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SMARCB1 loss defines a novel PTCL-NOS subtype displaying an immunosuppressive TME susceptible to HDAC inhibitors [bulk RNA-seq]

ABSTRACT: Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) are aggressive and heterogeneous tumors with poor outcome and scarce genetic characterization. We analyzed by immunohistochemistry tumor tissue of adult and pediatric PTCL-NOS patients and discovered frequent loss of SMARCB1 positivity, mostly associated with pediatric cases (45%). Using a genetically engineered mouse model (PTCL-NOSSmarcb1-) and single-cell RNA sequencing, we investigated the transcriptional landscape of this Smarcb1-negative PTCL-NOS tumor and the functional interactions between tumor and tumor microenvironment (TME). We unrevealed an immunosuppressive, exhausted and proinflammatory TME, characterized by high myeloid cell infiltration (predominantly myeloid derived suppressor cells, MDSC) and reduced lymphoid infiltration. In addition, using a multidrug epigenetic screen in vitro, we identified histone deacetylase inhibitors (HDACi) as promising agents against PTCL-NOSSmarcb1-. Treatment of PTCL-NOSSmarcb1- mice with SAHA, a pan-HDACi, triggered TME remodelling, promoting the replenishment of T- and B-cell compartments and the limitation/reversion of the exhaustion phenotype. In conclusion, we have identified a novel PTCL-NOS subtype characterized by the loss of SMARCB1 at pediatric ages, presenting an exhausted and immunosuppressive TME. Administration of SAHA reshaped the TME increasing lymphoid cells recruitment into the tumor bed, turning the tumor from cold to hot. These results provide the rationale for further investigations based on combination therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE190273 | GEO | 2024/07/18

REPOSITORIES: GEO

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SMARCB1 loss defines a novel PTCL-NOS subtype displaying an immunosuppressive TME susceptible to HDAC inhibitors [single-cell RNA-seq]

Project description:Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) are aggressive and heterogeneous tumors with poor outcome and scarce genetic characterization. We analyzed by immunohistochemistry tumor tissue of adult and pediatric PTCL-NOS patients and discovered frequent loss of SMARCB1 positivity, mostly associated with pediatric cases (45%). Using a genetically engineered mouse model (PTCL-NOSSmarcb1-) and single-cell RNA sequencing, we investigated the transcriptional landscape of this Smarcb1-negative PTCL-NOS tumor and the functional interactions between tumor and tumor microenvironment (TME). We unrevealed an immunosuppressive, exhausted and proinflammatory TME, characterized by high myeloid cell infiltration (predominantly myeloid derived suppressor cells, MDSC) and reduced lymphoid infiltration. In addition, using a multidrug epigenetic screen in vitro, we identified histone deacetylase inhibitors (HDACi) as promising agents against PTCL-NOSSmarcb1-. Treatment of PTCL-NOSSmarcb1- mice with SAHA, a pan-HDACi, triggered TME remodelling, promoting the replenishment of T- and B-cell compartments and the limitation/reversion of the exhaustion phenotype. In conclusion, we have identified a novel PTCL-NOS subtype characterized by the loss of SMARCB1 at pediatric ages, presenting an exhausted and immunosuppressive TME. Administration of SAHA reshaped the TME increasing lymphoid cells recruitment into the tumor bed, turning the tumor from cold to hot. These results provide the rationale for further investigations based on combination therapies.

2024-07-18 | GSE190274 | GEO

Single-nuclei gene expression profiling of human SMARCB1-deficient peripheral T cell lymphomas

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DNA methylation profiles of SMARCB1-deficient T cell lymphomas

Project description:Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of malignancies with poor outcome. Here we have identified a subgroup of SMARCB1 deficient PTCL-NOS, which is characterized by the lack of the SMARCB1 protein and is more common in young patients. Human and murine Smarcb1-negative PTCL-NOS from a corresponding mouse model show similar DNA methylation profiles, with hypermethylation of T-cell-related genes and hypomethylation of genes involved in myeloid development.

