Publications by authors named "Antje Sucker"

101 Publications

Targeting the Atf7ip-Setdb1 complex augments antitumor immunity by boosting tumor immunogenicity.

Cancer Immunol Res 2021 Aug 30. Epub 2021 Aug 30.

State Key Laboratory of Cell Biology, CAS center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences.

Substantial progress has been made in understanding how tumors escape immune surveillance. However, few measures to counteract tumor immune evasion have been developed. Suppression of tumor antigen expression is a common adaptive mechanism that cancers use to evade detection and destruction by the immune system. Epigenetic modifications play a critical role in various aspects of immune invasion, including the regulation of tumor antigen expression. To identify epigenetic regulators of tumor antigen expression, we established a transplantable syngeneic tumor model of immune escape with silenced antigen expression and used this system as a platform for a CRISPR-Cas9 suppressor screen for genes encoding epigenetic modifiers. We found that disruption of the genes encoding either of the chromatin modifiers activating transcription factor 7 interacting protein (Atf7ip) or its interacting partner SET domain bifurcated histone lysine methyltransferase 1 (Setdb1) in tumor cells restored tumor antigen expression. This resulted in augmented tumor immunogenicity concomitant with elevated endogenous retroviral (ERV) antigens and mRNA intron retention. ERV disinhibition was associated with a robust type I interferon response and increased T-cell infiltration, leading to rejection of cells lacking intact Atf7ip or Setdb1. ATF7IP or SETDB1 expression inversely correlated with antigen processing and presentation pathways, interferon signaling, and T-cell infiltration and cytotoxicity in human cancers. Our results provide a rationale for targeting Atf7ip or Setdb1 in cancer immunotherapy.
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http://dx.doi.org/10.1158/2326-6066.CIR-21-0543DOI Listing
August 2021

HDAC Inhibition Induces Cell Cycle Arrest and Mesenchymal-Epithelial Transition in a Novel Pleural-Effusion Derived Uterine Carcinosarcoma Cell Line.

Pathol Oncol Res 2021 26;27:636088. Epub 2021 Mar 26.

Department of Thoracic Surgery, Ruhrlandklinik, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.

Uterine carcinosarcoma (UCS) is a rare but highly aggressive malignancy with biphasic growth pattern. This morphology can be attributed to epithelial-mesenchymal transition (EMT) that often associates with tumor invasion and metastasis. Accordingly, we analyzed a novel patient-derived preclinical model to explore whether EMT is a potential target in UCS. A novel UCS cell line (PF338) was established from the malignant pleural effusion of a 59-year-old patient at time of disease progression. Immunohistochemistry was performed in primary and metastatic tumor lesions. Oncogenic mutations were identified by next-generation sequencing. Viability assays and cell cycle analyses were used to test sensitivity to different standard and novel treatments. E-cadherin, β-catenin and pSMAD2 expressions were measured by immunoblot. Whereas immunohistochemistry of the metastatic tumor showed a predominantly sarcomatous vimentin positive tumor that has lost E-cadherin expression, PF338 cells demonstrated biphasic growth and carried mutations in , , and . PF338 tumor cells were resistant to MEK- and TGF-β signaling-inhibition but sensitive to PIK3CA- and PARP-inhibition and first-line chemotherapeutics. Strikingly, histone deacetylase (HDAC) inhibition markedly reduced cell viability by inducing a dose-dependent G0/1 arrest and led to mesenchymal-epithelial transition as evidenced by morphological change and increased E-cadherin and β-catenin expression. Our data suggest that HDAC inhibition is effective in a novel UCS cell line by interfering with both viability and differentiation. These findings emphasize the dynamic manner of EMT/MET and epigenetics and the importance of molecular profiling to pave the way for novel therapies in UCS.
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http://dx.doi.org/10.3389/pore.2021.636088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262245PMC
March 2021

Role of Tumor-Infiltrating B Cells in Clinical Outcome of Patients with Melanoma Treated With Dabrafenib Plus Trametinib.

Clin Cancer Res 2021 Aug 9;27(16):4500-4510. Epub 2021 Jun 9.

Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Purpose: Although patients with unresectable or metastatic melanoma can experience long-term survival with BRAF- and MEK-targeted agents or immune checkpoint inhibitors over 5 years, resistance develops in most patients. There is a distinct lack of pretherapeutic biomarkers to identify which patients are likely to benefit from each therapy type. Most research has focused on the predictive role of T cells in antitumor responses as opposed to B cells.

Patients And Methods: We conducted prespecified exploratory biomarker analysis using gene expression profiling and digital pathology in 146 patients with previously untreated V600-mutant metastatic melanoma from the randomized, phase III COMBI-v trial and treated with dabrafenib plus trametinib who had available tumor specimens from screening.

Results: Baseline cell-cycle gene expression signature was associated with progression-free survival ( = 0.007). Patients with high T-cell/low B-cell gene signatures had improved median overall survival (not reached [95% confidence interval (CI), 33.8 months-not reached]) compared with patients with high T-cell/high B-cell signatures (19.1 months; 95% CI, 13.4-38.6 months). Patients with high B-cell signatures had high B-cell infiltration into the tumor compartment, corresponding with decreased MAPK activity and increased expression of immunosuppressive markers.

Conclusions: B cells may serve as a potential biomarker to predict clinical outcome in patients with advanced melanoma treated with dabrafenib plus trametinib. As separate studies have shown an opposite effect for B-cell levels and response to immunotherapy, B cells may serve as a potential biomarker to facilitate treatment selection. Further validation in a larger patient cohort is needed.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3586DOI Listing
August 2021

Clinical characteristics and therapy response in unresectable melanoma patients stage IIIB-IIID with in-transit and satellite metastases.

Eur J Cancer 2021 Jul 5;152:139-154. Epub 2021 Jun 5.

Dept. of Dermatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.

Introduction: Cutaneous melanoma is notorious for the development of in-transit metastases (ITM). For unknown biological reasons, ITM remain the leading tumour manifestation without progression to distant sites in some patients.

Methods: In total, 191 patients with initially unresectable stage III ITM and satellite metastases from 16 skin cancer centres were retrospectively evaluated for their tumour characteristics, survival and therapy response. Three groups according to disease kinetics (no distant progress, slow (>6 months) and fast (<6 months) distant progression) were analysed separately.

