Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The outcome of classical Hodgkin lymphoma (cHL) patients may be related to the tumor microenvironment, which in turn may be influenced by Epstein-Barr virus (EBV) infection. To characterize the cHL microenvironment, a set of 63 cHL tissue samples was profiled using DNA microarrays. Their gene expression profile differed from that of histiocyte T cell-rich B-cell lymphoma (H/TCRBCL) samples that were used as controls, mainly due to high expression of PDCD1/PD-1 in H/TCRBCL. EBV(+) cHL tissues could be distinguished from EBV(-) samples by a gene signature characteristic of Th1 and antiviral responses. Samples from cHL patients with favorable outcome overexpressed genes specific for B cells and genes involved in apoptotic pathways. An independent set of 146 cHL samples was analyzed using immunohistochemistry. It showed a significant adverse value in case of high percentage of either TIA-1(+)-reactive cells or topoisomerase-2(+) tumor cells, whereas high numbers of BCL11A(+), FOXP3(+), or CD20(+) reactive cells had a favorable influence. Our results suggest an antitumoral role for B cells in the cHL microenvironment and a stronger stromal influence of the PD1 pathway in H/TCRBCL than cHL. The observation of Th1/ antiviral response in EBV(+) cHL tissues provides a basis for novel treatment strategies.
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PMID:Molecular profiling of classical Hodgkin lymphoma tissues uncovers variations in the tumor microenvironment and correlations with EBV infection and outcome. 1909 12

Follicular helper T-cells (Tfh cells) are a subset of CD4(+) T-cells that are essential for normal production of high affinity antibodies. Tfh cells characteristically produce IL21 and IL4 and show high expression of surface markers CXCR5, ICOS, PDCD1 (PD-1) and the chemokine CXCL13. In this review we will focus on the emerging links between Tfh cells and subtypes of T-cell non-Hodgkin lymphoma: angioimmunoblastic T-cell lymphoma (AITL) and ~20% of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) have surface marker features of Tfh cells and share a spectrum of genetic abnormalities. The recurrent genetic abnormalities associated with AITL include mutations in epigenetic modifiers such as TET2 and DNMT3A and the motility and adhesion gene, RHOA, is mutated in up to 70% of cases. ~20% of PTCL-NOS demonstrate RHOA mutations and have other characteristics suggesting an origin in Tfh cells. The recognition that specific genetic and surface markers are associated with malignant Tfh cells suggests that the next few years will bring major changes in diagnostic and treatment possibilities. For example, antibodies against IL21, PDCD1 and ICOS are already in clinical trials for autoimmune disease or other malignancies and antibodies against CXCL13 are in pre-clinical development.
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PMID:Follicular helper T-cells: expanding roles in T-cell lymphoma and targets for treatment. 2481 71

The blockade of immunological checkpoints has been successfully employed for the treatment of various solid neoplasms including melanoma, mesothelioma, non-small cell lung carcinoma, and renal cell carcinoma. A recent study indicates that the vast majority of patients with advanced, heavily pretreated Hodgkin's lymphoma (HL) also respond to a monoclonal antibody targeting programmed cell death 1 (PDCD1, best known as PD-1). Thus, checkpoint blockers may soon become part of our therapeutic armamentarium against hematological tumors. This would be particularly important as it would spare (at least some) patients the deleterious toxic effects of combinatorial chemotherapies and bone marrow transplantation. We anticipate that the realm of immunotherapy will eventually conquer vast portions of the territory that now belongs to hematological malignancies.
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PMID:Immunotherapy of hematological cancers: PD-1 blockade for the treatment of Hodgkin's lymphoma. 2615 25

Although a poster child for the development and refinement of multi-modal multi-agent therapeutic strategies, Hodgkin Lymphoma has, until recently, lagged behind other lymphomas in terms of the use of therapeutic monoclonal antibodies. This situation has now changed dramatically, with the rapid emergence both of a toxin-conjugated tumour-selective anti-CD30 antibody, and of antibodies targeting immunological checkpoints, most notably PD-1 (also termed PDCD1). The former provides an efficient targeting vehicle for delivery of a potent synthetic anti-mitotic drug, with ultimate efficacy independent of immunological activity. The latter are members of a class of drugs representing a new paradigm in immune-oncological therapies that are designed to enhance pre-existent anti-tumour T cell activities. The role of both in the overall treatment pathway will continue to evolve over coming years. Hodgkin Lymphoma has once again become emblematic of the major trend shifts in cancer therapy.
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PMID:Recent advances in antibody-based therapies for Hodgkin Lymphoma. 2618 92

