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SMARCB1 loss defines a novel PTCL-NOS subtype displaying an immunosuppressive TME susceptible to HDAC inhibitors [single-cell 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: GSE190274 | 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 [bulk 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 | GSE190273 | GEO

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DNA methylation profiles of SMARCB1-deficient T cell lymphomas

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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]

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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: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.

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

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

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