Results: Median follow-up time was 30.5 (range 0.8-154.0) months from unresectable ITM. Progression to stage IV was observed in 56.5% of cases. Patients without distant metastasis were more often female, older (>70 years) and presented as stage III with lymph node or ITM at initial diagnosis in 45.7% of cases. Melanoma located on the leg had a significantly better overall survival (OS) from time of initial diagnosis compared to non-leg localised primaries (hazard ratio [HR] = 0.61, 95% confidence interval [CI] 0.40-0.91; p = 0.017), but not from diagnosis of unresectable stage III (HR = 0.67, 95% CI 0.45-1.02; p = 0.06). Forty percent of patients received local therapy for satellite and ITM. Overall response rate (ORR) to all local first-line treatments was 38%; disease control rate (DCR) was 49%. In total, 72.3% of patients received systemic therapy for unresectable stage IIIB-D. ORR for targeted therapy (n = 19) was highest with 63.2% and DCR was 84.2% compared to an ORR of 31.4% and a DCR of 54.3% in PD-1 treated patients (n = 70). Patients receiving PD-1 and intralesional talimogene laherparepvec (n = 12) had an ORR of 41.7% and a DCR of 75%.

Conclusion: Patients with unresectable ITM and without distant progression are more often female, older, and have a primary on the leg. Response to PD-1 inhibitors in this cohort was lower than expected, but further investigation is required to elucidate the biology of ITM development and the interplay with the immune system.
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http://dx.doi.org/10.1016/j.ejca.2021.04.032DOI Listing
July 2021

GNA14, GNA11, and GNAQ Mutations Are Frequent in Benign but Not Malignant Cutaneous Vascular Tumors.

Front Genet 2021 30;12:663272. Epub 2021 Apr 30.

Department of Dermatology, University Hospital Essen, University Duisburg-Essen and German Cancer Consortium (DKTK), Essen, Germany.

Cutaneous vascular tumors consist of a heterogeneous group of benign proliferations, including a range of hemangiomas and vascular malformations, as well as heterogeneous groups of both borderline and malignant neoplasms such as Kaposi's sarcoma and angiosarcomas. The genetics of these tumors have been assessed independently in smaller individual cohorts making comparisons difficult. In our study, we analyzed a representative cohort of benign vascular proliferations observed in a clinical routine setting as well as a selection of malignant vascular proliferations. Our cohort of 104 vascular proliferations including hemangiomas, malformations, angiosarcomas and Kaposi's sarcoma were screened by targeted next-generation sequencing for activating genetic mutations known or assumed to be potentially relevant in vascular proliferations. An association analysis was performed for mutation status and clinico-pathological parameters. Frequent activating hotspot mutations in genes, including Q205, and Q209 were identified in 16 of 64 benign vascular tumors (25%). gene mutations were particularly frequent (52%) in cherry (senile) hemangiomas (13 of 25). In angiosarcomas, activating mutations ( and ) were identified in three samples (16%). No activating or gene mutations were identified in Kaposi's sarcomas. Our study identifies Q205, and Q209 mutations as being the most common and mutually exclusive mutations in benign hemangiomas. These mutations were not identified in malignant vascular tumors, which could be of potential diagnostic value in distinguishing these entities.
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http://dx.doi.org/10.3389/fgene.2021.663272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141909PMC
April 2021

Melanoma Differentiation Trajectories Determine Sensitivity Toward Pre-Existing CD8 Tumor-Infiltrating Lymphocytes.

J Invest Dermatol 2021 Mar 30. Epub 2021 Mar 30.

Department of Dermatology, University Hospital Essen, University Duisburg-Essen and German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany. Electronic address:

The highly plastic nature of melanoma enables its transition among diverse cell states to survive hostile conditions. However, the interplay between specific tumor cell states and intratumoral T cells remains poorly defined. With MAPK inhibitor‒treated BRAF-mutant tumors as models, we linked human melanoma state transition to CD8 T cell responses. Repeatedly, we observed that isogenic melanoma cells could evolve along distinct differentiation trajectories on single BRAF inhibitor (BRAFi) treatment or dual BRAFi/MEKi treatment, resulting in BRAFi‒induced hyperdifferentiated and BRAFi/MEKi‒induced dedifferentiated resistant subtypes. Taking advantage of patient-derived autologous CD8 tumor-infiltrating lymphocytes (TILs), we demonstrate that progressive melanoma cell state transition profoundly affects TIL function. Tumor cells along the hyperdifferentiation trajectory continuously gained sensitivity toward tumor-reactive CD8 TILs, whereas those in the dedifferentiation trajectory acquired T cell resistance in part owing to the loss of differentiation antigens. Overall, our data reveal the tight connection of MAPKi‒induced temporary (drug-tolerant transition state) and stable (resistant state) phenotype alterations with T cell function and further broaden the current knowledge on melanoma plasticity in terms of sculpting local antitumor immune responses, with implications for guiding the optimal combination of targeted therapy and immunotherapy.
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http://dx.doi.org/10.1016/j.jid.2021.03.013DOI Listing
March 2021

Molecular pathology as a diagnostic aid in difficult-to-classify melanocytic tumours with spitzoid morphology.

Eur J Cancer 2021 May 25;148:340-347. Epub 2021 Mar 25.

Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany. Electronic address:

Accurate classification of melanocytic proliferations has important implications for prognostic prediction, treatment and follow-up. Although most melanocytic proliferations can be accurately classified using clinical and pathological criteria, classification (specifically distinction between nevus and melanoma) can be challenging in a subset of cases, including those with spitzoid morphology. Genetic studies have shown that mutation profiles differ between primary melanoma subtypes and Spitz nevi. These differences may aid in distinguishing benign from malignant in some melanocytic tumours. Here, we present a selection of melanocytic proliferations with equivocal histopathological criteria, wherein genetic analysis was requested to help guide classification. In two of four cases, the genetic results offered valuable insights, allowing a definitive diagnosis, indicating the diagnostic value of mutation profiling in a real-world routine clinical setting. Although histopathological assessment remains decisive in melanocytic proliferation classification, we recommend including genetic profiling in cases of borderline or atypical lesion to support accurate classification.
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http://dx.doi.org/10.1016/j.ejca.2021.02.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087654PMC
May 2021

Integrative Genomic Analyses of Patient-Matched Intracranial and Extracranial Metastases Reveal a Novel Brain-Specific Landscape of Genetic Variants in Driver Genes of Malignant Melanoma.

Cancers (Basel) 2021 Feb 10;13(4). Epub 2021 Feb 10.

Skin Cancer Unit of the Dermatology Department, Medical Faculty, West German Cancer Center, University Duisburg-Essen, 45147 Essen, Germany.

