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1.
Cell ; 171(2): 481-494.e15, 2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28985567

RESUMO

Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic and clinical heterogeneity. This heterogeneity poses a major barrier to understanding the genetic basis of the disease and its response to therapy. Here, we performed an integrative analysis of whole-exome sequencing and transcriptome sequencing in a cohort of 1,001 DLBCL patients to comprehensively define the landscape of 150 genetic drivers of the disease. We characterized the functional impact of these genes using an unbiased CRISPR screen of DLBCL cell lines to define oncogenes that promote cell growth. A prognostic model comprising these genetic alterations outperformed current established methods: cell of origin, the International Prognostic Index comprising clinical variables, and dual MYC and BCL2 expression. These results comprehensively define the genetic drivers and their functional roles in DLBCL to identify new therapeutic opportunities in the disease.


Assuntos
Sistemas CRISPR-Cas , Perfilação da Expressão Gênica , Linfoma Difuso de Grandes Células B/genética , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Células Cultivadas , Exoma , Feminino , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Rituximab/administração & dosagem
2.
Immunity ; 54(8): 1788-1806.e7, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34166622

RESUMO

Lymphoid stromal cells (LSCs) are essential organizers of immune responses. We analyzed tonsillar tissue by combining flow cytometry, in situ imaging, RNA sequencing, and functional assays, defining three distinct human LSC subsets. The integrin CD49a designated perivascular stromal cells exhibiting features of local committed LSC precursors and segregated cytokine and chemokine-producing fibroblastic reticular cells (FRCs) supporting B and T cell survival. The follicular dendritic cell transcriptional profile reflected active responses to B cell and non-B cell stimuli. We therefore examined the effect of B cell stimuli on LSCs in follicular lymphoma (FL). FL B cells interacted primarily with CD49a+ FRCs. Transcriptional analyses revealed LSC reprogramming in situ downstream of the cytokines tumor necrosis factor (TNF) and transforming growth factor ß (TGF-ß), including increased expression of the chemokines CCL19 and CCL21. Our findings define human LSC populations in healthy tissue and reveal bidirectional crosstalk between LSCs and malignant B cells that may present a targetable axis in lymphoma.


Assuntos
Linfócitos B/imunologia , Células Dendríticas/imunologia , Linfoma Folicular/imunologia , Linfoma Folicular/patologia , Tonsila Palatina/imunologia , Células Estromais/imunologia , Células Cultivadas , Quimiocina CCL19/metabolismo , Quimiocina CCL21/metabolismo , Humanos , Integrina alfa1/metabolismo , Tonsila Palatina/citologia , Transdução de Sinais/imunologia , Células Estromais/citologia , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
3.
Immunity ; 54(1): 116-131.e10, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33271120

RESUMO

Tumors frequently subvert major histocompatibility complex class I (MHC-I) peptide presentation to evade CD8+ T cell immunosurveillance, though how this is accomplished is not always well defined. To identify the global regulatory networks controlling antigen presentation, we employed genome-wide screening in human diffuse large B cell lymphomas (DLBCLs). This approach revealed dozens of genes that positively and negatively modulate MHC-I cell surface expression. Validated genes clustered in multiple pathways including cytokine signaling, mRNA processing, endosomal trafficking, and protein metabolism. Genes can exhibit lymphoma subtype- or tumor-specific MHC-I regulation, and a majority of primary DLBCL tumors displayed genetic alterations in multiple regulators. We established SUGT1 as a major positive regulator of both MHC-I and MHC-II cell surface expression. Further, pharmacological inhibition of two negative regulators of antigen presentation, EZH2 and thymidylate synthase, enhanced DLBCL MHC-I presentation. These and other genes represent potential targets for manipulating MHC-I immunosurveillance in cancers, infectious diseases, and autoimmunity.


