Project description:We produced and analyzed the transcriptomic profiles of 40 lymphoma patients. We used microarrays to compare the global gene expression profile between the different subtypes. These samples were analyzed with a tool predictive of immune escape mechanisms previously developped, IEGS33. Depending on lymphoma subtype, different immune escape signatures can be observed. Therapeutic based on PD-1/PD-L1 blockade shows promising results in Hodgkin lymphoma (HL) and in some diffuse large B-cell lymphoma (DLBCL) patients but biomarkers predicting therapeutic response are still lacking. To gain understanding on the overall immune-escape (IE) mechanism, we recently developed a tool to score the transcriptional IE hallmarks in lymphoma samples and identified four stages of cancer immune-editing in DLBCL that correlated with overall survival. Through this method, we described here the IE profiles in HL and DLBCL from a meta-analysis of large series of microarrays. We observed that HL clustered together at the late equilibrium-early escape stage of cancer immune-editing with significant enrichment of genes involved in IE and T-cell activation as compared to DLBCL. Deconvolution of transcriptomes and immunohistochimistry showed that HL had higher CD3+ and CD4+ T-cells than all DLBCL and shared high abundance of CD8+ T-cells with DLBCL ABC and low infiltrates of CD68+CD163+ macrophages with DLBCL GC. HL and DLBCL shared the same cellular distribution of PD-1 and TIM3 staining but HL exhibited a higher expression of PD-L1 in tumor cells as well as LAG3 overexpression in ME as compared to DLBCL. Finally, our bioinformatic tools based on IEGS33 and T cell activation scores as global approach of immune escape mechanisms help to investigate in details the ME of HL. This method may be useful tool to identify HL as well as DLBCL patients who better benefit from immunotherapy strategies.
Project description:Immunoglobulin gene rearrangement and somatic hypermutation have the potential to create neoantigens in non-Hodgkin B cell lymphoma. However, the presentation of these putative immunoglobulin neoantigens by B cell lymphomas has not been proven. We used MHC immunoprecipitation followed by liquid chromatography and tandem mass spectrometry (LC-MS/MS) to define antigens presented by follicular lymphomas (FL), chronic lymphocytic leukemias (CLL), diffuse large B cell lymphoma (DLBCL) and mantle cell lymphomas (MCL). We found presentation of the clonal immunoglobulin molecule, including neoantigens by both class I and class II MHC, though more commonly in class II MHC. To determine whether B cell activation could promote presentation of immunoglobulin neoantigens, we used a toll-like receptor 9 (TLR9) agonists to upregulate expression of MHC-II. This resulted in enhanced class II MHC presentation of the immunoglobulin variable region including neoantigens. These findings demonstrate that immunoglobulin neoantigens are presented across most subtypes of B cell lymphomas. Activation of lymphoma cells to upregulate antigen presentation boosts presentation of immunoglobulin neoantigens and represents a strategy for augmenting lymphoma immunotherapies.
Project description:Ocular adnexal lymphoma is a rare subtype of non-Hodgkin lymphoma. DIA LC-MS of serum samples collected at diagnosis was performed on 38 ocular adnexal lymphomas (28 extranodal marginal zone lymphomas, and 10 diffuse large B-cell lymphomas), and 20 controls (10 idiopathic orbital inflammation, and 10 reactive lymphoid hyperplasia). Complete clinicopathologic features of these patients were collected.
Project description:Nijmegen-breakage syndrome (NBS, OMIM #251260) is an autosomal recessive chromosomal instability syndrome characterized by a very distinct phenotype (microcephaly, growth retardation, immunodeficiency) associated with increased predisposition to develop malignancies, particularly of lymphoid origin (by the age of 20 years, over 40% of NBS patients develop cancer). Immunological lineage of lymphomas in NBS significantly differs from Non-Hodgkin Lymphomas (NHL) entities observed in general pediatric population as well as in primary immunodeficiencies. There is a strong predominance of diffuse large B-cell lymphoma (DLBCL) and T cell lymphoblastic lymphoma (T-LBL/ALL), all showing clonal Ig/TCR rearrangements. In the current study we aimed to examined gene expression signature of metabolic pathways in DLBCL cells.
Project description:Genomewide gene expression analysis of lymphoid cell lines of Hodgkin, non-Hodgkin and acute leukemia origin Affymetrix U133 Plus 2.0 oligonucleotide arrays were hybridized to determine the gene expression profile of Hodgkin (L428, L1236, KM-H2, HDLM-2, L540, L540Cy), non-Hodgkin (Namalwa, SU-DHL-4) and acute lymphoblastic leukemia (Reh) cell lines; all hybridizations were done in biological duplicates (except L540, L50Cy, SU-DHL-4).
Project description:Anaplastic large cell lymphoma (ALCL) is a main type of T cell lymphomas and comprises three distinct entities: systemic ALK+, systemic ALK- and cutaneous ALK- ALCL. Little is known about their pathogenesis and their cellular origin, and morphological and immunophenotypical overlap exists between ALK- ALCL and classical Hodgkin lymphoma (cHL). We conducted gene expression profiling of microdissected lymphoma cells of ALK+ and ALK- systemic ALCL, cutaneous ALCL and cHL, and of eight subsets of normal T and NK cells. The analysis supports a derivation of ALCL from activated T cells, but the lymphoma cells acquired a gene expression pattern hampering an assignment to a CD4+, CD8+ or CD30+ T cell origin. Indeed, ALCL display a general down-modulation of T cell characteristic molecules. All ALCL types show significant expression of NFκB target genes and upregulation of genes involved in oncogenesis (e.g. EZH2). Surprisingly few genes are differentially expressed between systemic and cutaneous ALK- ALCL despite their different clinical behaviour, and between ALK- ALCL and cHL despite their different cellular origin. ALK+ ALCL are characterized by expression of genes regulated by pathways constitutively activated by ALK. This study provides multiple novel insights into the molecular biology and pathogenesis of ALCL.
Project description:Non-Hodgkin lymphomas (NHL) make up the majority of lymphoma diagnoses and represent a very diverse set of malignancies. We sought to identify kinases uniquely upregulated in different NHL subtypes. Using Multiplexed Inhibitor Bead-mass spectrometry (MIB/MS), we found Tyro3 was uniquely upregulated and important for cell survival in primary effusion lymphoma (PEL), which is a viral lymphoma infected with Kaposi’s sarcoma-associated herpesvirus (KSHV).
Project description:Our studies identify the role of mIR-28 in germinal center response and its therapeutic potential for the treatment of non-Hodgkin lymphomas
Project description:Pet dogs may provide a useful large-animal model of spontaneously occuring non-Hodgkin lymphoma, but complete molecular characterization is lacking. We used gene expression microarrays to molecularly characterize canine lymphoma, and found similarities between canine B-cell lymphoma and human diffuse large B-cell lymphoma.