Background: Development of brain metastases in advanced melanoma patients is a frequent event that limits patients' quality of life and survival. Despite recent insights into melanoma genetics, systematic analyses of genetic alterations in melanoma brain metastasis formation are lacking. Moreover, whether brain metastases harbor distinct genetic alterations beyond those observed at different anatomic sites of the same patient remains unknown.

Experimental Design And Results: In our study, 54 intracranial and 18 corresponding extracranial melanoma metastases were analyzed for mutations using targeted next generation sequencing of 29 recurrently mutated driver genes in melanoma. In 11 of 16 paired samples, we detected nucleotide modifications in brain metastases that were absent in matched metastases at extracranial sites. Moreover, we identified novel genetic variants in and , genes that have not been linked to brain metastases before; albeit most frequent mutations were found in and Conclusion: Our data provide new insights into the genetic landscape of intracranial melanoma metastases supporting a branched evolution model of metastasis formation.
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http://dx.doi.org/10.3390/cancers13040731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916600PMC
February 2021

Serum CD73 is a prognostic factor in patients with metastatic melanoma and is associated with response to anti-PD-1 therapy.

J Immunother Cancer 2020 12;8(2)

Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Campania, Italy

Background: Inhibitors of immune checkpoint programmed cell death protein 1 (PD-1) receptor on T cells have shown remarkable clinical outcomes in metastatic melanoma. However, most patients are resistant to therapy. Production of extracellular adenosine, via CD73-mediated catabolism of AMP, contributes to suppress T-cell-mediated responses against cancer. In this study, we analyzed the expression and activity of soluble CD73 in sera of patients with melanoma undergoing anti-PD-1± cytotoxic T-lymphocyte-associated antigen 4 therapy.

Methods: Soluble CD73 expression and activity were retrospectively analyzed in serum of a total of 546 patients with melanoma from different centers before starting treatment (baseline) with anti-PD-1 agents, nivolumab or pembrolizumab, and compared with those of 96 healthy subjects. The CD73 activity was correlated with therapy response and survival of patients.

Results: Patients with melanoma show significantly higher CD73 activity and expression than those observed in healthy donors (p<0.0001). Elevated pretreatment levels of CD73 activity were associated with non-response to therapy with nivolumab or pembrolizumab. During treatment, levels of soluble CD73 activity remain unchanged from baseline and still stratify clinical responders from non-responders. High levels of serum CD73 enzymatic activity associate with reduced overall survival (OS; HR=1.36, 95% CI 1.03 to 1.78; p=0.03) as well as progression-free survival (PFS; HR=1.42, 95% CI 1.13 to 1.79, p=0.003). Further, the multivariate Cox regression analysis indicates that serum CD73 activity is an independent prognostic factor besides serum lactate dehydrogenase levels and the presence of brain metastases for both OS (p=0.009) and PFS (p=0.001).

Conclusion: Our data indicate the relevance of serum CD73 in patients with advanced melanoma receiving anti-PD-1 therapy and support further investigation on targeting CD73 in combination with anti-PD-1 antibodies.
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http://dx.doi.org/10.1136/jitc-2020-001689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759961PMC
December 2020

BRAF and MEK inhibition in melanoma patients enables reprogramming of tumor infiltrating lymphocytes.

Cancer Immunol Immunother 2021 Jun 4;70(6):1635-1647. Epub 2020 Dec 4.

Deutsches Konsortium Für Translationale Krebsforschung (DKTK), Partner Site Essen, Translational Skin Cancer Research, University of Duisburg-Essen, Universitätsstr. 1, 45141, Essen, Germany.

Background: Combined inhibition of BRAF/MEK is an established therapy for melanoma. In addition to its canonical mode of action, effects of BRAF/MEK inhibitors on antitumor immune responses are emerging. Thus, we investigated the effect of these on adaptive immune responses.

Patients, Methods And Results: Sequential tumor biopsies obtained before and during BRAF/MEK inhibitor treatment of four (n = 4) melanoma patients were analyzed. Multiplexed immunofluorescence staining of tumor tissue revealed an increased infiltration of CD4 and CD8 T cells upon therapy. Determination of the T-cell receptor repertoire usage demonstrated a therapy induced increase in T-cell clonotype richness and diversity. Application of the Grouping of Lymphocyte Interactions by Paratope Hotspots algorithm revealed a pre-existing immune response against melanoma differentiation and cancer testis antigens that expanded preferentially upon therapy. Indeed, most of the T-cell clonotypes found under BRAF/MEK inhibition were already present in lower numbers before therapy. This expansion appears to be facilitated by induction of T-bet and TCF7 in T cells, two transcription factors required for self-renewal and persistence of CD8 memory T cells.

Conclusions: Our results suggest that BRAF/MEK inhibition in melanoma patients allows an increased expansion of pre-existing melanoma-specific T cells by induction of T-bet and TCF7 in these.
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http://dx.doi.org/10.1007/s00262-020-02804-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139931PMC
June 2021

Targeting the innate immunoreceptor RIG-I overcomes melanoma-intrinsic resistance to T cell immunotherapy.

J Clin Invest 2020 08;130(8):4266-4281

Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Understanding tumor resistance to T cell immunotherapies is critical to improve patient outcomes. Our study revealed a role for transcriptional suppression of the tumor-intrinsic HLA class I (HLA-I) antigen processing and presentation machinery (APM) in therapy resistance. Low HLA-I APM mRNA levels in melanoma metastases before immune checkpoint blockade (ICB) correlated with nonresponsiveness to therapy and poor clinical outcome. Patient-derived melanoma cells with silenced HLA-I APM escaped recognition by autologous CD8+ T cells. However, targeted activation of the innate immunoreceptor RIG-I initiated de novo HLA-I APM transcription, thereby overcoming T cell resistance. Antigen presentation was restored in interferon-sensitive (IFN-sensitive) but also immunoedited IFN-resistant melanoma models through RIG-I-dependent stimulation of an IFN-independent salvage pathway involving IRF1 and IRF3. Likewise, enhanced HLA-I APM expression was detected in RIG-Ihi (DDX58hi) melanoma biopsies, correlating with improved patient survival. Induction of HLA-I APM by RIG-I synergized with antibodies blocking PD-1 and TIGIT inhibitory checkpoints in boosting the antitumor T cell activity of ICB nonresponders. Overall, the herein-identified IFN-independent effect of RIG-I on tumor antigen presentation and T cell recognition proposes innate immunoreceptor targeting as a strategy to overcome intrinsic T cell resistance of IFN-sensitive and IFN-resistant melanomas and improve clinical outcomes in immunotherapy.
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http://dx.doi.org/10.1172/JCI131572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410049PMC
August 2020

Macrophages/Microglia Represent the Major Source of Indolamine 2,3-Dioxygenase Expression in Melanoma Metastases of the Brain.