Assuntos
Linfócitos B/fisiologia , Biomarcadores Tumorais/genética , Antígenos HLA/genética , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe I/genética , Linfoma Difuso de Grandes Células B/genética , Carcinogênese/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Linhagem da Célula , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Regulação Neoplásica da Expressão Gênica , Testes Genéticos , Estudo de Associação Genômica Ampla , Antígenos HLA/metabolismo , Humanos , Vigilância Imunológica , Linfoma Difuso de Grandes Células B/metabolismo , Evasão Tumoral/genética
4.
Immunity ; 53(5): 952-970.e11, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33098766

RESUMO

Precise targeting of activation-induced cytidine deaminase (AID) to immunoglobulin (Ig) loci promotes antibody class switch recombination (CSR) and somatic hypermutation (SHM), whereas AID targeting of non-Ig loci can generate oncogenic DNA lesions. Here, we examined the contribution of G-quadruplex (G4) nucleic acid structures to AID targeting in vivo. Mice bearing a mutation in Aicda (AIDG133V) that disrupts AID-G4 binding modeled the pathology of hyper-IgM syndrome patients with an orthologous mutation, lacked CSR and SHM, and had broad defects in genome-wide AIDG133V chromatin localization. Genome-wide analyses also revealed that wild-type AID localized to MHCII genes, and AID expression correlated with decreased MHCII expression in germinal center B cells and diffuse large B cell lymphoma. Our findings indicate a crucial role for G4 binding in AID targeting and suggest that AID activity may extend beyond Ig loci to regulate the expression of genes relevant to the physiology and pathology of activated B cells.


Assuntos
Cromatina/genética , Cromatina/metabolismo , Citidina Desaminase/genética , Citidina Desaminase/metabolismo , Quadruplex G , Síndrome de Imunodeficiência com Hiper-IgM/etiologia , Síndrome de Imunodeficiência com Hiper-IgM/metabolismo , Mutação , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biologia Computacional/métodos , Modelos Animais de Doenças , Suscetibilidade a Doenças , Ativação Enzimática , Imunofluorescência , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Antígenos HLA/genética , Antígenos HLA/imunologia , Humanos , Síndrome de Imunodeficiência com Hiper-IgM/diagnóstico , Switching de Imunoglobulina/genética , Switching de Imunoglobulina/imunologia , Imunofenotipagem , Ativação Linfocitária/genética , Linfoma Difuso de Grandes Células B/etiologia , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Camundongos Transgênicos
5.
Immunity ; 50(5): 1305-1316.e6, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-30979688

RESUMO

Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with epithelial-cell cancers and B cell lymphomas. An effective EBV vaccine is not available. We found that antibodies to the EBV glycoprotein gH/gL complex were the principal components in human plasma that neutralized infection of epithelial cells and that antibodies to gH/gL and gp42 contributed to B cell neutralization. Immunization of mice and nonhuman primates with nanoparticle vaccines that displayed components of the viral-fusion machinery EBV gH/gL or gH/gL/gp42 elicited antibodies that potently neutralized both epithelial-cell and B cell infection. Immune serum from nonhuman primates inhibited EBV-glycoprotein-mediated fusion of epithelial cells and B cells and targeted an epitope critical for virus-cell fusion. Therefore, unlike the leading EBV gp350 vaccine candidate, which only protects B cells from infection, these EBV nanoparticle vaccines elicit antibodies that inhibit the virus-fusion apparatus and provide cell-type-independent protection from virus infection.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , Células Epiteliais/imunologia , Infecções por Vírus Epstein-Barr/prevenção & controle , Herpesvirus Humano 4/imunologia , Glicoproteínas de Membrana/imunologia , Proteínas do Envelope Viral/imunologia , Animais , Linfócitos B/virologia , Células CHO , Fusão Celular , Linhagem Celular Tumoral , Cricetulus , Células Epiteliais/virologia , Infecções por Vírus Epstein-Barr/imunologia , Feminino , Células HEK293 , Células HeLa , Humanos , Soros Imunes/administração & dosagem , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Vacinas de Partículas Semelhantes a Vírus/imunologia , Vacinas Virais/imunologia , Ligação Viral
6.
Mol Cell ; 80(5): 845-861.e10, 2020 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-33232656

