Dataset Information

Identification of cell surface proteins as potential immunotherapy targets in 12 pediatric cancers.

ABSTRACT: Technological advances now allow us to rapidly produce CARs and other antibody-derived therapeutics targeting cell surface receptors. To maximize the potential of these new technologies, relevant extracellular targets must be identified. The Pediatric Oncology Branch of the NCI curates a freely accessible database of gene expression data for both pediatric cancers and normal tissues, through which we have defined discrete sets of over-expressed transcripts in 12 pediatric cancer subtypes as compared to normal tissues. We coupled gene expression profiles to current annotation databases (i.e., Affymetrix, Gene Ontology, Entrez Gene), in order to categorize transcripts by their sub-cellular location. In this manner we generated a list of potential immune targets expressed on the cell surface, ranked by their difference from normal tissue. Global differences from normal between each of the pediatric tumor types studied varied, indicating that some malignancies expressed transcript sets that were more highly diverged from normal tissues than others. The validity of our approach is seen by our findings for pre-B cell ALL, where targets currently in clinical trials were top-ranked hits (CD19, CD22). For some cancers, reagents already in development could potentially be applied to a new disease class, as exemplified by CD30 expression on sarcomas. Moreover, several potential new targets shared among several pediatric solid tumors are herein identified, such as MCAM (MUC18), metadherin (MTDH), and glypican-2 (GPC2). These targets have been identified at the mRNA level and are yet to be validated at the protein level. The safety of targeting these antigens has yet to be demonstrated and therefore the identified transcripts should be considered preliminary candidates for new CAR and therapeutic antibody targets. Prospective candidate targets will be evaluated by proteomic analysis including Westerns and immunohistochemistry of normal and tumor tissues.

SUBMITTER: Orentas RJ

PROVIDER: S-EPMC3523547 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Identification of cell surface proteins as potential immunotherapy targets in 12 pediatric cancers.

Orentas Rimas J RJ Yang James J JJ Wen Xinyu X Wei Jun S JS Mackall Crystal L CL Khan Javed J

Frontiers in oncology 20121217

Technological advances now allow us to rapidly produce CARs and other antibody-derived therapeutics targeting cell surface receptors. To maximize the potential of these new technologies, relevant extracellular targets must be identified. The Pediatric Oncology Branch of the NCI curates a freely accessible database of gene expression data for both pediatric cancers and normal tissues, through which we have defined discrete sets of over-expressed transcripts in 12 pediatric cancer subtypes as comp ...[more]

PMID: 23251904

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Project description:Hepatocellular carcinoma (HCC) is a solid tumor prone to chemotherapy resistance, and combined immunotherapy is expected to bring a breakthrough in HCC treatment. However, the tumor and tumor microenvironment (TME) of HCC is highly complex and heterogeneous, and there are still many unknowns regarding tumor cell stemness and metabolic reprogramming in HCC. In this study, we combined single-cell RNA sequencing data from 27 HCC tumor tissues and 4 adjacent non-tumor tissues, and bulk RNA sequencing data from 374 of the Cancer Genome Atlas (TCGA)-liver hepatocellular carcinoma (LIHC) samples to construct a global single-cell landscape atlas of HCC. We analyzed the enrichment of signaling pathways of different cells in HCC, and identified the developmental trajectories of cell subpopulations in the TME using pseudotime analysis. Subsequently, we performed transcription factors regulating different subpopulations and gene regulatory network analysis, respectively. In addition, we estimated the stemness index of tumor cells and analyzed the intercellular communication between tumors and key TME cell clusters. We identified novel HCC cell clusters that specifically express HP (HCC_HP), which may lead to higher tumor differentiation and tumor heterogeneity. In addition, we found that the HP gene expression-positive neutrophil cluster (Neu_AIF1) had extensive and strong intercellular communication with HCC cells, tumor endothelial cells (TEC) and cancer-associated fibroblasts (CAF), suggesting that clearance of this new cluster may inhibit HCC progression. Furthermore, ErbB signaling pathway and GnRH signaling pathway were found to be upregulated in almost all HCC tumor-associated stromal cells and immune cells, except NKT cells. Moreover, the high intercellular communication between HCC and HSPA1-positive TME cells suggests that the immune microenvironment may be reprogrammed. In summary, our present study depicted the single-cell landscape heterogeneity of human HCC, identified new cell clusters in tumor cells and neutrophils with potential implications for immunotherapy research, discovered complex intercellular communication between tumor cells and TME cells.

Project description:BackgroundAdvanced stage/recurrent clear cell ovarian cancers (CCOCs) are characterized by a low response to chemotherapy and a poor prognosis. There is growing interest in investigating novel/molecular targeted therapies in patients with CCOC in histotype-specific trials. However, CCOCs are not a uniform entity and comprise a number of molecular subtypes and it is unlikely that a single approach to treatment will be appropriate for all patients. The aim of this study was to analyze the results of a multiplatform profiling panel in CCOCs to identify potential therapeutic targets.Patients and methodsTumor profiling was performed on 521 CCOCs. They were grouped into pure (n = 422) and mixed (n = 99) CCOC for analysis. Testing included a combination of DNA sequencing (including next-generation sequencing) using a 46-gene panel, immunohistochemistry, fluorescent or chromogenic in situ hybridization, and RNA fragment analysis.ResultsThe most common findings were in the PIK3CA/Akt/mTOR pathway, with 61% of all CCOCs showing a molecular alteration in one of these pathway components. Next-generation sequencing revealed PIK3CA mutations in 50% of pure CCOCs. Significant differences were observed between pure and mixed CCOCs with respect to hormone receptor expression (9% vs 34.7% for ER, 13.45 vs 26.4% for PR), cMET (24.1% vs 11.6%), PD-1 tumor infiltrating lymphocytes (48.1% vs 100%), expression of PD-L1 (7.4% vs 25%), and TOPO1 (41% vs 27.1%) on immunohistochemistry, whereas next-generation sequencing revealed significant differences in mutation frequency in PIK3CA (50% vs 18.5%), TP53 (18.1% vs 57.7%), KRAS (12.4% vs 3.7%), and cMET (1.9% vs 11.1%).ConclusionsThis large study confirms that the PIK3CA/Akt/mTOR pathway is commonly altered in CCOCs, and highlights the significant differences between pure and mixed CCOCs. Clear cell ovarian cancers are molecularly heterogeneous and there are a number of potential therapeutic targets which could be tested in clinical trials.

Dataset Information

Identification of cell surface proteins as potential immunotherapy targets in 12 pediatric cancers.

Publications

Identification of cell surface proteins as potential immunotherapy targets in 12 pediatric cancers.

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