Increased Phosphorylation of Vimentin in Noninfiltrative Meningiomas

International audienceBACKGROUND: Tissue invasion or tissue infiltration are clinical behaviors of a poor-prognosis subset of meningiomas. We carried out proteomic analyses of tissue extracts to discover new markers to accurately distinguish between infiltrative and noninfiltrative meningiomas. METHODOLOGY/PRINCIPAL FINDINGS: Protein lysates of 64 different tissue samples (including two brain-invasive and 32 infiltrative tumors) were submitted to SELDI-TOF mass spectrometric analysis. Mass profiles were used to build up both unsupervised and supervised hierarchical clustering. One marker was found at high levels in noninvasive and noninfiltrative tumors and appeared to be a discriminative marker for clustering infiltrative and/or invasive meningiomas versus noninvasive meningiomas in two distinct subsets. Sensitivity and specificity were 86.7% and 100%, respectively. This marker was purified and identified as a multiphosphorylated form of vimentin, a cytoskeletal protein expressed in meningiomas. CONCLUSIONS/SIGNIFICANCE: Specific forms of vimentin can be surrogate molecular indicators of the invasive/infiltrative phenotype in tumors

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Cancer Diagnosis Using proteomic Patterns

The advent of proteomics has brought with it the hope of discovering novel biomarkers that can be used to diagnose diseases, predict susceptibility and monitor progression. Much of this effort has focused upon the mass spectral identification of the thousands of proteins that populate complex biosystems such as serum and tissues. A revolutionary approach in proteomic pattern analysis has emerged as an effective method for the early diagnosis of diseases such as ovarian cancer. Proteomic pattern analysis relies on the pattern of proteins observed and does not rely on the identification of a traceable biomarker. Hundreds of clinical samples per day can be analyzed utilizing this technology, which has the potential to be a novel, highly sensitive diagnostic tool for the early detection of cancer

Cancer Proteomics: Many Technologies, One Goal

A major goal of the National Cancer Institute is to alleviate patient pain, suffering and death associated with cancer by the year 2015. This goal does not insinuate a cure for cancer, but rather the development of diagnostics and therapeutics that will eventually decrease cancer morbidity and mortality. A part of meeting this goal is to leverage the enormous data-gathering capabilities of proteomic technologies to discover disease-specific biomarkers in serum, plasma, urine, tissues and other biologic samples. The rapid advance in available technologies that have been spurred by the -omics era, has enabled biologic samples to be surveyed for biomarkers in ways never before possible. However, it is not yet clear which specific technologies will be the most successful. Therefore, proteomic laboratories within the National Cancer Institute are taking a multipronged approach to identify disease-specific biomarkers. This review discusses some of these approaches in their context of meeting the National Cancer Institute\u27s 2015 goal

Genomic and Proteomic Profiles Reveal the Association of Gelsolin to TP53 Status and Bladder Cancer Progression

Bladder cancer transformation and immortalization require the inactivation of key regulatory genes, including TP53. Genotyping of a large cohort of bladder cancer patients (n = 256) using the TP53 GeneChip showed mutations in 103 cases (40.2%), the majority of them mapping to the DNA-binding core domain. TP53 mutation status was significantly associated with tumor stage (P = 0.0001) and overall survival for patients with advanced disease (P = 0.01). Transcript profiling using oligonucleotide arrays was performed on a subset of these cases (n = 46). Supervised analyses identified genes differentially expressed between invasive bladder tumors with wild-type (n = 24) and mutated TP53 (n = 22). Pathway analyses of top-ranked genes supported the central role of TP53 in the functional network of such gene patterns. A proteomic strategy using reverse phase arrays with protein extracts of bladder cancer cell lines validated the association of identified differentially expressed genes, such as gelsolin, to TP53 status. Immunohistochemistry on tissue microarrays (n = 294) revealed that gelsolin was associated with tumor stage and overall survival, correlating positively with TP53 status in a subset of these patients. This study further reveals that TP53 mutations are frequent events in bladder cancer progression and identified gelsolin related to TP53 status, tumor staging, and clinical outcome by independent high-throughput strategies