RESUMO

Locus control region (LCR) functions define cellular identity and have critical roles in diseases such as cancer, although the hierarchy of structural components and associated factors that drive functionality are incompletely understood. Here we show that OCA-B, a B cell-specific coactivator essential for germinal center (GC) formation, forms a ternary complex with the lymphoid-enriched OCT2 and GC-specific MEF2B transcription factors and that this complex occupies and activates an LCR that regulates the BCL6 proto-oncogene and is uniquely required by normal and malignant GC B cells. Mechanistically, through OCA-B-MED1 interactions, this complex is required for Mediator association with the BCL6 promoter. Densely tiled CRISPRi screening indicates that only LCR segments heavily bound by this ternary complex are essential for its function. Our results demonstrate how an intimately linked complex of lineage- and stage-specific factors converges on specific and highly essential enhancer elements to drive the function of a cell-type-defining LCR.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Região de Controle de Locus Gênico/imunologia , Animais , Linfócitos B/citologia , Linhagem Celular Tumoral , Centro Germinativo/citologia , Células HEK293 , Humanos , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/imunologia , Camundongos , Camundongos Knockout , Transportador 2 de Cátion Orgânico/genética , Transportador 2 de Cátion Orgânico/imunologia , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/imunologia , Transativadores/genética , Transativadores/imunologia
7.
Proc Natl Acad Sci U S A ; 121(10): e2309957121, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38422022

RESUMO

Hypoxia signaling influences tumor development through both cell-intrinsic and -extrinsic pathways. Inhibiting hypoxia-inducible factor (HIF) function has recently been approved as a cancer treatment strategy. Hence, it is important to understand how regulators of HIF may affect tumor growth under physiological conditions. Here we report that in aging mice factor-inhibiting HIF (FIH), one of the most studied negative regulators of HIF, is a haploinsufficient suppressor of spontaneous B cell lymphomas, particular pulmonary B cell lymphomas. FIH deficiency alters immune composition in aged mice and creates a tumor-supportive immune environment demonstrated in syngeneic mouse tumor models. Mechanistically, FIH-defective myeloid cells acquire tumor-supportive properties in response to signals secreted by cancer cells or produced in the tumor microenvironment with enhanced arginase expression and cytokine-directed migration. Together, these data demonstrate that under physiological conditions, FIH plays a key role in maintaining immune homeostasis and can suppress tumorigenesis through a cell-extrinsic pathway.


Assuntos
Linfoma de Células B , Proteínas Repressoras , Animais , Camundongos , Hipóxia/metabolismo , Oxigenases de Função Mista/metabolismo , Proteínas Repressoras/metabolismo , Microambiente Tumoral
8.
Proc Natl Acad Sci U S A ; 120(11): e2218330120, 2023 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-36893259

RESUMO

Heterozygous inactivating mutations of the KMT2D methyltransferase and the CREBBP acetyltransferase are among the most common genetic alterations in B cell lymphoma and co-occur in 40 to 60% of follicular lymphoma (FL) and 30% of EZB/C3 diffuse large B cell lymphoma (DLBCL) cases, suggesting they may be coselected. Here, we show that combined germinal center (GC)-specific haploinsufficiency of Crebbp and Kmt2d synergizes in vivo to promote the expansion of abnormally polarized GCs, a common preneoplastic event. These enzymes form a biochemical complex on select enhancers/superenhancers that are critical for the delivery of immune signals in the GC light zone and are only corrupted upon dual Crebbp/Kmt2d loss, both in mouse GC B cells and in human DLBCL. Moreover, CREBBP directly acetylates KMT2D in GC-derived B cells, and, consistently, its inactivation by FL/DLBCL-associated mutations abrogates its ability to catalyze KMT2D acetylation. Genetic and pharmacologic loss of CREBBP and the consequent decrease in KMT2D acetylation lead to reduced levels of H3K4me1, supporting a role for this posttranslational modification in modulating KMT2D activity. Our data identify a direct biochemical and functional interaction between CREBBP and KMT2D in the GC, with implications for their role as tumor suppressors in FL/DLBCL and for the development of precision medicine approaches targeting enhancer defects induced by their combined loss.


