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 | 2022 Jan

REPOSITORIES: biostudies-literature

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

Zeng Zexian Z Wong Cheryl J CJ Yang Lin L Ouardaoui Nofal N Li Dian D Zhang Wubing W Gu Shengqing S Zhang Yi Y Liu Yang Y Wang Xiaoqing X Fu Jingxin J Zhou Liye L Zhang Boning B Kim Sarah S Yates Kathleen B KB Brown Myles M Freeman Gordon J GJ Uppaluri Ravindra R Manguso Robert R Liu X Shirley XS

Nucleic acids research 20220101 D1

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 MOu ...[more]

PMID: 34534350

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Project description:PurposeThe mortality in patients with MYCN-amplified high-risk neuroblastoma remains greater than 50% despite advances in multimodal therapy. Novel therapies are urgently needed that requires preclinical evaluation in appropriate mice models. Combinatorial treatment with high-dose radiotherapy (HDRT) and immunotherapy has emerged as an effective treatment option in a variety of cancers. Current models of neuroblastoma do not recapitulate the anatomic and immune environment in which multimodal therapies can be effectively tested, and there is a need for an appropriate syngeneic neuroblastoma mice model to study interaction of immunotherapy with host immune cells. Here, we develop a novel syngeneic mouse model of MYCN-amplified neuroblastoma and report the relevance and opportunities of this model to study radiotherapy and immunotherapy.Materials and methodsA syngeneic allograft tumor model was developed using the murine neuroblastoma cell line 9464D derived a tumor from TH-MYCN transgenic mouse. Tumors were generated by transplanting 1 mm3 portions of 9464D flank tumors into the left kidney of C57Bl/6 mice. We investigated the effect of combining HDRT with anti-PD1 antibody on tumor growth and tumor microenvironment. HDRT (8 Gy x 3) was delivered by the small animal radiation research platform (SARRP). Tumor growth was monitored by ultrasound. To assess the effect on immune cells tumors sections were co-imuunostained for six biomarkers using the Vectra multispectral imaging platform.ResultsTumor growth was uniform and confined to the kidney in 100% of transplanted tumors. HDRT was largely restricted to the tumor region with minimal scattered out-of-field dose. Combinatorial treatment with HDRT and PD-1 blockade significantly inhibited tumor growth and prolonged mice survival. We observed augmented T-lymphocyte infiltration, especially CD3+CD8+ lymphocytes, in tumors of mice which received combination treatment.ConclusionWe have developed a novel syngeneic mouse model of MYCN amplified high-risk neuroblastoma. We have utilized this model to show that combining immunotherapy with HDRT inhibits tumor growth and prolongs mice survival.

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

Dataset Information

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

Publications

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

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