Front Immunol 2020 5;11:120. Epub 2020 Feb 5.

Skin Cancer Unit of the Dermatology Department, Medical Faculty, West German Cancer Center, University Duisburg-Essen, Essen, Germany.

The manifestation of brain metastases in patients with advanced melanoma is a common event that limits patient's survival and quality of life. The immunosuppressive properties of the brain parenchyma are very different compared to the rest of the body, making it plausible that the current success of cancer immunotherapies is specifically limited here. In melanoma brain metastases, the reciprocal interplay between immunosuppressive mediators such as indoleamine 2, 3-dioxygenase (IDO) or programmed cell death-ligand 1 (PD-L1) in the context of neoplastic transformation are far from being understood. Therefore, we analyzed the immunoreactive infiltrate (CD45, CD3, CD8, Forkhead box P3 [FoxP3], CD11c, CD23, CD123, CD68, Allograft Inflammatory factor 1[AIF-1]) and PD-L1 with respect to IDO expression and localization in melanoma brain metastases but also in matched metastases at extracranial sites to correlate intra- and interpatient data with therapy response and survival. Comparative tissue analysis identified macrophages/microglia as the major source of IDO expression in melanoma brain metastases. In contrast to the tumor infiltrating lymphocytes, melanoma cells exhibited low IDO expression levels paralleled by cell surface presentation of PD-L1 in intracranial metastases. Absolute numbers and pattern of IDO-expressing cells in metastases of the brain correlated with recruitment and localization of CD8 T cells, implicating dynamic impact on the regulation of T cell function in the brain parenchyma. However, paired analysis of matched intra- and extracranial metastases identified significantly lower fractions of cytotoxic CD8 T cells in intracranial metastases while all other immune cell populations remain unchanged. In line with the already established clinical benefit for PD-L1 expression in extracranial melanoma metastases, Kaplan-Meier analyses correlated PD-L1 expression in brain metastases with favorable outcome in advanced melanoma patients undergoing immune checkpoint therapy. In summary, our data provide new insights into the landscape of immunosuppressive factors in melanoma brain metastases that may be useful in the implication of novel therapeutic strategies for patients undergoing cancer immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2020.00120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013086PMC
March 2021

Predominance of Central Memory T Cells with High T-Cell Receptor Repertoire Diversity is Associated with Response to PD-1/PD-L1 Inhibition in Merkel Cell Carcinoma.

Clin Cancer Res 2020 05 13;26(9):2257-2267. Epub 2020 Jan 13.

Translational Skin Cancer Research, German Consortium for Translational Cancer Research (Deutsches Konsortium für Translationale Krebsforschung; DKTK), Essen, Germany.

Purpose: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer, which can be effectively controlled by immunotherapy with PD-1/PD-L1 checkpoint inhibitors. However, a significant proportion of patients are characterized by primary therapy resistance. Predictive biomarkers for response to immunotherapy are lacking.

Experimental Design: We applied Bayesian inference analyses on 41 patients with MCC testing various clinical and biomolecular characteristics to predict treatment response. Further, we performed a comprehensive analysis of tumor tissue-based immunologic parameters including multiplexed immunofluorescence for T-cell activation and differentiation markers, expression of immune-related genes and T-cell receptor (TCR) repertoire analyses in 18 patients, seven objective responders, and 11 nonresponders.

Results: Bayesian inference analyses demonstrated that among currently discussed biomarkers only unimpaired overall performance status and absence of immunosuppression were associated with response to therapy. However, in responders, a predominance of central memory T cells and expression of genes associated with lymphocyte attraction and activation was evident. In addition, TCR repertoire usage of tumor-infiltrating lymphocytes (TILs) demonstrated low T-cell clonality, but high TCR diversity in responding patients. In nonresponders, terminally differentiated effector T cells with a constrained TCR repertoire prevailed. Sequential analyses of tumor tissue obtained during immunotherapy revealed a more pronounced and diverse clonal expansion of TILs in responders indicating an impaired proliferative capacity among TILs of nonresponders upon checkpoint blockade.

Conclusions: Our explorative study identified new tumor tissue-based molecular characteristics associated with response to anti-PD-1/PD-L1 therapy in MCC. These observations warrant further investigations in larger patient cohorts to confirm their potential value as predictive markers.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2244DOI Listing
May 2020

Tumor microenvironment-derived S100A8/A9 is a novel prognostic biomarker for advanced melanoma patients and during immunotherapy with anti-PD-1 antibodies.

J Immunother Cancer 2019 12 5;7(1):343. Epub 2019 Dec 5.

Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Predicting metastasis in melanoma patients is important for disease management and could help to identify those who might benefit from adjuvant treatment. The aim of this study was to investigate whether the tumor microenvironment-derived protein S100A8/A9 qualifies as prognostic marker for melanoma patients, also in the setting of immunotherapy.

Methods: S100A8/A9 gene and protein expression were analyzed on melanocytic nevi, primary melanomas and metastases using a cDNA library and three independent tissue-microarrays (TMA). Serum levels of S100A8/A9 were measured using a specific ELISA in two independent cohorts of 354 stage III and stage IV melanoma patients as well as in two independent cohorts of patients treated with the PD-1 antibody pembrolizumab.

Results: cDNA analysis revealed an upregulation of S100A8 and S100A9 gene expression in melanoma metastases compared to primary melanomas. Significantly higher numbers of infiltrating S100A8/A9 positive cells were found in tissue samples of metastasizing primary melanomas compared to non-metastasizing melanomas (P < .0001) and in melanomas of short-term survivors compared to long-term survivors (P < .0001). Serum S100A8/A9 levels > 5.5 mg/l were associated with impaired overall survival in two independent cohorts (both P < .0001). Importantly, patients with serum elevated S100A8/A9 treated with pembrolizumab showed significantly impaired survival compared to patients with lower S100A8/A9 levels (cohort 1: P = .0051; cohort 2: P < .0001).

Conclusions: The tumor microenvironment-associated protein S100A8/A9 serves as a novel prognostic marker for metastasis and survival of metastatic melanoma patients and predicts response to immunotherapy with pembrolizumab. These data underscore the significance of tumor microenvironment-derived factors as suitable biomarkers for melanoma.
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http://dx.doi.org/10.1186/s40425-019-0828-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896585PMC
December 2019

Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma.

Nat Med 2019 12 2;25(12):1916-1927. Epub 2019 Dec 2.