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SMARCB1 loss defines a novel PTCL-NOS subtype displaying an immunosuppressive TME susceptible to HDAC inhibitors

Project description:SMARCB1 loss defines a novel PTCL-NOS subtype displaying an immunosuppressive TME susceptible to HDAC inhibitors

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SMARCB1 loss defines a novel PTCL-NOS subtype displaying an immunosuppressive TME susceptible to HDAC inhibitors [bulk RNA-seq]

Project description:SMARCB1 loss defines a novel PTCL-NOS subtype displaying an immunosuppressive TME susceptible to HDAC inhibitors [bulk RNA-seq]

| PRJNA786573 | ENA

SMARCB1 loss defines a novel PTCL-NOS subtype displaying an immunosuppressive TME susceptible to HDAC inhibitors [single-cell RNA-seq]

Project description:SMARCB1 loss defines a novel PTCL-NOS subtype displaying an immunosuppressive TME susceptible to HDAC inhibitors [single-cell RNA-seq]

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SNP array genomic profiling of PTCL NOS

Project description:DNA extracted from frozen tissue of 47 peripheral T-cell lymphomasânot otherwise specified [PTCL-NOS] was hybridized to 250k StyI SNP arrays 47 PTCL NOS compared to healthy reference DNA. DNA of PTCL NOS was extracted from frozen tissue blocks, DNA of healthy individual was extracted from peripheral blood mononuclear cells. Array hybridization was performed according to manufacturerÂ´s protocol.

2010-03-17 | E-GEOD-15842 | biostudies-arrayexpress

Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma

Project description:Peripheral T-cell lymphoma (PTCL) encompasses a heterogeneous group of neoplasms with generally poor clinical outcome. Currently 50% of PTCL cases are not classifiable: PTCL-not otherwise specified (NOS). Gene-expression profiles on 372 PTCL cases were analyzed and robust molecular classifiers and oncogenic pathways that reflect the pathobiology of tumor cells and their microenvironment were identified for major PTCL-entities, including 114 angioimmunoblastic T-cell lymphoma (AITL), 31 anaplastic lymphoma kinase (ALK)-positive and 48 ALK-negative anaplastic large cell lymphoma, 14 adult T-cell leukemia/lymphoma and 44 extranodal NK/T-cell lymphoma that were further separated into NK-cell and gdT-cell lymphomas. Thirty-seven percent of morphologically diagnosed PTCL-NOS cases were reclassified into other specific subtypes by molecular signatures. Reexamination, immunohistochemistry, and IDH2 mutation analysis in reclassified cases supported the validity of the reclassification. Two major molecular subgroups can be identified in the remaining PTCL-NOS cases characterized by high expression of either GATA3 (33%; 40/121) or TBX21 (49%; 59/121). The GATA3 subgroup was significantly associated with poor overall survival (P=.01). High expression of cytotoxic genesignaturewithin the TBX21 subgroup also showed poor clinical outcome (P=.05). InAITL, high expression of several signatures associated with the tumor microenvironment was significantly associated with outcome. A combined prognostic score was predictive of survival in an independent cohort (P=.004).

2015-06-01 | GSE58445 | GEO

Peripheral T-cell lymphomas not otherwise specified correspond to distinct mature T-cell populations based on the global gene expression profile

Project description:Genome-wide analysis of nodal peripheral T-cell lymphomas (PTCL/NOS, AITL and ALCL) was used to identify molecular signatures corresponding to different subgroups. We also aimed to define the counterparts of PTCLs/NOS based on their global gene expression profiles. We developed a new molecular classifier able to distinct PTCL/NOS heterogeneity due to the correspondence to different counterparts.

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Peripheral T-cell lymphoma: Molecular profiling recognizes subclasses and identifies prognostic markers

Project description:Peripheral T-cell lymphoma (PTCL) is a clinically aggressive disease, with a poor response to therapy and a low overall survival rate of around 30% after 5 years. We have analyzed a series of 105 cases with a diagnosis of PTCL using a customized NanoString platform that includes 208 genes associated with T-cell differentiation, oncogenes and tumor suppressor genes, deregulated pathways and stromal cell subpopulations. A comparative analysis of the various histological types of PTCL (angioimmunoblastic T-cell lymphoma, AITL; PTCL-with T follicular helper phenotype, PTCL-TFH; PTCL-not otherwise signified, PTCL-NOS) showed that specific sets of genes were associated with each of the diagnoses. These included TFH markers, cytotoxic markers and genes whose expression was a surrogate for specific cellular subpopulations, including follicular dendritic cells, mast cells and genes belonging to precise survival (NF-κB) and other pathways. Furthermore, the mutational profile was analyzed using a custom panel that targeted 62 genes in 76 cases distributed in AITL, PTCL-TFH and PTCL-NOS. The main differences between the three nodal PTCL classes involved the RHOAG17V mutations (p<0.0001), which were approximately twice as frequent in AITL (34.09%) as in PTCL-TFH (16.66%) cases, but were not detected in PTCL-NOS. A multivariate analysis identified gene sets that allowed the series of cases to be stratified into different risk groups. This study supports and validates the current division of PTCL into these three categories, identifies sets of markers that can be used for a more precise diagnosis, and recognizes the expression of B-cell genes as an IPI-independent prognostic factor for AITL.

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