Platin-containing regimes are currently considered as state-of-the-art therapies in malignant pleural mesotheliomas (MPM) but show dissatisfying response rates ranging from 6 to 16% only. Still, the reasons for the rather poor efficacy remain largely unknown. A clear stratification of patients based on new biomarkers seems to be a promising approach to enhance clinical management, which would be a long-needed improvement for MPM patients but does not seem likely soon unless new biomarkers can be validated. Twenty-four formalin-fixed, paraffin-embedded (FFPE) tumour specimens were subjected to a miRNA expression screening of 800 important miRNAs using digital quantification via the nCounter technique (NanoString). We defined a small subset of miRNAs regulating the key enzymes involved in the repair of platin-associated DNA damage. Particularly, the TP53 pathway network for DNA damage recognition as well as genes related to the term "BRCAness" are the main miRNA targets within this context. The TP53 pathway network for DNA damage recognition as well as genes related to the term "BRCAness" are the main players for risk stratification in patients suffering from this severe disease. Taking the specific molecular profile of the tumour into account can help to enhance the clinical management prospectively and to smooth the way to better response prediction.

BackgroundMalignant pleural mesothelioma (MPM) is a tumour arising from pleural cavities with poor prognosis. Multimodality treatment with pemetrexed combined with cisplatin shows unsatisfying response-rates of 40%. The reasons for the rather poor efficacy of chemotherapeutic treatment are largely unknown. However, it is conceivable that DNA repair mechanisms lead to an impaired therapy response. We hypothesize a major role of homologous recombination (HR) for genome stability and survival of this tumour. Therefore, we analysed genes compiled under the term “BRCAness”. An inhibition of this pathway with olaparib might abrogate this effect and induce apoptosis.MethodsWe investigated the response of three MPM cell lines and lung fibroblasts serving as a control to treatment with pemetrexed, cisplatin and olaparib. Furthermore, we aimed to find possible correlations between response and gene expression patterns associated with BRCAness phenotype. Therefore, 91 clinical MPM samples were digitally screened for gene expression patterns of HR members.ResultsA BRCAness-dependent increase of apoptosis and senescence during olaparib-based treatment of BRCA-associated-protein 1 (BAP1)-mutated cell lines was observed. The gene expression pattern identified could be found in approx. 10% of patient samples. Against this background, patients could be grouped according to their defects in the HR system. Gene expression levels of Aurora Kinase A (AURKA), RAD50 as well as DNA damage-binding protein 2 (DDB2) could be identified as prognostic markers in MPM.ConclusionsDefects in HR compiled under the term BRCAness are a common event in MPM. The present data can lead to a better understanding of the underlaying cellular mechanisms and leave the door wide open for new therapeutic approaches for this severe disease with infaust prognosis. Response to Poly (ADP-ribose)-Polymerase (PARP)-Inhibition could be demonstrated in the BAP1-mutated NCI-H2452 cells, especially when combined with cisplatin. Thus, this combination therapy might be effective for up to 2/3 of patients, promising to enhance patients’ clinical management and outcome.Electronic supplementary materialThe online version of this article (10.1186/s12885-019-5314-0) contains supplementary material, which is available to authorized users.

PurposeResponse to platinum-based therapy is a major prognostic factor in high-grade serous ovarian cancer (HGSOC). While the exact mechanisms of platinum-resistance remain unclear, evidence is accumulating for a connection between the organism’s immune-response and response to platinum. However, predictive tools are missing. This study was performed to examine the putative role of the genetic tumor immune-microenvironment in mediating differential chemotherapy response in HGSOC patients.Patients and methodsExpression profiling of 770 immune-related genes was performed in tumor tissues from 23 HGSOC cases. Tumors were screened for prognostic and predictive biomarkers using the NanoString nCounter platform for digital gene expression analysis with the appurtenant PanCancer Immune Profiling panel. As validation cohort, gene expression data (RNA Seq) of 303 patients with epithelial ovarian carcinoma (EOC) were retrieved from the The Cancer Genome Atlas (TCGA) database. Different scoring-systems were computed for prediction of risk-of-resistance to cisplatin, disease-free survival (DFS) and overall survival (OS).ResultsValidated on the TCGA-dataset, the developed scores identified 11 significantly differentially expressed genes (p <0.01**) associated with platinum response. HSD11B1 was highly significantly associated with lower risk of recurrence and 7 targets were found highly significantly influencing OS time (p <0.01**).ConclusionOur results suggest that response to platinum-based therapy and DFS in ovarian HGSOC is associated with distinct gene-expression patterns related to the tumor immune-system. We generated predictive scoring systems which proved valid when applied to a set of 303 EOC patients.

