Abstract
BackgroundPRAME (preferentially expressed antigen in melanoma), a member of the cancer-testis antigen family, has been shown to have increased expression in solid tumors, including sarcoma, and PRAME-specific therapies are currently in development for other cancers such as melanoma.MethodsTo map the landscape of PRAME expression in sarcoma, we used publicly available data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE) projects and determined which sarcoma subtypes and subsets are associated with increased PRAME expression. We also analyzed how PRAME expression correlates with survival and expression of markers related to antigen presentation and T cell function. Furthermore, tumor and normal tissue expression comparisons were performed using data from the genotype-tissue expression (GTEx) project.ResultsWe found that uterine carcinosarcoma highly overexpresses the PRAME antigen, and synovial sarcomas and multifocal leiomyosarcomas also show high expressions suggesting that PRAME may be an effective target of immunotherapies of these tumors. However, we also discovered that PRAME expression negatively correlates with genes involved in antigen presentation, and in synovial sarcoma MHC class I antigen presentation deficiencies are also present, potentially limiting the efficacy of immunotherapies of this malignancy.ConclusionsWe determined that uterine carcinosarcoma, synovial sarcoma, and leiomyosarcoma patients would potentially benefit from PRAME-specific immunotherapies. Tumor escape through loss of antigen presentation needs to be further studied.
Highlights
Preferentially expressed antigen in melanoma (PRAME), a member of the cancer-testis antigen family, has been shown to have increased expression in solid tumors, including sarcoma, and PRAME-specific therapies are currently in development for other cancers such as melanoma
PRAME is expressed in sarcoma and shows high overexpression in uterine carcinosarcoma To determine the relevance of PRAME as a target in sarcoma, we compared all normal (GTEx, n = 30 tissue types, n = 8153 samples) and tumor tissue (TCGA, n = 33 cancers) expressions (Fig. 1)
PRAME is expressed in sarcoma cell lines In the Cell Line Encyclopedia (CCLE) cell line data (n = 46 with microarray, n = 40 with RNA-sequencing data) we found that sarcoma subtypes show diverse PRAME expressions (Fig. 2), in the microarray data, all four chondrosarcoma lines had lower expressions than other bone sarcoma cell lines such as Ewing’s sarcoma (p < 0.01) and osteosarcoma (p < 0.1)
Summary
PRAME (preferentially expressed antigen in melanoma), a member of the cancer-testis antigen family, has been shown to have increased expression in solid tumors, including sarcoma, and PRAME-specific therapies are currently in development for other cancers such as melanoma. Expressed antigen in melanoma (PRAME) was first discovered in melanomas and it was associated with cytotoxic T cell activation [1]. The function of PRAME appears to be extensive though it was first identified as a repressor of the retinoic acid receptor pathway [3]. PRAME inhibits myeloid differentiation in a retinoic aciddependent and independent manner as well [4]. PRAME, Cancer-testis antigens such as MAGE-A and NYESO-1 have been widely explored, and these tumor-associated antigens have served as the therapeutic target of various vaccine strategies and adoptive cellular therapies. Patients with synovial sarcoma treated with genetically engineered autologous T cells with NY-ESO-1 recognition experienced RECIST partial responses as noted in 11 of 18 cases (61%) [6]
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