Assuntos
Linfoma Folicular , Linfoma Difuso de Grandes Células B , Animais , Humanos , Camundongos , Acetilação , Linfócitos B/metabolismo , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/metabolismo , Centro Germinativo , Linfoma Folicular/genética , Linfoma Folicular/metabolismo , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/patologia , Mutação , Processamento de Proteína Pós-Traducional
9.
J Biol Chem ; 300(11): 107788, 2024 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-39303914

RESUMO

The incidence of germinal center B-cell-like type diffuse large B-cell lymphoma (GCB DLBCL) is steadily increasing, with a known hereditary component. Although some molecular mechanisms in GCB DLBCL have been elucidated, understanding remains incomplete, limiting the effectiveness of targeted therapies. In GCB DLBCL patients, abnormally high expression of zeste homologs 2 (EZH2) is noted, and the compensatory effect of EZH1 following EZH2 inhibition contributes to poor prognosis. This highlights the potential of dual targeting of EZH1/2 as a promising strategy. In this study, we developed a novel inhibitor, EZH-1-P2, targeting EZH1/2 and evaluated its antitumor effects on DLBCL cells. Mechanistically, inhibition of EZH1/2 affects the epigenetic regulation of gene expression related to p53, impacting cell cycle progression and GCB DLBCL cell growth. Additionally, while EZH1/2 inhibition impacts NOTCH signaling, the precise mechanism by which it affects M2-type tumor-associated macrophage polarization and germinal center expansion requires further investigation. Our research introduces EZH-1-P2 as a novel inhibitor with potential as a candidate for GCB DLBCL therapy, although further studies are needed to fully elucidate its mechanisms.

10.
J Biol Chem ; 300(7): 107463, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38876304

RESUMO

Chemotherapeutic agents for treating colorectal cancer (CRC) primarily induce apoptosis in tumor cells. The ubiquitin-proteasome system is critical for apoptosis regulation. Deubiquitinating enzymes (DUBs) remove ubiquitin from substrates to reverse ubiquitination. Although over 100 DUB members have been discovered, the biological functions of only a small proportion of DUBs have been characterized. Here, we aimed to systematically identify the DUBs that contribute to the development of CRC. Among the DUBs, ubiquitin-specific protease 36 (USP36) is upregulated in CRC. We showed that the knockdown of USP36 induces intrinsic and extrinsic apoptosis. Through gene silencing and coimmunoprecipitation techniques, we identified survivin and cIAP1 as USP36 targets. Mechanistically, USP36 binds and removes lysine-11-linked ubiquitin chains from cIAP1 and lysine-48-linked ubiquitin chains from survivin to abolish protein degradation. Overexpression of USP36 disrupts the formation of the XIAP-second mitochondria-derived activator of caspase complex and promotes receptor-interacting protein kinase 1 ubiquitination, validating USP36 as an inhibitor to intrinsic and extrinsic apoptosis through deubiquitinating survivin and cIAP1. Therefore, our results suggest that USP36 is involved in CRC progression and is a potential therapeutic target.


Assuntos
Apoptose , Neoplasias Colorretais , Proteínas Inibidoras de Apoptose , Survivina , Ubiquitina Tiolesterase , Ubiquitinação , Humanos , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Inibidoras de Apoptose/metabolismo , Proteínas Inibidoras de Apoptose/genética , Survivina/metabolismo , Survivina/genética , Ubiquitina Tiolesterase/metabolismo , Ubiquitina Tiolesterase/genética
11.
J Pathol ; 262(3): 255-270, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38180354

