Abstract:BackgroundPrimary testicular lymphoma (PTL) is a rare and lethal disease. The most common histological subtype is diffuse large B-cell lymphoma (DLBCL). Standard treatments are frequently ineffective. Thus, the development of novel forms of therapy is urgently required. Specific immunotherapy generating immune responses directed against antigen predominantly expressed by cancer cells such as cancer-testis antigens (CTA) may provide a valid alternative treatment for patients bearing PTL, alone or in combination… Show more
“…A number of monoclonal antibodies have been described to be specific for certain members of the MAGE family of genes. However, the degree of specificity of the respective antibodies has remained somewhat unclear and, accordingly, for example the 57B antibody has been described as being MAGE‐A4‐specific, whereas others describe this clone as targeting a variety of MAGE‐A‐family members . Testing the different antibodies against a number of recombinant full‐length MAGE proteins in an ELISA, we found clone 57B to recognize MAGE‐A3, MAGE‐A4 and, to a lesser extent, MAGE‐A6 (Fig.…”
The prognosis of head and neck squamous cell carcinoma (HNSCC) patients remains poor. The identification of high-risk subgroups is needed for the development of custom-tailored therapies. The expression of cancer-testis antigens (CTAs) has been linked to a worse prognosis in other cancer types; however, their prognostic value in HNSCC is unclear because only few patients have been examined and data on CTA protein expression are sparse. A tissue microarray consisting of tumor samples from 453 HNSCC patients was evaluated for the expression of CTA proteins using immunohistochemistry. Frequency of expression and the subcellular expression pattern (nuclear, cytoplasmic, or both) was recorded. Protein expression of melanoma antigen (MAGE)-A family CTA, MAGE-C family CTA and NY-ESO-1 was found in approximately 30, 7 and 4% of tumors, respectively. The subcellular expression pattern in particular had a marked impact on the patients' prognosis. Median overall survival (OS) of patients with (i) simultaneous cytoplasmic and nuclear expression compared to (ii) either cytoplasmic or nuclear expression and (iii) negative patients was 23.0 versus 109.0 versus 102.5 months, for pan-MAGE (p < 0.0001), 46.6 versus 50.0 versus 109.0 for MAGE-A3/A4 (p 5 0.0074) and 13.3 versus 50.0 versus 100.2 months for NY-ESO-1 (p 5 0.0019). By multivariate analysis, these factors were confirmed as independent markers for poor survival. HNSCC patients showing protein expression of MAGE-A family members or NY-ESO-1 represent a subgroup with an extraordinarily poor survival. The development of immunotherapeutic strategies targeting these CTA may, therefore, be a promising approach to improve the outcome of HNSCC patients.
“…A number of monoclonal antibodies have been described to be specific for certain members of the MAGE family of genes. However, the degree of specificity of the respective antibodies has remained somewhat unclear and, accordingly, for example the 57B antibody has been described as being MAGE‐A4‐specific, whereas others describe this clone as targeting a variety of MAGE‐A‐family members . Testing the different antibodies against a number of recombinant full‐length MAGE proteins in an ELISA, we found clone 57B to recognize MAGE‐A3, MAGE‐A4 and, to a lesser extent, MAGE‐A6 (Fig.…”
The prognosis of head and neck squamous cell carcinoma (HNSCC) patients remains poor. The identification of high-risk subgroups is needed for the development of custom-tailored therapies. The expression of cancer-testis antigens (CTAs) has been linked to a worse prognosis in other cancer types; however, their prognostic value in HNSCC is unclear because only few patients have been examined and data on CTA protein expression are sparse. A tissue microarray consisting of tumor samples from 453 HNSCC patients was evaluated for the expression of CTA proteins using immunohistochemistry. Frequency of expression and the subcellular expression pattern (nuclear, cytoplasmic, or both) was recorded. Protein expression of melanoma antigen (MAGE)-A family CTA, MAGE-C family CTA and NY-ESO-1 was found in approximately 30, 7 and 4% of tumors, respectively. The subcellular expression pattern in particular had a marked impact on the patients' prognosis. Median overall survival (OS) of patients with (i) simultaneous cytoplasmic and nuclear expression compared to (ii) either cytoplasmic or nuclear expression and (iii) negative patients was 23.0 versus 109.0 versus 102.5 months, for pan-MAGE (p < 0.0001), 46.6 versus 50.0 versus 109.0 for MAGE-A3/A4 (p 5 0.0074) and 13.3 versus 50.0 versus 100.2 months for NY-ESO-1 (p 5 0.0019). By multivariate analysis, these factors were confirmed as independent markers for poor survival. HNSCC patients showing protein expression of MAGE-A family members or NY-ESO-1 represent a subgroup with an extraordinarily poor survival. The development of immunotherapeutic strategies targeting these CTA may, therefore, be a promising approach to improve the outcome of HNSCC patients.
