Expression of cancer-testis antigens MAGEA1, MAGEA3, ACRBP, PRAME, SSX2, and CTAG2 in myxoid and round cell liposarcoma

Abstract

Myxoid and round-cell liposarcoma is a frequently encountered liposarcoma subtype. The mainstay of treatment remains surgical excision with or without chemoradiation. However, treatment options are limited in the setting of metastatic disease. Cancer-testis antigens are immunogenic antigens with the expression largely restricted to testicular germ cells and various malignancies, making them attractive targets for cancer immunotherapy. Gene expression studies have reported the expression of various cancer-testis antigens in liposarcoma, with mRNA expression of CTAG1B, CTAG2, MAGEA9, and PRAME described specifically in myxoid and round-cell liposarcoma. Herein, we further explore the expression of the cancer-testis antigens MAGEA1, ACRBP, PRAME, and SSX2 in myxoid and round-cell liposarcoma by immunohistochemistry in addition to determining mRNA levels of CTAG2 (LAGE-1), PRAME, and MAGEA3 by quantitative real-time PCR. Samples in formalin-fixed paraffin-embedded blocks (n=37) and frozen tissue (n=8) were obtained for immunohistochemistry and quantitative real-time PCR, respectively. Full sections were stained with antibodies to MAGEA1, ACRBP, PRAME, and SSX2 and staining was assessed for intensity (1–2+) and percent tumor positivity. The gene expression levels of CTAG2, PRAME, and MAGEA3 were measured by quantitative real-time PCR. In total, 37/37 (100%) of the samples showed predominantly strong, homogenous immunoreactivity for PRAME. There was a variable, focal expression of MAGEA1 (11%) and SSX2 (16%) and no expression of ACRBP. Quantitative real-time PCR demonstrated PRAME and CTAG2 transcripts in all eight samples: six tumors with high mRNA levels; two tumors with low mRNA levels. The gene expression of MAGEA3 was not detected in the majority of cases. In conclusion, myxoid and round-cell liposarcomas consistently express PRAME by immunohistochemistry as well as CTAG2 and PRAME by qualitative real-time PCR. This supports the use of cancer-testis antigen-targeted immunotherapy in the treatment of this malignancy.

Cancer‐testis antigens PRAME and NY‐ESO‐1 correlate with tumour grade and poor prognosis in myxoid liposarcoma

“…Among the up‐regulated genes, we focused on the cancer‐testis antigen PRAME . MLS samples were recently reported to show a high level of PRAME expression, and other recent studies demonstrated that another cancer‐testis antigen, NY‐ESO‐1 ( CTAG1B ), was hyper‐expressed in MLS . In our microarray results, 111 cancer‐testis antigens were included, and eight cancer‐testis antigens were up‐regulated by more than fourfold compared to their levels in normal adipose tissue (Table ).…”

“…Recently published studies have reported that NY-ESO-1 was expressed in 100% (25/25) and 89% (16/ 18) of the MLS samples, and in 10% (1/10) of the DDLS, none (0/10) of the WLS and 50% (3/6) of the PLS samples and that PRAME was expressed in 100% of 37 MLSs by immunohistochemistry [19][20][21]. Our data are nearly coincident with these results and, as with NY-ESO-1, PRAME was highly expressed in the MLSs among the liposarcomas in this study.…”

“…MLS was recently reported to show a high level of PRAME expression, and other recent studies demonstrated that another cancer-testis antigen, NY-ESO-1 [New York ESOphageal squamous cell carcinoma 1] (CTAG1B), which is also described as a promising immunotherapy target [16,17], was hyper-expressed in MLS [18][19][20][21]. Correlation of the expression of PRAME and NY-ESO-1 with tumour grade or poor prognosis has been reported in several cancers [22][23][24][25][26][27][28][29][30][31][32].…”

New Strategies in Sarcoma: Linking Genomic and Immunotherapy Approaches to Molecular Subtype

“…Cytotoxic T lymphocytes (CTL) are critical effectors of tumor cell killing in animal models, and intense CTL infiltration correlates with good prognosis in sarcomas (43,44). To stimulate CTL responses, MHCI-directed peptide vaccines have been pursued extensively, (45,46). Trials of such vaccines have historically shown disappointing clinical effects (47), likely due in part to insufficiency of vaccine adjuvants but also to the mutability of advanced cancers and to mechanisms of immunoevasion.…”

MAGE-A3: an Immunogenic Target Used in Clinical Practice

“…[54] Melanocytic lesions Melanoma 9/16 (56%)/RT-PCR [67] 5/10 (50%)/nested RT-PCR [68] 4/5 (80%)/RT-PCR [69] 72/105 (69%)/RT-PCR [70] Metastatic tumor 110/145 (76%)/RT-PCR [71] Primary tumor 36/100 (36%)/RT-PCR Metastatic tumor 2/3 (67%)/RT-PCR [72] Primary tumor 1/4 (25%)/RT-PCR 7/12 (58%)/RT-PCR [26] Malignant melanomas 12/23 (52%)/RT-PCR [73] Malignant 18/28 (64%)/RT-PCR 14/31 (45%)/FACS [74] 3 primary, 21 metastasis 11/24 (46%)/RT-PCR [32] Lymph node metastasis 35 [76] Sentinel node 25/53 (47%)/qRT-PCR [77] Sentinel node from melanoma free patients 24/55 (44%)/RT-PCR [78] Primary tumor 4/10 (40%)/RT-PCR Sentinel node from melanoma patients 12/17 (71%)/RT-PCR 111/202 (55%)/RT-PCR [79] Esophageal mucosa 6/6 (100%)/IHC/M3H67 [80] Metastatic tumor 116/191 (61%)/IHC/57B [81] CTL: Cytotoxic T lymphocyte; ELISA: Enzyme-linked immunosorbent assay; IHC: Immunohistochemistry; mAb: Monoclonal antibody; (q)RT-PCR: (Quantitative) reverse transcription PCR; TIL: Tumor-infiltrating lymphocyte. [83] 'In situ' melanoma 0/3 (0%)/RT-PCR [72] Benign melanocytic nevus 0/10 (0%)/RT-PCR Nevus 0/19 (0%)/IHC/M3H67 [83] Dysplastic nevus 0/14 (0%)/RT-PCR 0/4 (0%)/RT-PCR [71] Benign nevocellular nevus 0/12 (0%)/RT-PCR [37] Primary tumor 9/26 (35%)/RT-PCR [32] Primary tumor 7/51 (14%)/RT-PCR [73] Primary tumor 37/362 (10%)/qPCR [85] Neuroblastoma Primary tumor 23/47 (49%)/RT-PCR [86] Gastrointestinal stromal tumor 7/86 (8%)/IHC/M3H67 [87] 5/35 (14%)/IHC/M3H67 [88] Gastric cancer 12/12 (100%)/qRT-PCR [90] Sarcoma Osteosarcoma 28/28 (100%)/qRT-PCR [91] Myxoid and round cell liposarcoma 2/8 (25%)/qRT-PCR [92] CTL: Cytotoxic T lymphocyte; ELISA: Enzyme-linked immunosorbent assay; IHC: Immunohistochemistry; mAb: Monoclonal antibody; (q)RT-PCR: (Quantitative) reverse transcription PCR; TIL...…”