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Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in osteosarcoma.

ABSTRACT: Osteosarcoma patient survival has remained stagnant for 30 years. Novel therapeutic approaches are needed to improve outcomes. We examined the expression of Programmed Death Ligand 1 (PD-L1) and defined the tumor immune microenvironment to assess the prognostic utility in osteosarcoma. PD-L1 expression in osteosarcoma was examined in two patient cohorts using immunohistochemistry (IHC) (n?=?48, n?=?59) and expression was validated using quantitative real time PCR (n?=?21) and western blotting (n?=?9). IHC was used to determine the presence of tumor infiltrating lymphocytes and antigen-presenting cells (APCs) in the tumor. Expression of PD-L1 was correlated with immune cell infiltration and event-free-survival (EFS). The 25% of primary osteosarcoma tumors that express PD-L1 were more likely to contain cells that express PD-1 than PD-L1 negative tumors (91.7% vs 47.2%, p?=?0.002). Expression of PD-L1 was significantly associated with the presence of T cells, dendritic cells, and natural killer cells. Although all immune cell types examined were present in osteosarcoma samples, only infiltration by dendritic cells (28.3% vs. 83.9%, p?=?0.001) and macrophages (45.5% vs. 84.4%, p?=?0.031) were associated with worse five-year-EFS. PD-L1 expression was significantly associated with poorer five-year-EFS (25.0%. vs. 69.4%, p?=?0.014). Further studies in osteosarcoma are needed to determine if targeting the PD-L1:PD-1 axis improves survival.

SUBMITTER: Koirala P

PROVIDER: S-EPMC4960483 | biostudies-other | 2016 Jul

REPOSITORIES: biostudies-other

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Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in osteosarcoma.

Koirala Pratistha P Roth Michael E ME Gill Jonathan J Piperdi Sajida S Chinai Jordan M JM Geller David S DS Hoang Bang H BH Park Amy A Fremed Michael A MA Zang Xingxing X Gorlick Richard R

Scientific reports 20160726

Osteosarcoma patient survival has remained stagnant for 30 years. Novel therapeutic approaches are needed to improve outcomes. We examined the expression of Programmed Death Ligand 1 (PD-L1) and defined the tumor immune microenvironment to assess the prognostic utility in osteosarcoma. PD-L1 expression in osteosarcoma was examined in two patient cohorts using immunohistochemistry (IHC) (n = 48, n = 59) and expression was validated using quantitative real time PCR (n = 21) and western blotting (n ...[more]

PMID: 27456063

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Project description:BackgroundEven though immunotherapy has been an effective treatment for solid tumors, its efficacy in osteosarcoma remains sub-optimal. It is therefore imperative to understand the complex tumor microenvironment (TME) of osteosarcoma to facilitate the development of immunotherapies against this cancer.MethodsThe mRNA expression profiles of osteosarcoma tissues were downloaded from The Cancer Genome Atlas (TCGA) database. Next, the ssGSEA, MCP-counter, CIBERSORT, and Xcell algorithm analyses were performed to characterize the tumor microenvironment of osteosarcoma tissues. The tumor tissues were divided into inflammatory and non-inflammatory. A comprehensive assessment of immune cell infiltration in osteosarcoma tissues was then performed. Sub-group analysis of immune cell infiltration between men and women patients with osteosarcoma was also carried out.ResultsThe results revealed that the infiltration of immune cells including activated B cell, activated CD8 T cell, CD56dim natural killer cell, and cytotoxic lymphocytes cells, in osteosarcoma tissues was higher in male than in female patients. Based on the infiltration profile of different immune cells, the osteosarcoma tissues were grouped into four clusters. The four clusters were further divided into hot and cold tumors. The differently expressed genes (DEGs) between cold and hot tumors were mainly associated with the activation and regulation of immune response. Additionally, a neuronal pentraxin (NPTX2) expression which was upregulated in cold tumors was found to be negatively correlated with the expression of CD8a Molecule (CD8A), Granzyme B (GZMB), and Interferon Gamma (IFNG). NPTX2 decreased CCL4 secretion. Knockdown of NPTX2 in osteosarcoma cells inhibited tumor growth and increased tumor cell apoptosis. Moreover, a prognosis prediction model of osteosarcoma was constructed and validated in patients receiving immunotherapy using external data.ConclusionsTo the best of our knowledge, this is the first study to characterize the infiltration of immune cells in osteosarcoma tissues from patients receiving immune infiltration therapy.

Project description:BackgroundsOsteosarcomas are one of the most common primary malignant tumors of bone. It primarily occurs in children and adolescents, with the second highest incidence among people over 50 years old. Although there were immense improvements in the survival of patients with osteosarcoma in the past 30 years, targetable mutations and agents of osteosarcomas still have been generally not satisfactory. Therefore, it is of great importance to further explore the highly specialized immune environment of bone, genes related to macrophage infiltration and potential therapeutic biomarkers and targets.MethodsThe 11 expression data sets of OS tissues and the 11 data sets of adjacent non-tumorous tissues available in the GEO database GSE126209 were used to conduct immune infiltration analysis. Then, through WGCNA analysis, we acquired the co-expression modules related to Mast cells activated and performed the GO and KEGG enrichment analysis. Next, we did the survival prognosis analysis and plotted a survival curve. Finally, we analyzed the COX multivariate regression of gene expression on clinical parameters and drew forest maps for visualization by the forest plot package.ResultsOS disease-related immune cell populations, mainly Mast cells activated, have higher cell content (p = 0.006) than the normal group. Then, we identified co-expression modules related to Mast cells activated. In sum, a total of 822 genes from the top three strongest positive correlation module MEbrown4, MEdarkslateblue and MEnavajowhite2 and the strongest negative correlation module MEdarkturquoise. From that, we identified nine genes with different levels in immune cell infiltration related to osteosarcoma, eight of which including SORBS2, BAIAP2L2, ATAD2, CYGB, PAMR1, PSIP1, SNAPC3 and ZDHHC21 in their low abundance have higher disease-free survival probability than the group in their high abundances.ConclusionThese results could assist clinicians to select targets for immunotherapies and individualize treatment strategies for patients with OS.

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Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in osteosarcoma.

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Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in osteosarcoma.

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