced T cells (CD45RO+GzmB+) closer to tumor cells (n=35, p=0.017) in stage I and II compared to stage III tumors. Untreated patient tumors exhibited higher proximity between CD20+ B cells and CD57+ NK cells (n=59, p=0.012), CD3+ T cells and PD-L1+ tumor cells (n=56, p=0.027), and CD68+ macrophages and PD-L1+ tumor cells (n=52, p=0.016) than neoadjuvant chemotherapy-treated patients. Patients with no recurrence presented higher AUC in antigen-experienced CD45RO+GzmB+ T cells and tumor cells (n=36, p=0.006), while those with improved survival demonstrated greater proximity between CD68+ macrophages and PD-L1+ tumors (n=52, p=0.016), CD20+ B cells and GzmB+ cells (n=49, p=0.03), and antigen-experienced CD45RO+GzmB+ T cells and tumor cells (n=36, p=0.047). Lastly, patients with improved survival also displayed greater proximity between CD3+CD8+ cytotoxic T cells and PD-L1- epithelial cells (n=76, p=0.04) in tumors versus matched adjacent lungs.ConclusionsOverall, our findings shed light on some of the potential cell interactions at play in the tumor microenvironment of early-stage NSCLC patients and suggest cell distributions could be utilized to predict clinical outcomes in early-stage NSCLC patients.

scholarly journals Selective Induction of Th2-Attracting Chemokines CCL17 and CCL22 in Human B Cells by Latent Membrane Protein 1 of Epstein-Barr Virus

2004 ◽  
Vol 78 (4) ◽  
pp. 1665-1674 ◽  
Author(s):  
Takashi Nakayama ◽  
Kunio Hieshima ◽  
Daisuke Nagakubo ◽  
Emiko Sato ◽  
Masahiro Nakayama ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Regulatory T Cells ◽  
Epstein Barr Virus ◽  
Cytotoxic T Cells ◽  
Th2 Cells ◽  
Th1 Cells ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

ABSTRACT Chemokines are likely to play important roles in the pathophysiology of diseases associated with Epstein-Barr virus (EBV). Here, we have analyzed the repertoire of chemokines expressed by EBV-infected B cells. EBV infection of B cells induced expression of TARC/CCL17 and MDC/CCL22, which are known to attract Th2 cells and regulatory T cells via CCR4, and also upregulated constitutive expression of MIP-1α/CCL3, MIP-1β/CCL4, and RANTES/CCL5, which are known to attract Th1 cells and cytotoxic T cells via CCR5. Accordingly, EBV-immortalized B cells secreted these chemokines, especially CCL3, CCL4, and CCL22, in large quantities. EBV infection or stable expression of LMP1 also induced CCL17 and CCL22 in a B-cell line, BJAB. The inhibitors of the TRAF/NF-κB pathway (BAY11-7082) and the p38/ATF2 pathway (SB202190) selectively suppressed the expression of CCL17 and CCL22 in EBV-immortalized B cells and BJAB-LMP1. Consistently, transient-transfection assays using CCL22 promoter-reporter constructs demonstrated that two NF-κB sites and a single AP-1 site were involved in the activation of the CCL22 promoter by LMP1. Finally, serum CCL22 levels were significantly elevated in infectious mononucleosis. Collectively, LMP1 induces CCL17 and CCL22 in EBV-infected B cells via activation of NF-κB and probably ATF2. Production of CCL17 and CCL22, which attract Th2 and regulatory T cells, may help EBV-infected B cells evade immune surveillance by Th1 cells. However, the concomitant production of CCL3, CCL4, and CCL5 by EBV-infected B cells may eventually attract Th1 cells and cytotoxic T cells, leading to elimination of EBV-infected B cells at latency III and to selection of those with limited expression of latent genes.

scholarly journals P2.03-37 The Efficiency of Octamer-4 Specific Cytotoxic T Cells Induce By CD40-B Cells in Killing Lung Cancer Stem-Like Cells

2018 ◽  
Vol 13 (10) ◽  
pp. S730
Author(s):  
X. Zhang ◽  
J. Xu ◽  
F. Hu ◽  
H. Wang ◽  
X. Zheng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
B Cells ◽  
Cytotoxic T Cells

scholarly journals Participation of the H-2 antigens of tumor cells in their lysis by syngeneic T cells.