Successful treatment of many patients with advanced cancer using antibodies against programmed cell death 1 (PD-1; also known as PDCD1) and its ligand (PD-L1; also known as CD274) has highlighted the critical importance of PD-1/PD-L1-mediated immune escape in cancer development. However, the genetic basis for the immune escape has not been fully elucidated, with the exception of elevated PD-L1 expression by gene amplification and utilization of an ectopic promoter by translocation, as reported in Hodgkin and other B-cell lymphomas, as well as stomach adenocarcinoma. Here we show a unique genetic mechanism of immune escape caused by structural variations (SVs) commonly disrupting the 3' region of the PD-L1 gene. Widely affecting multiple common human cancer types, including adult T-cell leukaemia/lymphoma (27%), diffuse large B-cell lymphoma (8%), and stomach adenocarcinoma (2%), these SVs invariably lead to a marked elevation of aberrant PD-L1 transcripts that are stabilized by truncation of the 3'-untranslated region (UTR). Disruption of the Pd-l1 3'-UTR in mice enables immune evasion of EG7-OVA tumour cells with elevated Pd-l1 expression in vivo, which is effectively inhibited by Pd-1/Pd-l1 blockade, supporting the role of relevant SVs in clonal selection through immune evasion. Our findings not only unmask a novel regulatory mechanism of PD-L1 expression, but also suggest that PD-L1 3'-UTR disruption could serve as a genetic marker to identify cancers that actively evade anti-tumour immunity through PD-L1 overexpression.
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PMID:Aberrant PD-L1 expression through 3'-UTR disruption in multiple cancers. 2727 43

T cell non-Hodgkin lymphomas are a heterogeneous group of highly aggressive malignancies with poor clinical outcomes. T cell lymphomas originate from peripheral T cells and are frequently characterized by genetic gain-of-function variants in T cell receptor (TCR) signalling molecules. Although these oncogenic alterations are thought to drive TCR pathways to induce chronic proliferation and cell survival programmes, it remains unclear whether T cells contain tumour suppressors that can counteract these events. Here we show that the acute enforcement of oncogenic TCR signalling in lymphocytes in a mouse model of human T cell lymphoma drives the strong expansion of these cells in vivo. However, this response is short-lived and robustly counteracted by cell-intrinsic mechanisms. A subsequent genome-wide in vivo screen using T cell-specific transposon mutagenesis identified PDCD1, which encodes the inhibitory receptor programmed death-1 (PD-1), as a master gene that suppresses oncogenic T cell signalling. Mono- and bi-allelic deletions of PDCD1 are also recurrently observed in human T cell lymphomas with frequencies that can exceed 30%, indicating high clinical relevance. Mechanistically, the activity of PD-1 enhances levels of the tumour suppressor PTEN and attenuates signalling by the kinases AKT and PKC in pre-malignant cells. By contrast, a homo- or heterozygous deletion of PD-1 allows unrestricted T cell growth after an oncogenic insult and leads to the rapid development of highly aggressive lymphomas in vivo that are readily transplantable to recipients. Thus, the inhibitory PD-1 receptor is a potent haploinsufficient tumour suppressor in T cell lymphomas that is frequently altered in human disease. These findings extend the known physiological functions of PD-1 beyond the prevention of immunopathology after antigen-induced T cell activation, and have implications for T cell lymphoma therapies and for current strategies that target PD-1 in the broader context of immuno-oncology.
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PMID:PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis. 2918 26

Background and Aims: Polymorphisms in the immune response genes can contribute to clearance of hepatitis C virus (HCV) infection but also mediate liver inflammation and cancer pathogenesis. This study aimed to investigate the association of polymorphisms in PD-1 (PDCD1), IFNL3 (IL28B), and TLR2 immune related genes in chronic HCV patients with different hepatic and lymphoproliferative HCV-related diseases. Methods: Selected PDCD1, IFNL3, and TLR2 genes were tested by molecular approaches in 450 HCV-positive patients with increasing severity of underlying liver diseases [including chronic infection (CHC), cirrhosis and hepatocellular carcinoma (HCC)], in 238 HCV-positive patients with lymphoproliferative diseases [such as cryoglobulinemia and non-Hodgkin lymphoma (NHL)] and in 94 blood donors (BD). Results: While the rs12979860 IFNL3 T allele was found a good marker associated with HCV-outcome together with the rs111200466 TLR2 del variant, the rs10204525 PD-1.6 A allele was found to have an insignificant role in patients with HCV-related hepatic disorders. Though in Asian patients the combination of IFNL3 and PD-1.6 markers better define the HCV-related outcomes, in our series of Caucasian patients the PD-1.6 A-allele variant was observed very rarely. Conclusion: Differences in the incidence of HCV-related HCC and clinical response between Asians and Europeans may be partially due to the distribution of PD-1.6 genotype that we found divergent between these two populations. On the other hand, we confirmed in this study that the polymorphic variants within IFNL3 and TLR2 immune response genes are significantly associated with HCV-related disease progression in our cohort of Italian patients.
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PMID:Clinical Significance of Polymorphisms in Immune Response Genes in Hepatitis C-Related Hepatocellular Carcinoma. 3093 Aug 76