RESUMO

The fifth edition of the World Health Organization Classification of Haematolymphoid Tumours (WHO-HAEM5) is the product of an evidence-based evolution of the revised fourth edition with wide multidisciplinary consultation. Nonetheless, while every classification incorporates scientific advances and aims to improve upon the prior version, medical knowledge remains incomplete and individual neoplasms may not be easily subclassified in a given scheme. Thus, optimal classification requires ongoing study, and there are certain aspects of some entities and subtypes that require further refinements. In this review, we highlight a selection of these challenging areas to prompt more research investigations. These include (1) a 'placeholder term' of splenic B-cell lymphoma/leukaemia with prominent nucleoli (SBLPN) to accommodate many of the splenic lymphomas previously classified as hairy cell leukaemia variant and B-prolymphocytic leukaemia, a clear new start to define their pathobiology; (2) how best to classify BCL2 rearrangement negative follicular lymphoma including those with BCL6 rearrangement, integrating the emerging new knowledge on various germinal centre B-cell subsets; (3) what is the spectrum of non-IG gene partners of MYC translocation in diffuse large B-cell lymphoma/high-grade B-cell lymphoma and how they impact MYC expression and clinical outcome; how best to investigate this in a routine clinical setting; and (4) how best to define high-grade B-cell lymphoma not otherwise specified and high-grade B-cell lymphoma with 11q aberrations to distinguish them from their mimics and characterise their molecular pathogenetic mechanism. Addressing these questions would provide more robust evidence to better define these entities/subtypes, improve their diagnosis and/or prognostic stratification, leading to better patient care. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Assuntos
Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Translocação Genética , Reino Unido , Organização Mundial da Saúde
12.
Exp Cell Res ; 442(2): 114248, 2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39260673

RESUMO

Ibrutinib, a Bruton Tyrosine Kinase (BTK) inhibitor, has shown effectiveness against various B-cell lymphoid malignancies. However, prolonged usage can induce resistance, affecting treatment outcomes. The oncogenic microRNA, miR-155-5p, is associated with poor prognosis in B-cell lymphomas, prompting our investigation into the mechanism of acquired ibrutinib resistance in these cells. We generated ibrutinib-resistant OCI-Ly1 cells (OCI-Ly1-IbtR) through continuous exposure to 1 µM and 2 µM of ibrutinib. We conducted microRNA profiling of OCI-Ly1-IbtR and isolated exosomes via ultracentrifugation. Comparative studies of microRNA levels in cells and exosomes, as well as exploration of targets of up-regulated microRNAs in OCI-Ly1-IbtR, were performed. Target validation involved transfection of candidate microRNAs, and co-culture experiments utilized OCI-Ly1 cells with exosomes from OCI-Ly1-IbtR. Elevated levels of miR-155-5p were observed in OCI-Ly1-IbtR and its exosomes, correlating with AKT and NF-κB activation. Transfection of miR-155-5p induced AKT/NF-κB pathway activation in OCI-Ly1, resulting in ibrutinib resistance, enhanced colony formation, and sustained BTK activity. Primary cell lines from ibrutinib-refractory B-cell lymphoma patients exhibited similar signaling protein activation. Target evaluation identified KDM5B and DEPTOR as miR-155-5p targets, confirmed by downregulation after transfection. We observed KDM5B and DEPTOR enrichment in Ago2 during ibrutinib resistance and miR-155-5p transfection. Co-culture experiments demonstrated exosome-mediated transfer of miR-155-5p, inducing ibrutinib resistance and KDM5B/DEPTOR downregulation in OCI-Ly1. Our findings suggest that miR-155-5p overexpression is associated with AKT and NF-κB pathway activation in ibrutinib-resistant cells, proposing a potential role for acquired miR-155-5p upregulation in B-cell lymphoma ibrutinib resistance.

