NY-ESO-1 (CTAG1B) expression in mesenchymal tumors

Endo, Makoto; Graaff, Marieke A. de; Ingram, Davis R.; Lim, Siew Lan; Lev, Dina; Bruijn, Inge H. Briaire-de; Somaiah, Neeta; Bovée, Judith V.M.G.; Lazar, Alexander J.; Nielsen, Torsten O.

doi:10.1038/modpathol.2014.155

Cited by 68 publications

(50 citation statements)

References 31 publications

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“…36,37 NY-ESO-1 expression was observed not only on dedifferentiated but also on conventional chondrosarcoma. 38 Importantly, the matched primary tumor and subcutaneous metastasis evaluated in one patient displayed discordant PD-L1 expression. Also, the higher proportion of FoxP3 + T regulatory cells in metastases compared with primary tumors may suggest a specific role of these immunosuppressive cells in later stages of the disease.…”

Section: Discussionmentioning

confidence: 99%

Analysis of PD-L1, T-cell infiltrate and HLA expression in chondrosarcoma indicates potential for response to immunotherapy specifically in the dedifferentiated subtype

et al. 2016

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Therapies targeting the programmed cell death 1 (PD-1) or its ligand (PD-L1) promote antitumor T-cell activity, leading to unprecedented long-lasting tumor responses in some advanced cancers. Because of radiotherapy and chemotherapy resistance, no effective treatments have been defined for advanced chondrosarcomas. We here report an immunohistochemical analysis of PD-L1 expression in a large series of conventional, mesenchymal, clear cell and dedifferentiated chondrosarcomas using tissue microarrays. In the PD-L1-positive tumors, we analyzed the immune microenvironment (T-cell and macrophage infiltration as well as HLA class I expression) using whole sections. PD-L1 expression was absent in conventional (n = 119), mesenchymal (n = 19) and clear cell (n = 20) chondrosarcomas. Forty-one percent (9 of the 22) of dedifferentiated chondrosarcomas displayed PD-L1 positivity. These results were confirmed in an independent cohort using whole tissue sections of dedifferentiated chondrosarcomas in which PD-L1 expression was detected in 52% (11 of the 21) of cases. PD-L1 expression was exclusively found in the dedifferentiated component and expression positively correlated with other immune parameters such as high number of tumor-infiltrating lymphocytes (P = 0.014) and positive HLA class I expression (P = 0.024) but not with patient overall survival (P = 0. Chondrosarcomas constitute a malignant group of cartilaginous matrix-producing neoplasms, with diverse morphological features and clinical behavior. 1 Conventional chondrosarcoma is the second most common primary bone malignancy after osteosarcoma and can be categorized according to their location into central (85%) and peripheral chondrosarcomas (15%). Their histology is similar, with atypical chondrocytes and abundant extracellular matrix, but they differ at the genetic level. Notably, mutations in isocitrate dehydrogenase (IDH) 1 and 2 are found in approximately half of conventional central chondrosarcomas while mutations in genes encoding exostosin (EXT) 1 and 2 characterize peripheral chondrosarcomas. 2,3 Histological grade is strongly correlated with clinical prognosis with a 10-year survival rate of 83% for atypical cartilaginous tumor/grade I but only 29% for grade III. In addition to conventional chondrosarcoma, several rare subtypes of chondrosarcoma are discerned (dedifferentiated, mesenchymal and clear cell), together constituting 10-15% of all chondrosarcomas. Clear cell chondrosarcoma is a low-grade malignant tumor with a 10-year survival rate reported around 90% while dedifferentiated and mesenchymal chondrosarcoma are both highly malignant, with frequent occurrence of distant metastases and o30% survival at 5 and 10 years, respectively. 4

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Section: Discussionmentioning

confidence: 99%

Analysis of PD-L1, T-cell infiltrate and HLA expression in chondrosarcoma indicates potential for response to immunotherapy specifically in the dedifferentiated subtype

et al. 2016

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“…CTAG1B) has recently shown to be almost universally expressed in MLS (89–100%). 28–30 NY-ESO-1 expression is normally limited to germ cells making it a good cancer immunotherapeutic target. 31;32 …”

Section: Introductionmentioning

confidence: 99%

Establishment and characterization of a new human myxoid liposarcoma cell line (DL-221) with the FUS-DDIT3 translocation

Graaff

Beird

et al. 2016

Laboratory Investigation

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Myxoid liposarcoma has the pathognomonic fusion oncogene FUS-DDIT3 encoding a chimeric transcription factor. Metastatic risk is higher with an increased round cell component and has been linked to aberrations involving the IGFR/PI3K/AKT pathway. These molecular insights have yet to translate to targeted therapies and the lack of experimental models is a major hindrance. We describe the initial in-depth characterization of a new cell line (DL-221) and establishment of a mouse xenograft model. The cell line DL-221 was derived from a metastatic pleural lesion showing myxoid and round cell histology. This newly established cell line was characterized for phenotypic properties and molecular cytogenetic profile, using PCR, COBRA-FISH and western blot. Next-generation whole exome sequencing was performed to further characterize the cell line and the parent tumor. NOD-SCID-IL2R gamma knockout mice were xenograft hosts. DL-221 cells grew an adhering monolayer and COBRA-FISH showed an aneuploid karyotype with t(12;16)(q13;p11) and several other rearrangements; RT-PCR demonstrated a FUS-DDIT3 fusion transcript type 1. Both the cell line and the original tumor harbored a TP53 compound heterozygous mutation in exon 4 and 7 and were wild type for PIK3CA. Moreover, among the 1254 variants called by whole exome sequencing, there was 77% concordance between the cell line and parent tumor. The recently described hotspot mutation in the TERT promoter region in myxoid liposarcomas was also found at C228T in DL-221. Xenografts suitable for additional pre-clinical studies were successfully established in mice after subcutaneous injection. The established DL-221 cell line is the only published available myxoid liposarcoma cell line that underwent spontaneous immortalization, without requiring SV40 transformation. The cell line and its xenograft model are unique and helpful tools to study the biology and novel potential targeted treatment approaches for myxoid liposarcoma.

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“…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.…”

Section: Advances In Immunotherapymentioning

confidence: 99%

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

Lim

Poulin

Nielsen

2015

Clinical Cancer Research

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There are more than 100 sarcoma subtypes, each uncommon and diagnostically challenging. Conventional chemotherapy has little benefit for most soft-tissue sarcomas; new treatment strategies are needed. Multiple recent genomic studies have provided detailed insights into sarcoma biology, including more accurate classification by molecular subtype, identification of recurrent mutations in oncogenic pathways, and evidence of epigenetic dysregulation. Advances in immunotherapy (adoptive immune cell transfer, tumor vaccine strategies, and immune checkpoint inhibition) have also provided a better understanding of how immuno-oncology might best be applied to sarcoma treatment, including connections to oncogenic pathways that may support combination strategies with conventional and targeted therapies. In this article, we review the latest sarcoma genomic studies and immuno-oncology developments and discuss how the findings suggest potential strategies to improve diagnosis and treatment across multiple sarcoma subtypes.

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NY-ESO-1 (CTAG1B) expression in mesenchymal tumors

Cited by 68 publications

References 31 publications

Analysis of PD-L1, T-cell infiltrate and HLA expression in chondrosarcoma indicates potential for response to immunotherapy specifically in the dedifferentiated subtype

Analysis of PD-L1, T-cell infiltrate and HLA expression in chondrosarcoma indicates potential for response to immunotherapy specifically in the dedifferentiated subtype

Establishment and characterization of a new human myxoid liposarcoma cell line (DL-221) with the FUS-DDIT3 translocation

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

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