Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Whole-genome sequencing of canine oral melanoma and matched peripheral blood pre- and post-radiotherapy

ABSTRACT: Canine oral melanoma is a highly aggressive tumor with limited therapeutic options and a poor prognosis. To elucidate the molecular mechanisms underlying its progression and response to radiation therapy (RT), we performed a longitudinal multi-omics analysis incorporating whole-genome sequencing (WGS) and RNA sequencing (RNA-seq) on tumor and blood samples from a single canine case. WGS was performed on tumor and blood collected before RT (Pre-RT) and on blood collected immediately after the final radiation fraction (Post-RT 0m). RNA-seq was performed on tumor and blood collected before RT (Pre-RT) and immediately after the final radiation fraction (Post-RT 0m), and on tumor collected 4 months after RT (Post-RT 4m).

INSTRUMENT(S): Tru-cut biopsy needle (Marquee®, 16 G × 10 cm), Illumina NovaSeq X, ., TruSeq PCR-free Sample Preparation Kit

ORGANISM(S): Canis lupus familiaris

SUBMITTER: Seungwan Woo

PROVIDER: E-MTAB-15592 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Accumulating data support the concept that ionizing radiation therapy (RT) has the potential to convert the tumor into an in situ, individualized vaccine; however this potential is rarely realized by RT alone. Transforming growth factor β (TGFβ) is an immunosuppressive cytokine that is activated by RT and inhibits the antigen-presenting function of dendritic cells and the differentiation of effector CD8+ T cells. Here we tested the hypothesis that TGFβ hinders the ability of RT to promote anti-tumor immunity. Development of tumor-specific immunity was examined in a pre-clinical model of metastatic breast cancer. Mice bearing established 4T1 mouse mammary carcinoma treated with pan-isoform specific TGFβ neutralizing antibody, 1D11, showed significantly improved control of the irradiated tumor and non-irradiated metastases, but no effect in the absence of RT. Notably, whole tumor transcriptional analysis demonstrated the selective upregulation of genes associated with immune-mediated rejection only in tumors of mice treated with RT+TGFβ blockade. Mice treated with RT+TGFβ blockade exhibited cross-priming of CD8+ T cells producing IFNγ in response to three tumor-specific antigens in tumor-draining lymph nodes, which was not evident for single modality treatment. Analysis of the immune infiltrate in mouse tumors showed a significant increase in CD4+ and CD8+ T cells only in mice treated with the combination of RT+TGFβ blockade. Depletion of CD4+ or CD8+ T cells abrogated the therapeutic benefit of RT+TGFβ blockade. These data identify TGFβ as a master inhibitor of the ability of RT to generate an in situ tumor vaccine, which supports testing inhibition of TGFβ during radiotherapy to promote therapeutically effective anti-tumor immunity. We used genome-wide microarray to depict main biological processes responsibles for the therapeutic benefit of the combination ofTGF-beta blockade and local radiotherapy. To gain a more comprehensice protrait of the effects of RT and TGFbeta blockade on gene expressionin tumors, we collected 4T1 tumors 4 days after completion of RT. Three tumors from each group were then subjected to RNA extraction and hybridization on affymetrix array.

Dataset Information

Whole-genome sequencing of canine oral melanoma and matched peripheral blood pre- and post-radiotherapy

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