13.
Exp Cell Res ; 435(2): 113937, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38242344

RESUMO

Lung carcinoma (LC) is a complicated and highly heterogeneous disease with high morbidity and mortality. Both lysyl oxidase-like (LOXL) 2 and 3 act in cancer progression. This work endeavors to illustrate the influence of LOXL2/LOXL3 on LC progression and the underlying mechanisms. LOXL family genes and CCAAT enhancer binding protein A (CEBPA) were analyzed in the TCGA database for their expression patterns in LC patients and their correlations with the patient's prognosis. CEBPA, LOXL2, and LOXL3 expression levels were determined in LC cells. Gain- and loss-of-function assays were conducted, followed by assays for cell proliferation, epithelial-mesenchymal transition (EMT), apoptosis, invasion, and migration. The binding of CEBPA or B cell lymphoma protein (BCL)-2 to LOXL2/LOXL3 was verified. The ubiquitination level of BCL-2 and histone acetylation level of LOXL2/LOXL3 in LC cells were analyzed. Database analyses revealed that LC patients had high CEBPA, LOXL2, and LOXL3 expression, which were related to poor prognosis. LC cells also exhibited high CEBPA, LOXL2, and LOXL3 levels. LOXL2/LOXL3 knockdown subdued EMT, proliferation, migration, and invasion while enhancing the apoptosis of LC cells. LOXL2/LOXL3 could bind to CEBPA and BCL-2. LOXL2/LOXL3 knockdown upregulated BCL-2 ubiquitination level and diminished BCL-2 expression in LC cells. CEBPA recruited Tip60 to enhance histone acetylation and transcription of LOXL2/LOXL3 in LC cells. BCL-2 overexpression abolished the impacts of LOXL2/LOXL3 knockdown on LC cells. In conclusion, CEBPA boosts LOXL2 and LOXL3 transcription to facilitate BCL-2 stability by recruiting Tip60 and thus contributes to LC cell growth and metastasis.


Assuntos
Carcinoma , Neoplasias Pulmonares , Humanos , Histonas , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Pulmão/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Aminoácido Oxirredutases/genética , Proteínas Estimuladoras de Ligação a CCAAT
14.
Mol Ther ; 32(5): 1252-1265, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38504519

RESUMO

Chimeric antigen receptor (CAR) T cell therapy has made great progress in treating lymphoma, yet patient outcomes still vary greatly. The lymphoma microenvironment may be an important factor in the efficacy of CAR T therapy. In this study, we designed a highly multiplexed imaging mass cytometry (IMC) panel to simultaneously quantify 31 biomarkers from 13 patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL) who received CAR19/22 T cell therapy. A total of 20 sections were sampled before CAR T cell infusion or after infusion when relapse occurred. A total of 35 cell clusters were identified, annotated, and subsequently redefined into 10 metaclusters. The CD4+ T cell fraction was positively associated with remission duration. Significantly higher Ki67, CD57, and TIM3 levels and lower CD69 levels in T cells, especially the CD8+/CD4+ Tem and Te cell subsets, were seen in patients with poor outcomes. Cellular neighborhood containing more immune cells was associated with longer remission. Fibroblasts and vascular endothelial cells resided much closer to tumor cells in patients with poor response and short remission after CAR T therapy. Our work comprehensively and systematically dissects the relationship between cell composition, state, and spatial arrangement in the DLBCL microenvironment and the outcomes of CAR T cell therapy, which is beneficial to predict CAR T therapy efficacy.


Assuntos
Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B , Receptores de Antígenos Quiméricos , Análise de Célula Única , Microambiente Tumoral , Humanos , Imunoterapia Adotiva/métodos , Microambiente Tumoral/imunologia , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/imunologia , Análise de Célula Única/métodos , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Feminino , Masculino , Resultado do Tratamento , Pessoa de Meia-Idade , Adulto , Biomarcadores Tumorais , Idoso
15.
Mol Ther ; 32(8): 2444-2460, 2024 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-38822527

RESUMO

In recent years, the therapeutic landscape for hematological malignancies has markedly advanced, particularly since the inaugural approval of autologous chimeric antigen receptor T cell (CAR-T) therapy in 2017 for relapsed/refractory acute lymphoblastic leukemia (ALL). Autologous CAR-T therapy involves the genetic modification of a patient's T cells to specifically identify and attack cancer cells, while bispecific antibodies (BsAbs) function by binding to both cancer cells and immune cells simultaneously, thereby triggering an immune response against the tumor. The subsequent approval of various CAR-T therapies and BsAbs have revolutionized the treatment of multiple hematological malignancies, highlighting high response rates and a subset of patients achieving prolonged disease control. This review explores the mechanisms underlying autologous CAR-T therapies and BsAbs, focusing on their clinical application in multiple myeloma, ALL, and non-Hodgkin lymphoma. We provide comprehensive insights into their individual efficacy, limitations concerning broad application, and the potential of combination therapies. These upcoming strategies aim to propel the field forward, paving the way for safer and more effective therapeutic interventions in hematological malignancies.