1976 ◽  
Vol 143 (3) ◽  
pp. 601-614 ◽  
Author(s):  
J W Schrader ◽  
G M Edelman
Keyword(s):  
T Cells ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Target Cell ◽  
Cytotoxic T Cells ◽  
Hybrid Origin ◽  
Target Cells ◽  
Cytotoxic Lymphocytes ◽  
Effector Cells

Cytotoxic T lymphocytes were generated in vitro against H-2 compatible or syngeneic tumor cells. In vitro cytotoxic activity was inhibited by specific anti-H2 sera, suggesting that H-2 antigens are involved in cell lysis. Two observations directly demonstrated the participation of the H-2 antigens on the tumor cells in their lysis by H-2-compatible T cells. First, coating of the H-2 antigens on the target tumor cell reduced the number of cells lysed on subsequent exposure to cytotoxic T cells. Second, when cytotoxic T cells were activated against an H-2 compatible tumor and assayed against an H-2-incompatible tumor, anti-H-2 serum that could bind to the target cell, but not to the cytotoxic lymphocyte, inhibited lysis. H-2 antigens were also shown to be present on the cytotoxic lymphocytes. Specific antisera reacting with these H-2 antigens, but not those of the target cell, failed to inhibit lysis when small numbers of effector cells were assayed against H-2-incompatible target cells or when effector cells of F1-hybrid origin and bearing two H-2 haplotypes were assayed against a tumor cell of one of the parental strains. These findings suggest that it is the H-2 antigens on the tumor cell and not those on the cytotoxic lymphocytes that are important in cell-mediated lysis of H-2-compatible tumor cells.

scholarly journals Hematopoietic lineage-converted T cells carrying tumor-associated antigen-recognizing TCRs effectively kill tumor cells

2020 ◽  
Vol 8 (2) ◽  
pp. e000498
Author(s):  
Fangxiao Hu ◽  
Dehao Huang ◽  
Yuxuan Luo ◽  
Peiqing Zhou ◽  
Cui Lv ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Tumor Cells ◽  
Cell Receptor ◽  
Histocompatibility Complex ◽  
Tumor Associated Antigen ◽  
Engineered T Cells ◽  
Antitumor Immunotherapy

Tumor-associated antigen (TAA) T-cell receptor (TCR) gene-engineered T cells exhibit great potential in antitumor immunotherapy. Considering the high costs and low availability of patient-derived peripheral blood T cells, substantial efforts have been made to explore alternatives to natural T cells. We previously reported that enforced expression of Hoxb5 converted B cells into induced T (iT) cells in vivo. Here, we successfully regenerated naive OT1 (major histocompatibility complex I restricted ovalbumin antigen) iT cells (OT1-iT) in vivo by expressing Hoxb5 in pro-pre-B cells in the OT1 transgenic mouse. The OT1-iT cells can be activated and expanded in vitro in the presence of tumor cells. Particularly, these regenerated OT1-iT cells effectively eradicated tumor cells expressing the TAA (ovalbumin) both in vitro and in vivo. This study provides insights into the translational applications of blood lineage-transdifferentiated T cells in immunotherapy.

scholarly journals Novel agents and immune invasion in Hodgkin lymphoma

Hematology ◽  
2019 ◽  
Vol 2019 (1) ◽  
pp. 243-248 ◽  
Author(s):  
Reid W. Merryman ◽  
Ann LaCasce
Keyword(s):  
T Cells ◽  
Hodgkin Lymphoma ◽  
Cytotoxic T Cells ◽  
Rapid Development ◽  
Predictive Biomarkers ◽  
Treatment Resistance ◽  
Brentuximab Vedotin ◽  
Antibody Drug Conjugate ◽  
Barr Virus ◽  
Epstein Barr

Abstract The approval of brentuximab vedotin (BV) and the PD-1 inhibitors nivolumab and pembrolizumab has dramatically improved outcomes for patients with relapsed or refractory (R/R) classic Hodgkin lymphoma (HL). With the goal of increasing long-term disease control rates and decreasing late toxicities, these agents are currently being tested in earlier phases of treatment in combination with chemotherapy agents. In the R/R setting, our expanding understanding of HL’s various mechanisms of immune evasion and treatment resistance has spurred a growing number of rationally designed combination trials. Beyond BV and PD-1 blockade, other novel therapies have demonstrated encouraging preliminary results, including targeted agents, like the CD25 antibody-drug conjugate ADCT-301, and cellular therapies, including CD30 chimeric antigen receptor T cells and Epstein-Barr virus (EBV)-directed cytotoxic T cells. These trials, coupled with the rapid development of prognostic and predictive biomarkers, should drive additional breakthroughs that promise safer and more effective therapies for patients with HL in the future.

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