Background Immune checkpoint inhibitors (ICIs) are currently one of the most promising therapy options in the field of oncology. Although the first pivotal ICI trial results were published in 2011, few biomarkers exist to predict their therapy outcome. PD-L1 expression and tumor mutational burden (TMB) were proven to be sometimes-unreliable biomarkers. We have previously suggested the analysis of processing escapes, a qualitative measurement of epitope structure alterations under immune system pressure, to provide predictive information on ICI response. Here, we sought to further validate this approach and characterize interactions with different forms of immune pressure. Methods We identified a cohort consisting of 48 patients with advanced non-small cell lung cancer (NSCLC) treated with nivolumab as ICI monotherapy. Tumor samples were subjected to targeted amplicon-based sequencing using a panel of 22 cancer-associated genes covering 98 mutational hotspots. Altered antigen processing was predicted by NetChop, and MHC binding verified by NetMHC. The NanoString nCounter® platform was utilized to provide gene expression data of 770 immune-related genes. Patient data from 408 patients with NSCLC were retrieved from The Cancer Genome Atlas (TCGA) as a validation cohort. Results The two immune escape mechanisms of PD-L1 expression (TPS score) (n = 18) and presence of altered antigen processing (n = 10) are mutually non-exclusive and can occur in the same patient (n = 6). Both mechanisms have exclusive influence on different genes and pathways, according to differential gene expression analysis and gene set enrichment analysis, respectively. Interestingly, gene expression patterns associated with altered processing were enriched in T cell and NK cell immune activity. Though both mechanisms influence different genes, they are similarly linked to increased immune activity. Conclusion Pressure from the immune system will lay the foundations for escape mechanisms, leading to acquisition of resistance under therapy. Both PD-L1 expression and altered antigen processing are induced similarly by pronounced immunoactivity but in different context. The present data help to deepen our understanding of the underlying mechanisms behind those immune escapes.

Background: Immune checkpoint inhibition, especially the blockade of PD-1 and PD-L1, has become one of the most thriving therapeutic approaches in modern oncology. Immune evasion caused by altered tumor epitope processing (so-called processing escapes) may be one way to explain immune checkpoint inhibition therapy failure. In the present study, we aim to demonstrate the effects of processing escapes on immunotherapy outcome in NSCLC patients. Patients and Methods: Whole exome sequencing data of 400 NSCLC patients (AdC and SCC) were extracted from the TCGA database. The ICB cohort was composed of primary tumor probes from 48 NSCLC patients treated with nivolumab. Mutations were identified by targeted amplicon-based sequencing including hotspots and whole exomes of 22 genes. The effect of mutations on proteasomal processing was evaluated by deep learning methods previously trained on 1260 known MHC-I ligands. Cox regression modelling was used to determine the influence on overall survival. Results: In the TCGA cohort, processing escapes were associated with decreased overall survival (p= 0.0140). In the ICB cohort, patients showing processing escapes in combination with high levels of PD-L1 (n=8/48) also showed significantly decreased overall survival, independently of mutational load or PD-L1 status. Conclusion: The concept of altered epitope processing may help to understand immunotherapy failure. Especially when combined with PD-L1 status, this method can be used as a biomarker to identify patients not suitable for immunotherapy.