Dana-Farber Cancer Institute, Boston, MA, USA.

Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort of patients with melanoma (n = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transcriptomic features predicted selective response, including features associated with MHC-I and MHC-II antigen presentation. Furthermore, previous anti-CTLA4 ICB exposure was associated with different predictors of response compared to tumors that were naive to ICB, suggesting selective immune effects of previous exposure to anti-CTLA4 ICB. Finally, we developed parsimonious models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 ICB in individual tumors, with validation in smaller independent cohorts limited by the availability of comprehensive data. Broadly, we present a framework to discover predictive features and build models of ICB therapeutic response.
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http://dx.doi.org/10.1038/s41591-019-0654-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898788PMC
December 2019

Sustained Type I interferon signaling as a mechanism of resistance to PD-1 blockade.

Cell Res 2019 Oct 3;29(10):846-861. Epub 2019 Sep 3.

Université Paris-Saclay, Le Kremlin-Bicêtre, France.

PD-1 blockade represents a major therapeutic avenue in anticancer immunotherapy. Delineating mechanisms of secondary resistance to this strategy is increasingly important. Here, we identified the deleterious role of signaling via the type I interferon (IFN) receptor in tumor and antigen presenting cells, that induced the expression of nitric oxide synthase 2 (NOS2), associated with intratumor accumulation of regulatory T cells (Treg) and myeloid cells and acquired resistance to anti-PD-1 monoclonal antibody (mAb). Sustained IFNβ transcription was observed in resistant tumors, in turn inducing PD-L1 and NOS2 expression in both tumor and dendritic cells (DC). Whereas PD-L1 was not involved in secondary resistance to anti-PD-1 mAb, pharmacological or genetic inhibition of NOS2 maintained long-term control of tumors by PD-1 blockade, through reduction of Treg and DC activation. Resistance to immunotherapies, including anti-PD-1 mAb in melanoma patients, was also correlated with the induction of a type I IFN signature. Hence, the role of type I IFN in response to PD-1 blockade should be revisited as sustained type I IFN signaling may contribute to resistance to therapy.
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http://dx.doi.org/10.1038/s41422-019-0224-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796942PMC
October 2019

Clinical and genetic analysis of melanomas arising in acral sites.

Eur J Cancer 2019 09 14;119:66-76. Epub 2019 Aug 14.

Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Essen, Germany; Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom. Electronic address:

Study Aim: Melanomas arising in acral sites are associated with a poorer prognosis than other melanoma subtypes. The aim of this study was to evaluate clinical-pathological and genetic characteristics as well as therapeutic responses of a larger cohort of patients with melanomas arising in acral sites.

Methods: Clinical data of 134 patients with melanomas arising in acral sites from the Dept. of Dermatology Essen were collected and analysed with regard to clinicopathological characteristics and treatment responses. Genetic analysis with targeted next-generation sequencing was done on 50 samples.

Results: In our cohort, BRAF (30%), NRAS (28%), TERT promoter (26%), NF1 (14%) and KIT (6%) were frequently identified mutations. Comparing tumours situated on palms and soles with melanomas arising on dorsal acral sites, a higher frequency of NRAS (39.1% versus 25%) and NF1 (17.3% versus 0%) and lower frequencies of BRAF (21.7% versus 75%) and TERT promoter (8.6% versus 50%) mutations were observed. MAPK activating mutations were identified in 64% of tumours. Overall survival was longer in patients treated with immune checkpoint inhibitors as first-line treatment than in patients receiving other systemic therapies (i.e. BRAF/MEK inhibitors and chemotherapy).

Conclusion: Our data suggest that the genetics of melanomas arising in acral sites varies by tumour location and may influence biological behaviour.
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http://dx.doi.org/10.1016/j.ejca.2019.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140290PMC
September 2019

Impact of American Joint Committee on Cancer 8th edition classification on staging and survival of patients with melanoma.

Eur J Cancer 2019 09 8;119:18-29. Epub 2019 Aug 8.

Department of Dermatology, University Hospital Essen, Essen, Germany and German Cancer Consortium of Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address:

Objective: The American Joint Committee on Cancer (AJCC) 8th staging system introduced several revisions. To assess the impact of the 8th edition American Joint Committee on Cancer (AJCC8) staging system on subgrouping and survival, patients with melanoma from two tertiary skin cancer centres were classified according to both the 7th edition American Joint Committee on Cancer (AJCC7) and AJCC8.

Methods: A total of 1948 patients aged ≥18 years with cutaneous melanoma stage II-IV were included. The impact of sex and age on reclassification was assessed by log binomial models. The inverse probability of censoring weighting method was used to compute ROC curves from time-to-event data to assess the discriminatory ability of AJCC7 and AJCC8. Melanoma-specific survival (MSS) and overall survival (OS) were calculated, and age- and sex-adjusted MSS hazard ratios were estimated using Cox proportional hazards models.

Results: Of all, 23.5% of patients were assigned a different subgroup when classified according to AJCC8. Owing to upshifting to stage IIIC (AJCC7 24.8% vs. AJCC8 50.8%), patient numbers of stages IIIA and IIIB decreased from 28.7% to 16.2% and 46.5% to 28.3%. The prediction accuracy for AJCC7 and AJCC8 was comparable (integrated time-dependent area under the curve [AUC] of 0.75 and 0.74, respectively). Five-year MSS of IIB and IIC AJCC8 was poor and lower than that of IIIA AJCC8 (80%, 67% and 89%, respectively). Compared to results of the International Melanoma Database and Discovery Platform, 5-year MSS was 10-15% points lower for stages IIC, IIIB and IIIC.

Conclusions: Upshifting affects primarily stage III subgroups, while effects in stage II are minor. Stage IIB/C (AJCC8) patients have 67-80% MSS and should be considered for adjuvant treatment, while in stage IIIA, the indication of adjuvant treatment is questionable.
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http://dx.doi.org/10.1016/j.ejca.2019.06.011DOI Listing
September 2019

Prognostic factors for pulmonary metastasectomy in malignant melanoma: size matters.

Eur J Cardiothorac Surg 2019 Dec;56(6):1104-1109

Department of Thoracic Surgery, University Medicine Essen-Ruhrlandklinik, University of Duisburg-Essen, Essen, Germany.

Objectives: Pulmonary metastasectomy for malignant melanoma requires an individualized therapeutic decision. Due to recently developed novel treatment options, the prognosis of patients with melanoma has improved significantly. Validated prognostic factors that identify patients who are most likely to benefit from metastasectomy are urgently needed.

