Dataset Information

TISMO: syngeneic mouse tumor database to model tumor immunity and immunotherapy response.

ABSTRACT: Syngeneic mouse models are tumors derived from murine cancer cells engrafted on genetically identical mouse strains. They are widely used tools for studying tumor immunity and immunotherapy response in the context of a fully functional murine immune system. Large volumes of syngeneic mouse tumor expression profiles under different immunotherapy treatments have been generated, although a lack of systematic collection and analysis makes data reuse challenging. We present Tumor Immune Syngeneic MOuse (TISMO), a database with an extensive collection of syngeneic mouse model profiles with interactive visualization features. TISMO contains 605 in vitro RNA-seq samples from 49 syngeneic cancer cell lines across 23 cancer types, of which 195 underwent cytokine treatment. TISMO also includes 1518 in vivo RNA-seq samples from 68 syngeneic mouse tumor models across 19 cancer types, of which 832 were from immune checkpoint blockade (ICB) studies. We manually annotated the sample metadata, such as cell line, mouse strain, transplantation site, treatment, and response status, and uniformly processed and quality-controlled the RNA-seq data. Besides data download, TISMO provides interactive web interfaces to investigate whether specific gene expression, pathway enrichment, or immune infiltration level is associated with differential immunotherapy response. TISMO is available at http://tismo.cistrome.org.

SUBMITTER: Zeng Z

PROVIDER: S-EPMC8728303 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Targeting the PD-1/PD-L1 pathway has changed the landscape of cancer immunotherapy, revolutionizing the treatment of many cancers. Somatic tumor mutational burden (TMB) and T-cell–inflamed gene expression profile (GEP) are clinically validated pan-tumor genomic biomarkers that predict responsiveness to anti-PD-1/anti-PD-L1 monotherapy in a variety of tumor types. Here we analyze the association between these biomarkers and efficacy in 11 commonly used preclinical murine syngeneic models using a rodent surrogate antibody (muDX400) of pembrolizumab, a humanized monoclonal antibody against PD-1. Response to muDX400 treatment was broadly classified in these models into 3 categories: highly responsive, partially responsive, and intrinsically resistant to therapy. Molecular and cellular profiling validated differences in immune-cell infiltration and activation in the tumor microenvironment of muDX400 responsive tumors. Baseline and post-treatment genomic analysis showed an association between murine-GEP and TMB and response to muDX400 treatment. To better understand the limitations, predictive nature and role of these models in guiding treatment options at the bedside, we extended our analysis to investigate a canonical set of cancer and immune biology-related gene expression signatures, including signatures of angiogenesis, monocytic myeloid derived suppressor cell (mMDSC) and stromal/EMT/TGF-β biology previously shown to have potential negative impact on immunotherapy efficacy in the clinic. Finally, reverse translation studies were performed to evaluate the association between murine-GEP and preclinical efficacy with standard of care and anti-angiogenic combinations with muDX400 which show promising clinical activity. These efforts begin to elucidate which biological mechanisms can and cannot be appropriately and productively tested in these preclinical models to facilitate the development of rational orthogonal combination strategies with checkpoint blockade as well as the evaluation of underlying biological mechanisms associated with response in the clinic

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TISMO: syngeneic mouse tumor database to model tumor immunity and immunotherapy response.

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