Characterization of Ewing sarcoma associated cancer/testis antigens

Mahlendorf, Dorothea E.; Staege, Martin S.

doi:10.4161/cbt.23298

Cited by 22 publications

(24 citation statements)

References 52 publications

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“…15 NKX2-2 was significantly upregulated in our Ewing's sarcoma samples, along with LIPI, which was recently identified as a highly specific antigen abnormally expressed in Ewing's sarcomas (and is therefore a strong candidate for immunotherapy: it could be used for targeting therapies specifically to sarcoma cells). 16 FLT4, a marker for lymphatic vessels, was previously reported to be upregulated in sarcoma, including angiosarcoma, as we also found in our study. 17,18 Previous studies have reported amplification of FLT4 and MYC in radiation-induced secondary angiosarcomas, but not in other radiation-associated sarcomas.…”

Section: Discussionsupporting

confidence: 79%

Identification, by systematic RNA sequencing, of novel candidate biomarkers and therapeutic targets in human soft tissue tumors

Sarver

Thayanithy

et al. 2015

Laboratory Investigation

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Human sarcomas comprise a heterogeneous group of more than 50 subtypes broadly classified into two groups: bone and soft tissue sarcomas. Such heterogeneity and their relative rarity have made them challenging targets for classification, biomarker identification, and development of improved treatment strategies. In this study, we used RNA sequencing to analyze 35 primary human tissue samples representing 13 different sarcoma subtypes, along with benign schwannoma, and normal bone and muscle tissues. For each sarcoma subtype, we detected unique messenger RNA (mRNA) expression signatures, which we further subjected to bioinformatic functional analysis, upstream regulatory analysis, and microRNA (miRNA) targeting analysis. We found that, for each sarcoma subtype, significantly upregulated genes and their deduced upstream regulators included not only previously implicated known players but also novel candidates not previously reported to be associated with sarcoma. For example, the schwannoma samples were characterized by high expression of not only the known associated proteins GFAP and GAP43 but also the novel player GJB6. Further, when we integrated our expression profiles with miRNA expression data from each sarcoma subtype, we were able to deduce potential key miRNA-gene regulator relationships for each. In the Ewing's sarcoma and fibromatosis samples, two sarcomas where miR-182-5p is significantly downregulated, multiple predicted targets were significantly upregulated, including HMCN1, NKX2-2, SCNN1G, and SOX2. In conclusion, despite the small number of samples per sarcoma subtype, we were able to identify key known players; concurrently, we discovered novel genes that may prove to be important in the molecular classification of sarcomas and in the development of novel treatments.

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Section: Discussionsupporting

confidence: 79%

Identification, by systematic RNA sequencing, of novel candidate biomarkers and therapeutic targets in human soft tissue tumors

Sarver

Thayanithy

et al. 2015

Laboratory Investigation

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“…Motivated by the findings that the cancer/testis antigen PRAME is expressed in a high proportion of unspecified sarcoma samples [20] and was among the candidate antigens emerging from an expression screening in EwS [19], we analyzed PRAME mRNA expression in our EwS cell lines and found that 5 of 9 cell lines express PRAME. The role of this antigen in EwS is unclear and could be worth exploring in primary tumor material in a prospective cohort of patients.…”

Section: Discussionmentioning

confidence: 99%

“…In EwS, the characteristic molecular translocation generates specific protein breakpoints that provide unique targets for T cell recognition, but these antigens have failed to evoke potent autologous T cell responses [12][13][14][15]. Expression screening analyses in EwS have identified alternative candidate antigens, including six-transmembrane epithelial antigen of the prostate-1 (STEAP1) [16,17], the human cancer/testis antigens X-antigen family member 1 (XAGE1) [18] and preferentially expressed antigen in melanoma (PRAME) [19]. PRAME expression was also found in many sarcoma cell lines and in 9 of 23 tissue samples in a report including various, not further specified, sarcomas [20].…”

Section: Introductionmentioning

confidence: 99%

Common Ewing sarcoma-associated antigens fail to induce natural T cell responses in both patients and healthy individuals

