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Linking the ovarian cancer transcriptome and immunome.

ABSTRACT: Autoantigens have been reported in a variety of tumors, providing insight into the interplay between malignancies and the immune response, and also giving rise to novel diagnostic and therapeutic concepts. Why certain tumor-associated proteins induce an immune response remains largely elusive.This paper analyzes the proposed link between increased abundance of a protein in cancerous tissue and the increased potential of the protein for induction of a humoral immune response, using ovarian cancer as an example. Public domain data sources on differential gene expression and on autoantigens associated with this malignancy were extracted and compared, using bioinformatics analysis, on the levels of individual genes and proteins, transcriptional coregulation, joint functional pathways, and shared protein-protein interaction networks. Finally, a selected list of ovarian cancer-associated, differentially regulated proteins was tested experimentally for reactivity with antibodies prevalent in sera of ovarian cancer patients.Genes reported as showing differential expression in ovarian cancer exhibited only minor overlap with the public domain list of ovarian cancer autoantigens. However, experimental screening for antibodies directed against antigenic determinants from ovarian cancer-associated proteins yielded clear reactions with sera.A link between tumor protein abundance and the likelihood of induction of a humoral immune response in ovarian cancer appears evident.

SUBMITTER: Rapberger R

PROVIDER: S-EPMC2265674 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Linking the ovarian cancer transcriptome and immunome.

Rapberger Ronald R Perco Paul P Sax Cornelia C Pangerl Thomas T Siehs Christian C Pils Dietmar D Bernthaler Andreas A Lukas Arno A Mayer Bernd B Krainer Michael M

BMC systems biology 20080103

<h4>Background</h4>Autoantigens have been reported in a variety of tumors, providing insight into the interplay between malignancies and the immune response, and also giving rise to novel diagnostic and therapeutic concepts. Why certain tumor-associated proteins induce an immune response remains largely elusive.<h4>Results</h4>This paper analyzes the proposed link between increased abundance of a protein in cancerous tissue and the increased potential of the protein for induction of a humoral im ...[more]

PMID: 18173842

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Project description:BackgroundPolyploid giant cancer cells (PGCCs) have been observed in epithelial ovarian tumors. They can resist antimitotic drugs, thus participating in tumor maintenance and recurrence. Although their origin remains unclear, PGCC formation seems to be enhanced by conditions that trigger the unfolded protein response (UPR) such as hypoxia or chemotherapeutic drugs like paclitaxel. Hypoxia has been shown to promote the formation of ovarian PGCCs by cell fusion. We thus hypothesized that the UPR could be involved in EOC cell fusion, possibly explaining the occurrence of PGCCs and the aggressiveness of EOC.MethodsThe UPR was induced in two ovarian cancer cell lines (SKOV3 and COV318). The UPR activation was assessed by Western blot and polyploidy indexes were calculated. Then, to confirm the implication of cell fusion in PGCC formation, two populations of SKOV3 cells were transfected with plasmids encoding for two distinct nuclear fluorescent proteins (GFP and mCherry) associated with different antibiotic resistance genes, and the two cell populations were mixed in co-culture. The co-culture was submitted to a double-antibiotic selection. The resulting cell population was characterized for its morphology, cyclicity, and proliferative and tumorigenic capacities, in addition to transcriptomic characterization.ResultsWe demonstrated that cell fusion could be involved in the generation of ovarian PGCCs and this process was promoted by paclitaxel and the UPR activation. Double-antibiotic treatment of PGCCs led to the selection of a pure population of cells containing both GFP- and mCherry-positive nuclei. Interestingly, after 3 weeks of selection, we observed that these cells were no longer polynucleated but displayed a single nucleus positive for both fluorescent proteins, suggesting that genetic material mixing had occurred. These cells had reinitiated their normal cell cycles, acquired an increased invasive capacity, and could form ovarian tumors in ovo.ConclusionsThe UPR activation increased the in vitro formation of PGCCs by cell fusion, with the newly generated cells further acquiring new properties. The UPR modulation in ovarian cancer patients could represent an interesting therapeutic strategy to avoid the formation of PGCCs and therefore limit cancer relapse and drug resistance.

Project description:Immunotherapies are rapidly being integrated into standard of care (SOC) therapy in conjunction with surgery, chemotherapy, and radiotherapy for many cancers and a large number of clinical studies continue to explore immunotherapy alone and as part of combination therapies in patients with cancer. It is evident that clinical effectiveness of immunotherapy is limited to a subset of patients and improving immunotherapy related outcomes remains a major scientific and clinical effort. Understanding the immune cell subset phenotype and activation/functional status (cellular immunome) prior to and post therapy is therefore critical to develop biomarkers that (1) will predict if a patient will respond to immunotherapy and (2) are a result of immunotherapy. In this study, we investigated local (tumor) and peripheral (blood) cellular immunome of patients with melanoma, breast cancer, and brain cancer using a rapid and reliable standardized, multiparameter flow cytometry assay. We used this approach to monitor changes in the peripheral cellular immunome in women with breast cancer undergoing SOC therapy. Our analysis is unique because it is conducted using matched fresh tumor tissue and blood from patients in real-time, within 2-3 h of sample acquisition, and provides insight into the innate and adaptive immune cell profile in blood and tumor. Specific to blood, this approach involves no manipulation and evaluates all immune subsets such as T cells, B cells, natural killer (NK) cells, monocytes, dendritic cells (DCs), neutrophils, eosinophils, and basophils using 0.5 ml of blood. Analysis of the corresponding tumor provides much needed insight into the phenotype and activation status of immune cells, especially T and B cells, in the tumor microenvironment vs. the periphery. This analysis will be used to assess baseline and therapy-mediated changes in local and peripheral cellular immunome in patients with glioblastoma, breast cancer, and melanoma in planned immunotherapy clinical studies.

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Linking the ovarian cancer transcriptome and immunome.

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Linking the ovarian cancer transcriptome and immunome.

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