“…Among them we found not only many established CSGs such as LIPI for Ewing sarcoma, 21
PRAME for neuroblastoma 22,23 and members of the MAGE -family for germinoma, 24 neuroblastoma, 25 synovial sarcoma, 26 multiple myeloma, 27 diffuse large B cell lymphoma (DLBCL), 28 and osteosarcoma, 29 but also many novel candidates of which some appear to be suitable for targeting multiple cancer entities (Figure 2, Supplementary Table 5, Supplementary Figure 1). 10.1080/2162402X.2018.1481558-F0002Figure 2.Overexpressed CSGs in multiple cancer entities identified with RAVEN.…”
Immunotherapy can revolutionize anti-cancer therapy if specific targets are available. Immunogenic peptides encoded by cancer-specific genes (CSGs) may enable targeted immunotherapy, even of oligo-mutated cancers, which lack neo-antigens generated by protein-coding missense mutations. Here, we describe an algorithm and user-friendly software named RAVEN (Rich Analysis of Variable gene Expressions in Numerous tissues) that automatizes the systematic and fast identification of CSG-encoded peptides highly affine to Major Histocompatibility Complexes (MHC) starting from transcriptome data. We applied RAVEN to a dataset assembled from 2,678 simultaneously normalized gene expression microarrays comprising 50 tumor entities, with a focus on oligo-mutated pediatric cancers, and 71 normal tissue types. RAVEN performed a transcriptome-wide scan in each cancer entity for gender-specific CSGs, and identified several established CSGs, but also many novel candidates potentially suitable for targeting multiple cancer types. The specific expression of the most promising CSGs was validated in cancer cell lines and in a comprehensive tissue-microarray. Subsequently, RAVEN identified likely immunogenic CSG-encoded peptides by predicting their affinity to MHCs and excluded sequence identity to abundantly expressed proteins by interrogating the UniProt protein-database. The predicted affinity of selected peptides was validated in T2-cell peptide-binding assays in which many showed binding-kinetics like a very immunogenic influenza control peptide. Collectively, we provide an exquisitely curated catalogue of cancer-specific and highly MHC-affine peptides across 50 cancer types, and a freely available software (https://github.com/JSGerke/RAVENsoftware) to easily apply our algorithm to any gene expression dataset. We anticipate that our peptide libraries and software constitute a rich resource to advance anti-cancer immunotherapy.
“…In addition, vesicles may participate in protein storage or transport [22]. Other studies aimed at demonstrating subcellular localization of NY-ESO-1 have shown both cytoplasmic and nuclear expression in head and neck cancer samples, whereas cytoplasmic expression in diffuse large B-cell testicular lymphoma specimens [25,26]. Finally, in intrahepatic cholagiocarcinoma samples, NY-ESO-1 showed a predominantly, although not exclusively, cytoplasmic staining [27].…”
“…Humoral and CD8 + T-cell responses in 1/4 (25%) of synovial sarcoma samples/ELISA and ELISPOT [173] Angiosarcoma 2/20 (10%)/IHC [171] Ewing sarcoma [174] Seminona (classical) 12/73 (16%)/IHC/E978 [30] Diffuse large B-cell testicular lymphoma 9/24 (37%) IHC [26] Penile Carcinoma 29/30 (97%)/IHC/D8.38 [175] ELISA cination were more focused than naturally induced ones [72]. Historically, the first peptides from NY-ESO-1 recognized by CD8 + T cells were identified in a mixed tumor lymphocyte culture.…”
New York esophageal squamous cell carcinoma 1 (NY-ESO-1) is a known cancer testis gene with exceptional immunogenicity and prevalent expression in many cancer types. These characteristics have made it an appropriate vaccine candidate with the potential application against various malignancies. This article reviews recent knowledge about the NY-ESO-1 biology, function, immunogenicity and expression in cancers as well as and the results of clinical trials with this antigen.
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