Altvater¹,

Kailayangiri²,

Theimann³

et al. 2014

Cancer Immunol Immunother

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Disseminated or relapsed Ewing sarcoma (EwS) has remained fatal in the majority of patients. A promising approach to preventing relapse after conventional therapy is to establish tumor antigen-specific immune control. Efficient and specific T cell memory against the tumor depends on the expansion of rare T cells with native specificity against target antigens overexpressed by the tumor. Candidate antigens in EwS include six-transmembrane epithelial antigen of the prostate-1 (STEAP1), and the human cancer/testis antigens X-antigen family member 1 (XAGE1) and preferentially expressed antigen in melanoma (PRAME). Here, we screened normal donors and EwS patients for the presence of circulating T cells reactive with overlapping peptide libraries of these antigens by IFN-γ Elispot analysis. The majority of 22 healthy donors lacked detectable memory T cell responses against STEAP1, XAGE1 and PRAME. Moreover, ex vivo detection of T cells specific for these antigens in both blood and bone marrow were limited to a minority of EwS patients and required nonspecific T cell prestimulation. Cytotoxic T cells specific for the tumor-associated antigens were efficiently and reliably generated by in vitro priming using professional antigen-presenting cells and optimized cytokine stimulation; however, these T cells failed to interact with native antigen processed by target cells and with EwS cells expressing the antigen. We conclude that EwS-associated antigens fail to induce efficient T cell receptor (TCR)-mediated antitumor immune responses even under optimized conditions. Strategies based on TCR engineering could provide a more effective means to manipulating T cell immunity toward targeted elimination of tumor cells.

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“…In vitro priming of T cells against individual peptides derived from STEAP1 was effective to induce selective expansion of effector T cells that specifically interacted with antigenexpressing EwS cell lines in an MHC-restricted manner [65][66][67]. Furthermore, T cells expanded in response to membrane-associated phospholipase A1-β-derived peptides were found to lyze EwS cells that express the antigen within the adequate MHC context in vitro [52].…”

Section: In Vitro Expansion Of T Cells With Native Tcr Specificity Fomentioning

confidence: 98%

“…Alternative targets have been identified by systematic gene expression analysis of EwS [9,47], or by screening tumor tissue arrays for aberrant (over)expression of candidate self-antigens. Potential targets in EwS include cancer/testis antigens XAGE-1 and -2 [47][48][49] and phosphatidic acid-specific membrane-associated phospholipase A1-β [50][51][52]. Cancer/testis antigens are proteins with tightly regulated expression, normally restricted to male germ cells.…”

Section: Potential T-cell Targets: Intracellular Antigens In Ewsmentioning

confidence: 99%

Cellular Immunotherapy Strategies for Ewing Sarcoma

Rossig

2014

Immunotherapy

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Ewing sarcoma is a rare cancer of bone and soft tissues defined by a specific chromosomal rearrangement. Preclinical development of immunological treatment strategies includes expansion of T cells with native or grafted T-cell receptor specificities for Ewing sarcoma-associated intracellular antigens, and T-cell engineering with chimeric antigen receptors targeting surface antigens. In vitro preactivated NK cells may also have activity in this cancer. Major challenges are the heterogeneity of antigen expression in individual Ewing sarcomas, and the coexpression of most candidate targets on normal cells. Moreover, homing of therapeutic effector cells to both primary and metastatic tumor sites and adequate function within the immunosuppressive tumor microenvironment will have to be ensured to allow for effective immune targeting of this cancer.

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Characterization of Ewing sarcoma associated cancer/testis antigens

Cited by 22 publications

References 52 publications

Identification, by systematic RNA sequencing, of novel candidate biomarkers and therapeutic targets in human soft tissue tumors

Identification, by systematic RNA sequencing, of novel candidate biomarkers and therapeutic targets in human soft tissue tumors

Common Ewing sarcoma-associated antigens fail to induce natural T cell responses in both patients and healthy individuals

Cellular Immunotherapy Strategies for Ewing Sarcoma

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