Methods: We retrospectively reviewed all consecutive patients with melanoma undergoing complete pulmonary metastasectomy between January 2010 and December 2016. The impact of age, sex, extrapulmonary metastases, preoperative systemic therapy, number of metastases, laterality and largest diameter of metastasis on survival after metastasectomy was analysed.

Results: A total of 29 male and 32 female patients were included in the study. The median follow-up time was 25.6 months. The mean number of resected metastases was 1.7 ± 1.1 (range 1-5). Ten patients had repetitive pulmonary metastasectomies. The median survival time was 31.3 months with a 2-year survival rate of 54%. Bilateral metastases or multiple nodules were not associated with a significantly decreased overall survival rate after metastasectomy. Shorter overall survival times were observed in male patients [hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.42-5.92; P = 0.0035] and in patients with nodules larger than 2 cm (HR 3.18, 95% CI 1.45-6.98; P = 0.004). In multivariable analysis, both gender and tumour size remained significant independent prognostic factors.

Conclusions: Excellent overall survival rates after pulmonary metastasectomy for melanoma metastases were observed in patients with a metastatic diameter less than 2 cm and in female patients. In view of improved long-term outcome due to novel treatment options, the selection of patients for pulmonary metastasectomy based on prognostic factors will become increasingly important.
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http://dx.doi.org/10.1093/ejcts/ezz211DOI Listing
December 2019

Frequent Occurrence of and Mutations in Human Acral Naevi.

Cancers (Basel) 2019 Apr 16;11(4). Epub 2019 Apr 16.

Department of Dermatology, Venerology and Allergology, University Hospital Essen, 45147 Essen, Germany.

Acral naevi are benign melanocytic tumors occurring at acral sites. Occasionally they can progress to become malignant tumors (melanomas). The genetics of acral naevi have not been assessed in larger studies. In our study, a large cohort of 130 acral naevi was screened for gene mutations known to be important in other naevi and melanoma subtypes by targeted next-generation sequencing. Mutation status was correlated with clinicopathological parameters. Frequent mutations in genes activating the MAP kinase pathway were identified, including = 87 (67%) , = 24 (18%) , and one (1%) mutations. mutations were almost exclusively V600E ( = 86, 99%) and primarily found in junctional and compound naevi. mutations were either Q61K or Q61R and frequently identified in dermal naevi. Recurrent non-V600E , , , and promoter mutations, present in acral melanoma, were not identified. Our study identifies and mutations as the primary pathogenic event in acral naevi, however, distributed differently to those in non-acral naevi. The mutational profile of acral naevi is distinct from acral melanoma, which may be of diagnostic value in distinguishing these entities.
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http://dx.doi.org/10.3390/cancers11040546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520878PMC
April 2019

MHC class-I downregulation in PD-1/PD-L1 inhibitor refractory Merkel cell carcinoma and its potential reversal by histone deacetylase inhibition: a case series.

Cancer Immunol Immunother 2019 Jun 16;68(6):983-990. Epub 2019 Apr 16.

Department of Dermatology, University Clinic Essen, Essen, Germany.

Background: Merkel cell carcinoma (MCC) is an aggressive skin cancer in which PD-1/PD-L1 blockade has shown remarkable response rates. However, a significant proportion of patients shows primary or secondary resistance against PD-1/PD-L1 inhibition, with HLA class-I downregulation and insufficient influx of CD8 T cells into the tumor as possible immune escape mechanisms. Histone deacetylase inhibitors (HDACi) have been demonstrated to reverse low HLA class-I expression caused by epigenetic downregulation of the antigen machinery (APM) in vitro and in pre-clinical models in vivo.

Case Presentations: We report four cases of patients with metastatic MCC who did not respond to immunotherapy by PD-1/PD-L1 blockade. Two of the patients received, subsequently, the HDACi panobinostat in combination with PD-1/PD-L1 blockade. Tumor biopsies of the patients were analyzed for cellular and molecular markers of antigen processing and presentation as well as the degree of T-cell infiltration.

Results And Conclusion: Low expression of APM-related genes associated with low HLA class-I surface expression was observed in all MCC patients, progressing on PD-1/PD-L1 blockade. In one evaluable patient, of the two treated with the combination therapy of the HDACi, panobinostat and PD-1/PD-L1 blockade, reintroduction of HLA class-I-related genes, enhanced HLA class-I surface expression, and elevated CD8 T-cell infiltration into the MCC tumor tissue were observed; however, these changes did not translate into a clinical benefit. Our findings suggest that HDACi may be useful to overcome HLA class-I downregulation as a resistance mechanism against anti-PD-1/PD-L1 antibodies in MCC patients. Prospective clinical trials are needed to evaluate this notion.
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http://dx.doi.org/10.1007/s00262-019-02341-9DOI Listing
June 2019

Application of Circulating Cell-Free Tumor DNA Profiles for Therapeutic Monitoring and Outcome Prediction in Genetically Heterogeneous Metastatic Melanoma.

JCO Precis Oncol 2020 15;3. Epub 2019 Feb 15.

University Hospital of Essen, University Duisburg-Essen and German Cancer Consortium partner site Essen/Düsseldorf, Essen, Germany.

Purpose: Circulating cell-free tumor DNA (ctDNA) reflects the heterogeneous spectrum of tumor-specific mutations, especially in systemic disease. We validated plasma-based assays that allow the dynamic quantitative detection of ctDNA as a prognostic biomarker for tumor load and prediction of therapy response in melanoma.

Materials And Methods: We analyzed plasma-derived ctDNA from a large training cohort (n = 96) of patients with advanced-stage melanoma, with assays for the and driver mutations as well as and promoter mutations. An independent patient cohort (n = 35) was used to validate the utility of ctDNA monitoring under mitogen-activated protein kinase-targeted or immune checkpoint therapies.

Results: Elevated plasma ctDNA level at baseline was an independent prognostic factor of disease progression when compared with serum S100 and lactate dehydrogenase levels in multivariable analyses (hazard ratio [HR], 7.43; 95% CI, 1.01 to 55.19; = .05). The change in ctDNA levels during therapy correlated with treatment response, where increasing ctDNA was predictive for shorter progression-free survival (eg, for ctDNA, HR, 3.70; 95% CI, 1.86 to 7.34; < .001). Increasing ctDNA levels predicted disease progression significantly earlier than did routine radiologic scans ( < .05), with a mean lead time of 3.5 months. -mutant ctDNA was detected in a significant proportion of patients with -mutant tumors under therapy, but unexpectedly also at baseline. In vitro sensitivity studies suggested that this represents higher-than-expected intratumoral heterogeneity. The detection of ctDNA in baseline samples of patients with mutation who were treated with mitogen-activated protein kinase inhibitors significantly correlated with shorter progression-free survival (HR, 3.18; 95% CI, 1.31 to 7.68; = .03) and shorter overall survival (HR, 4.08; 95% CI, 1.57 to 10.58; = .01).

