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| Status |
Public on Jul 18, 2024 |
| Title |
SMARCB1 loss defines a novel PTCL-NOS subtype displaying an immunosuppressive TME susceptible to HDAC inhibitors [bulk RNA-seq] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
We analyzed gene expression profiling (bulk RNA-seq) of the T15 cell line, derived from a murine Smarcb1-negative PTCL model (doi.org/10.1172/JCI37210). Additionally, bulk RNA of T15 cells treated with SAHA and T15-Smarcb1 cells, in which a Doxycycline-inducible Smarcb1 gene was transduced, was analyzed and compared to the T15 control. Total RNA from the cells was extracted and submitted to RNA-Sequencing.
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| Contributor(s) |
Kerl K, Moreno N, Interlandi M |
| Citation(s) |
39362842 |
| |
| Submission date |
Dec 06, 2021 |
| Last update date |
Oct 17, 2024 |
| Contact name |
Carolin Walter |
| E-mail(s) |
c_walt03@uni-muenster.de
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| Organization name |
Westfälische Wilhelms-Universität Münster
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| Department |
Medical Faculty of the WWU Münster
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| Lab |
Institute of Medical Informatics
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| Street address |
Domagkstraße 9
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| City |
Münster |
| ZIP/Postal code |
48149 |
| Country |
Germany |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (9)
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| This SubSeries is part of SuperSeries: |
| GSE190276 |
SMARCB1 loss defines a novel PTCL-NOS subtype displaying an immunosuppressive TME susceptible to HDAC inhibitors |
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| Relations |
| BioProject |
PRJNA786573 |
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