Assuntos
Anticorpos Biespecíficos , Neoplasias Hematológicas , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Humanos , Anticorpos Biespecíficos/uso terapêutico , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/imunologia , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Terapia Combinada
16.
Mol Cell Proteomics ; 22(9): 100625, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37500057

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, although disease stratification using in-depth plasma proteomics has not been performed to date. By measuring more than 1000 proteins in the plasma of 147 DLBCL patients using data-independent acquisition mass spectrometry and antibody array, DLBCL patients were classified into four proteomic subtypes (PS-I-IV). Patients with the PS-IV subtype and worst prognosis had increased levels of proteins involved in inflammation, including a high expression of metalloproteinase inhibitor-1 (TIMP-1) that was associated with poor survival across two validation cohorts (n = 180). Notably, the combination of TIMP-1 with the international prognostic index (IPI) identified 64.00% to 88.24% of relapsed and 65.00% to 80.49% of deceased patients in the discovery and two validation cohorts, which represents a 24.00% to 41.67% and 20.00% to 31.70% improvement compared to the IPI score alone, respectively. Taken together, we demonstrate that DLBCL heterogeneity is reflected in the plasma proteome and that TIMP-1, together with the IPI, could improve the prognostic stratification of patients.


Assuntos
Linfoma Difuso de Grandes Células B , Inibidor Tecidual de Metaloproteinase-1 , Humanos , Prognóstico , Proteômica , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Biomarcadores , Estudos Retrospectivos
17.
J Cell Mol Med ; 28(14): e18576, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39054569

RESUMO

Diagnosis of intravascular large B-cell lymphoma (IVLBCL) is a challenge due to its heterogeneous clinical presentation and lack of specific markers. This retrospective study investigated the utility of circulating tumour DNA (ctDNA) sequencing for diagnosing IVLBCL and analysing its mutation landscape. A cohort of 34 IVLBCL patients enrolled and underwent plasma ctDNA targeted sequencing. The median plasma ctDNA concentration was 135.0 ng/mL, significantly higher than that in diffuse large B-cell lymphoma (DLBCL) controls. Correlations were found between ctDNA concentration and disease severity indicators, LDH and SF. Mutation analysis revealed frequent mutations in B-cell receptor and NF-κB signalling pathways, including MYD88 (56%), CD79B (44%), TNFAIP3 (38%) and IRF4 (29%). CNS involvement was significantly related with BCL6 and CD58 mutation. Patients with complicated hemophagocytic lymphohistiocytosis had significantly higher mutation rates in B2M. Comparison with DLBCL subtypes showed distinctive mutation profiles in IVLBCL. Moreover, plasma ctDNA detected more mutations with higher variant allele fraction than tissue DNA, suggesting its superiority in sensitivity and accessibility. Dynamic monitoring of ctDNA during treatment correlated with therapeutic responses. This study revealed the role of ctDNA in IVLBCL diagnosis, mutation analysis, and treatment monitoring, offering a promising avenue for improving patient diagnosis in this rare lymphoma subtype.


Assuntos
Biomarcadores Tumorais , DNA Tumoral Circulante , Linfoma Difuso de Grandes Células B , Mutação , Humanos , DNA Tumoral Circulante/genética , DNA Tumoral Circulante/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/sangue , Análise Mutacional de DNA/métodos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Adulto , Estudos Retrospectivos , Idoso de 80 Anos ou mais
18.
J Biol Chem ; 299(7): 104883, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37269947

