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Metastatic immune infiltrates correlate with those of the primary tumour in canine osteosarcoma.

ABSTRACT: Our lack of understanding of the immune microenvironment in canine osteosarcoma (cOSA) has limited the identification of potential immunotherapeutic targets. In particular, our ability to utilize readily available tissue from a dog's primary tumour to predict the type and extent of immune response in their pulmonary metastatic lesions is unknown. We, therefore, collected 21 matched pairs of primary tumours and pulmonary metastatic lesions from dogs with OSA and performed immunohistochemistry to quantify T-lymphocyte (CD3), FOXP3+ cell, B-lymphocyte (Pax-5), and CD204+ macrophage infiltration. We found that T-lymphocytes and FOXP3+ infiltrates in primary tumours positively correlated with that of metastatic lesions (? = 0.512, P = 0.038 and ? = 0.698, P = 0.007, respectively), while a strong trend existed for CD204+ infiltrates (??= 0.404, P = 0.087). We also observed T- and B-lymphocytes, and CD204+ macrophages to be significantly higher in a dog's pulmonary metastasis compared to their primary tumour (P = 0.018, P = 0.018, P = 0.016, respectively), while FOXP3+ cells were only significantly higher in metastases when all primary tumour and metastasis lesions were compared without pairing (P = 0.036). Together, these findings suggest that the metastatic immune microenvironment may be influenced by that of the primary cOSA, and that primary tumour immune biomarkers could potentially be applied to predict immunotherapeutic responses in gross metastatic disease. We, therefore, provide a rationale for the treatment of cOSA pulmonary metastases with immunotherapeutics that enhance the anti-tumour activity of these immune cells, particularly in dogs with moderate to high immune cell infiltration in their primary tumours.

SUBMITTER: Withers SS

PROVIDER: S-EPMC6658355 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Metastatic immune infiltrates correlate with those of the primary tumour in canine osteosarcoma.

Withers Sita S SS York Daniel D Choi Jin W JW Woolard Kevin D KD Laufer-Amorim Renee R Sparger Ellen E EE Burton Jenna H JH McSorley Stephen J SJ Monjazeb Arta M AM Murphy William J WJ Canter Robert J RJ Rebhun Robert B RB

Veterinary and comparative oncology 20190408 3

Our lack of understanding of the immune microenvironment in canine osteosarcoma (cOSA) has limited the identification of potential immunotherapeutic targets. In particular, our ability to utilize readily available tissue from a dog's primary tumour to predict the type and extent of immune response in their pulmonary metastatic lesions is unknown. We, therefore, collected 21 matched pairs of primary tumours and pulmonary metastatic lesions from dogs with OSA and performed immunohistochemistry to ...[more]

PMID: 30684301

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Project description:BackgroundOsteosarcoma (OS) is the most widespread bone tumour among childhood cancers, and distant metastasis is the dominant factor in poor prognosis for patients with OS. Therefore, it is necessary to identify new prognostic biomarkers for identifying patients with aggressive disease.MethodsTwo OS datasets (GSE21257 and GSE33383) were downloaded from the Gene Expression Omnibus (GEO) and subsequently subjected to weighted gene co-expression network analysis (WGCNA) and differential gene expression analysis (DGE) to screen candidate genes. A prognostic model was constructed using OS data derived from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program to further screen key genes and perform gene ontology (GO) analysis. The prognostic values of key genes were assessed using the Kaplan-Meier (KM) plotter. The GEO dataset was used for immune infiltration analysis and association analysis of key genes. In addition, quantitative real-time polymerase chain reaction (qRT-PCR) was employed to validate the expression levels of potentially crucial genes in OS cell lines.ResultsIn the present study, we found 114 genes with a highly significant correlation in the module and 44 downregulated genes; 25 candidate genes overlapped in the two parts of the genes. Among these, three key genes, C1QA, C1QB, and C1QC, were the most significant hub genes, which had the highest node degrees, were clustered into one group, and implicated in most significant biological processes (regulation of immune effector process). Moreover, these three key genes were negatively associated with the prognosis of OS and positively associated with three immune cells (follicular helper T cells, memory B cells, and CD8 T cells). Additionally, compared to non-metastatic OS cell lines, the expression of three key genes was significantly downregulated in metastatic OS cell lines.ConclusionOur results revealed that three key genes (C1QA, C1QB, and C1QC) were implicated in tumour immune infiltration and may be promising biomarkers for predicting metastasis and prognosis of patients with OS.

Dataset Information

Metastatic immune infiltrates correlate with those of the primary tumour in canine osteosarcoma.

Publications

Metastatic immune infiltrates correlate with those of the primary tumour in canine osteosarcoma.

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