Conclusion: Our results show the potential role of ctDNA measurement as a sensitive monitoring and prediction tool for the early assessment of disease progression and therapeutic response in patients with metastatic melanoma.
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http://dx.doi.org/10.1200/PO.18.00229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446476PMC
February 2019

Evolution of melanoma cross-resistance to CD8 T cells and MAPK inhibition in the course of BRAFi treatment.

Oncoimmunology 2018;7(8):e1450127. Epub 2018 Apr 18.

Department of Dermatology, University Hospital Essen, University Duisburg-Essen and German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany.

The profound but frequently transient clinical responses to BRAF inhibitor (BRAFi) treatment in melanoma emphasize the need for combinatorial therapies. Multiple clinical trials combining BRAFi and immunotherapy are under way to further enhance therapeutic responses. However, to which extent BRAF inhibition may affect melanoma immunogenicity over time remains largely unknown. To support the development of an optimal treatment protocol, we studied the impact of prolonged BRAFi exposure on the recognition of melanoma cells by T cells in different patient models. We demonstrate that autologous CD8 tumor-infiltrating lymphocytes (TILs) efficiently recognized short-term (3, 7 days) BRAFi-treated melanoma cells but were less responsive towards long-term (14, 21 days) exposed tumor cells. Those long-term BRAFi-treated melanoma cells showed a non-proliferative dedifferentiated phenotype and were less sensitive to four out of five CD8 T cell clones, present in the preexisting TIL repertoire, of which three recognized shared antigens (Tyrosinase, Melan-A and CSPG4) and one being neoantigen-specific. Only a second neoantigen was steadily recognized independent of treatment duration. Notably, in all cases the impaired T cell activation was due to a time-dependent downregulation of their respective target antigens. Moreover, combinatorial treatment of melanoma cells with BRAFi and an inhibitor of its downstream kinase MEK had similar effects on T cell recognition. In summary, MAP kinase inhibitors (MAPKi) strongly alter the tumor antigen expression profile over time, favoring evolution of melanoma variants cross-resistant to both T cells and MAPKi. Our data suggest that simultaneous treatment with MAPKi and immunotherapy could be most effective for tumor elimination.
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http://dx.doi.org/10.1080/2162402X.2018.1450127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136878PMC
April 2018

Tumor CDKN2A-Associated JAK2 Loss and Susceptibility to Immunotherapy Resistance.

J Natl Cancer Inst 2018 06;110(6):677-681

Department of Dermatology, University Hospital Essen, University Duisburg-Essen, and German Cancer Consortium partner site Essen/Düsseldorf, Essen, Germany (DKTK).

Poor clinical responses to checkpoint blockade with anti-CTLA-4 and anti-PD-1 antibodies in melanoma have recently been associated with acquired IFNγ resistance that protects tumor cells from the antiproliferative and pro-apoptotic cytokine activity. IFNγ-resistant melanoma cells very often lack functional expression of the IFNγ signaling pathway gene JAK2 due to gene deletions or inactivating gene mutations. Analyzing melanoma cell lines (n = 46, applying next-generation targeted sequencing and single nucleotide polymorphism arrays) as well as available genomic data sets from The Cancer Genome Atlas (TCGA) tumor tissue samples (cutaneous melanoma n = 367, lung squamous cell carcinoma n = 501, bladder urothelial carcinoma n = 408, breast invasive carcinoma n = 768, colorectal adenocarcinoma n = 257), we demonstrate that the frequent chromosomal losses of the tumor suppressor CDKN2A in melanoma and other tumor entities enhance the susceptibility to IFNγ resistance by concomitant deletion of the JAK2 gene (odds ratio = 223.17, 95% confidence interval = 66.91 to 1487.38, two-sided P = 7.6×10-46). Tumors with JAK2 mutations or homozygous JAK2 deletions demonstrate allelic losses covering both CDKN2A and JAK2. This suggests that patients with tumor chromosomal CDKN2A losses are susceptible to developing immunotherapy resistance and should be screened for JAK2 deficiency prior to and under immune checkpoint blocking therapy.
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http://dx.doi.org/10.1093/jnci/djx271DOI Listing
June 2018

Integrated Genomic Classification of Melanocytic Tumors of the Central Nervous System Using Mutation Analysis, Copy Number Alterations, and DNA Methylation Profiling.

Clin Cancer Res 2018 09 11;24(18):4494-4504. Epub 2018 Jun 11.

Department of Dermatology, University Hospital Essen, West German Cancer Center, University Duisburg-Essen and the German Cancer Consortium (DKTK), Germany.

In the central nervous system, distinguishing primary leptomeningeal melanocytic tumors from melanoma metastases and predicting their biological behavior solely using histopathologic criteria may be challenging. We aimed to assess the diagnostic and prognostic value of integrated molecular analysis. Targeted next-generation sequencing, array-based genome-wide methylation analysis, and BAP1 IHC were performed on the largest cohort of central nervous system melanocytic tumors analyzed to date, including 47 primary tumors of the central nervous system, 16 uveal melanomas, 13 cutaneous melanoma metastases, and 2 blue nevus-like melanomas. Gene mutation, DNA-methylation, and copy-number profiles were correlated with clinicopathologic features. Combining mutation, copy-number, and DNA-methylation profiles clearly distinguished cutaneous melanoma metastases from other melanocytic tumors. Primary leptomeningeal melanocytic tumors, uveal melanomas, and blue nevus-like melanoma showed common DNA-methylation, copy-number alteration, and gene mutation signatures. Notably, tumors demonstrating chromosome 3 monosomy and BAP1 alterations formed a homogeneous subset within this group. Integrated molecular profiling aids in distinguishing primary from metastatic melanocytic tumors of the central nervous system. Primary leptomeningeal melanocytic tumors, uveal melanoma, and blue nevus-like melanoma share molecular similarity with chromosome 3 and alterations, markers of poor prognosis. .
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0763DOI Listing
September 2018

Role of Elevated Copy Number as a Prognostic and Progression Marker for Cutaneous Melanoma.

Clin Cancer Res 2018 09 18;24(17):4119-4125. Epub 2018 May 18.

Center for Melanoma Research and Treatment, California Pacific Medical Center (CPMC) Research Institute, San Francisco, California.