RESUMO

Chimeric antigen receptor (CAR) T-cell therapy has had considerable success in the treatment of B-cell malignancies. Targeting the B-lineage marker CD19 has brought great advances to the treatment of acute lymphoblastic leukemia and B-cell lymphomas. However, relapse remains an issue in many cases. Such relapse can result from downregulation or loss of CD19 from the malignant cell population or expression of alternate isoforms. Consequently, there remains a need to target alternative B-cell antigens and diversify the spectrum of epitopes targeted within the same antigen. CD22 has been identified as a substitute target in cases of CD19-negative relapse. One anti-CD22 antibody-clone m971-targets a membrane-proximal epitope of CD22 and has been widely validated and used in the clinic. Here, we have compared m971-CAR with a novel CAR derived from IS7, an antibody that targets a central epitope on CD22. The IS7-CAR has superior avidity and is active and specific against CD22-positive targets, including B-acute lymphoblastic leukemia patient-derived xenograft samples. Side-by-side comparisons indicated that while IS7-CAR killed less rapidly than m971-CAR in vitro, it remains efficient in controlling lymphoma xenograft models in vivo. Thus, IS7-CAR presents a potential alternative candidate for the treatment of refractory B-cell malignancies.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico , Humanos , Antígenos CD19 , Epitopos , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva
19.
Lab Invest ; 104(4): 102027, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38311062

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma. New therapeutic strategies are needed for the treatment of refractory DLBCL. 4-Hydroxy-2-nonenal (4-HNE) is a cytotoxic lipid peroxidation marker, which alters intracellular signaling and induces genetic mutations. Lipid peroxidation is associated with nonapoptotic cell death, called ferroptosis. However, the relationship between 4-HNE accumulation and feroptotic regulators in DLBCL has not been fully evaluated. Here, we aimed to evaluate the accumulation of lipid peroxide and the expression of ferroptosis suppressor protein 1 (FSP1) in DLBCL using immunohistochemistry. We found a significant increase in the expression of FSP1 in cases with nuclear 4-HNE accumulation (P = .021). Both nuclear and cytoplasmic 4-HNE accumulation and FSP1 positivity were independent predictors of worse prognosis. In vitro exposure to 4-HNE resulted in its concentration- and time-dependent intracellular accumulation and increased expression of FSP1. Furthermore, short-term (0.25 and 1.0 µM) or long-term (0.25 µM) exposure to 4-HNE induced resistance to not only apoptosis but also ferroptosis. Taken together, regulation of FSP1 through 4-HNE accumulation may attenuate resistance to cell death in treatment-resistant DLBCL and might help develop novel therapeutic strategies for refractory DLBCL.


Assuntos
Aldeídos , Ferroptose , Linfoma Difuso de Grandes Células B , Humanos , Ferroptose/genética , Apoptose , Morte Celular , Linfoma Difuso de Grandes Células B/genética
20.
Mol Cancer ; 23(1): 42, 2024 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-38402205

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma. A major mutagenic process in DLBCL is aberrant somatic hypermutation (aSHM) by activation-induced cytidine deaminase (AID), which occurs preferentially at RCH/TW sequence motifs proximal to transcription start sites. Splice sequences are highly conserved, rich in RCH/TW motifs, and recurrently mutated in DLBCL. Therefore, we hypothesized that aSHM may cause recurrent splicing mutations in DLBCL. In a meta-cohort of > 1,800 DLBCLs, we found that 77.5% of splicing mutations in 29 recurrently mutated genes followed aSHM patterns. In addition, in whole-genome sequencing (WGS) data from 153 DLBCLs, proximal mutations in splice sequences, especially in donors, were significantly enriched in RCH/TW motifs (p < 0.01). We validated this enrichment in two additional DLBCL cohorts (N > 2,000; p < 0.0001) and confirmed its absence in 12 cancer types without aSHM (N > 6,300). Comparing sequencing data from mouse models with and without AID activity showed that the splice donor sequences were the top genomic feature enriched in AID-induced mutations (p < 0.0001). Finally, we observed that most AID-related splice site mutations are clonal within a sample, indicating that aSHM may cause early loss-of-function events in lymphomagenesis. Overall, these findings support that AID causes an overrepresentation of clonal splicing mutations in DLBCL.


Assuntos
Linfoma Difuso de Grandes Células B , Humanos , Animais , Camundongos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Mutação , Citidina Desaminase/genética
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