Previous studies have indicated an important role for pleckstrin homology domain-interacting protein (PHIP) as a marker and mediator of melanoma metastasis. Here we aimed to confirm the role of copy number in successive stages of melanoma progression. copy number was examined using FISH in three independent cohorts by recording the percentage of cells harboring ≥3 copies of The impact of copy number on survival was assessed using Cox regression analysis. The enrichment of was assessed in various molecular melanoma subtypes. expression was analyzed in The Cancer Genome Atlas (TCGA) melanoma cohort. Elevated copy number was significantly predictive of reduced distant metastasis-free survival (DMFS) and disease-specific survival (DSS), and increased prevalence of ulceration in primary melanoma (cohort No. 1). By multivariate analysis, FISH scores were independently predictive of DMFS and DSS. copy number was enriched in metastatic melanomas harboring mutant or expressing PTEN protein (cohort No. 2). copy number was significantly elevated in metastatic melanomas when compared with matched primary tumors from the same patient (cohort No. 3). Several of these associations were replicated using TCGA cohort analysis. These results underscore the important role of copy-number elevation in melanoma progression, and identify molecular subtypes of melanoma in which is enriched. Finally, as elevated copy number appears to be selected for during the progression of primary to metastatic melanoma, these results confirm PHIP as a promising therapeutic target for melanoma. .
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125189PMC
September 2018

STAT5 expression correlates with recurrence and survival in melanoma patients treated with interferon-α.

Melanoma Res 2018 06;28(3):204-210

Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg.

Interferons (IFN) have a direct growth-inhibiting effect on tumor cells through Janus kinase-dependent activation of the transcription factor signal transducer and activator of transcription (STAT1). In vitro, signaling through STAT5 has been demonstrated to counteract this effect and lead to IFN resistance of melanoma cell lines. In 32 patients treated with IFN-α in an adjuvant setting, we investigated paraffin-embedded tumor tissue from primary melanomas and melanoma metastases for expression of STAT3 and STAT5, by immunohistochemistry, and for expression of phosphorylated signaling transduction activating transcription factor (pSTAT)3 and pSTAT5, by immunofluorescence. Tumor cell expression levels of these proteins were correlated with patient characteristics and clinical outcomes. The patient cohort consisted of 12 (37.5%) patients at AJCC stage I/II (primary melanoma) and 20 (62.5%) at stage III/IV (metastatic melanoma). Recurrence was observed for 25 (78.1%) either during or after IFN-α therapy. χ Correlation of staining intensities with clinical data revealed association of pSTAT3 and STAT5 expression with sex (P=0.003 and 0.016, respectively) and of STAT3 with tumor stage (P=0.019). Recurrence of melanoma was found to be associated with high STAT5 expression (P=0.017). Multivariable regression analysis revealed STAT5 expression as an independent factor for predicting progression-free survival (P<0.0001) and overall survival (P=0.022). In summary, high expression of STAT5 correlated with melanoma recurrence and survival of patients treated with IFN-α in the adjuvant setting. Recently, it has been suggested that mutations of Janus kinases are involved in resistance to immune checkpoint blocker treatments implying a possible role of STAT5 for immune checkpoint resistance.
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http://dx.doi.org/10.1097/CMR.0000000000000435DOI Listing
June 2018

Liquid Profiling of Circulating Tumor DNA in Plasma of Melanoma Patients for Companion Diagnostics and Monitoring of BRAF Inhibitor Therapy.

Clin Chem 2018 05 26;64(5):830-842. Epub 2018 Feb 26.

Department of Clinical Chemistry, University Medical Centre, Ruprecht-Karls University of Heidelberg, Mannheim, Germany;

Background: The current standard for determining eligibility of patients with metastatic melanoma for BRAF-targeted therapy is tissue-based testing of mutations. As patients are rarely rebiopsied, detection in blood might be advantageous by enabling a comprehensive assessment of tumor mutational status in real time and thereby representing a noninvasive biomarker for monitoring BRAF therapy.

Methods: In all, 634 stage I to IV melanoma patients were enrolled at 2 centers, and 1406 plasma samples were prospectively collected. Patients were assigned to 3 separate study cohorts: study 1 for assessment of circulating tumor DNA (ctDNA) as part of companion diagnostics, study 2 for assessment of ctDNA for patients with low tumor burden and for follow-up, and study 3 for monitoring of resistance to BRAF inhibitor (BRAFi) or mitogen-activated protein kinase inhibitor therapy.

Results: Overall, a high degree of concordance between plasma and tissue testing results was observed at 90.9% (study 1) and 90.1% (study 2), respectively. Interestingly, discrepant results were in some cases associated with nonresponse to BRAFi (n = 3) or a secondary -mutant malignancy (n = 5). Importantly, ctDNA results correlated with the clinical course of disease in 95.7% and with response to treatment. Significantly, the detection of mutant ctDNA preceded relapse assessed by Response Evaluation Criteria in Solid Tumors, and was more specific than serum S100 and lactate dehydrogenase.

Conclusions: Blood-based testing compares favorably with standard-of-care tissue-based mutation testing. Importantly, blood-based testing correlates with the clinical course, even for early-stage patients, and may be used to predict response to treatment, recurrence, and resistance before radioimaging under BRAFi therapy, thereby enabling considerable improvements in patient treatment.
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http://dx.doi.org/10.1373/clinchem.2017.281543DOI Listing
May 2018

Intraventricular melanocytoma diagnosis confirmed by gene mutation profile.

Neuropathology 2018 Jun 11;38(3):288-292. Epub 2017 Dec 11.

Institute of Pathology, Ruhr University Bochum, Bochum, Germany.

Primary leptomeningeal melanocytic tumors (PLMTs) are rare. They usually arise along the spinal cord and at the skull base. Here we report on a patient with a very rare intraventricular melanocytoma. Histologically, a melanocytic tumor was clearly diagnosed. However, to make the uncommon diagnosis of an intraventricular melanocytoma, metastatic melanoma needed to be excluded. Next generation sequencing covering gene mutations that may occur in PLMTs and cutaneous melanoma was performed. The unique gene mutation profile detected, consisting of an activating CYSLTR2 L129Q mutation and EIF1AX G9R mutation and a lack of mutations in genes known to occur in metastatic melanoma (i.e. BRAF or NRAS) confirmed the diagnosis of an intraventricular melanocytoma. This case report is the second intraventricular melanocytoma published to date and demonstrates the value of applying novel genetic assays to make this diagnosis.
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http://dx.doi.org/10.1111/neup.12443DOI Listing
June 2018
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