المؤلفون: In, Gino K., Ribeiro, Jennifer R., Yin, Jun, Xiu, Joanne, Bustos, Matias A., Ito, Fumito, Chow, Frances, Zada, Gabriel, Hwang, Lindsay, Salama, April K. S., Park, Soo J., Moser, Justin C., Darabi, Sourat, Domingo-Musibay, Evidio, Ascierto, Maria L., Margolin, Kim, Lutzky, Jose, Gibney, Geoffrey T., Atkins, Michael B., Izar, Benjamin

المصدر: NPJ Precision Oncology; 11/14/2023, Vol. 7 Issue 1, p1-10, 10p

مصطلحات موضوعية: TUMOR microenvironment, KILLER cells, MELANOMA, OXIDATIVE phosphorylation, IMMUNE checkpoint proteins

مستخلص: Melanoma brain metastases (MBM) are clinically challenging to treat and exhibit variable responses to immune checkpoint therapies. Prior research suggests that MBM exhibit poor tumor immune responses and are enriched in oxidative phosphorylation. Here, we report results from a multi-omic analysis of a large, real-world melanoma cohort. MBM exhibited lower interferon-gamma (IFNγ) scores and T cell-inflamed scores compared to primary cutaneous melanoma (PCM) or extracranial metastases (ECM), which was independent of tumor mutational burden. Among MBM, there were fewer computationally inferred immune cell infiltrates, which correlated with lower TNF and IL12B mRNA levels. Ingenuity pathway analysis (IPA) revealed suppression of inflammatory responses and dendritic cell maturation pathways. MBM also demonstrated a higher frequency of pathogenic PTEN mutations and angiogenic signaling. Oxidative phosphorylation (OXPHOS) was enriched in MBM and negatively correlated with NK cell and B cell-associated transcriptomic signatures. Modulating metabolic or angiogenic pathways in MBM may improve responses to immunotherapy in this difficult-to-treat patient subset. [ABSTRACT FROM AUTHOR]

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المؤلفون: Capone, Mariaelena, Ascierto, Maria Libera, Stroncek, David F., Casula, Milena, Palla, Marco, Mozzillo, Nicola, Palmieri, Giuseppe, Gentilcore, Giusy, Sini, Maria Cristina, Ascierto, Paolo Antonio

المساهمون: Capone, Mariaelena, Ascierto, Maria Libera, Stroncek, David F., Casula, Milena, Palla, Marco, Mozzillo, Nicola, Palmieri, Giuseppe, Gentilcore, Giusy, Sini, Maria Cristina, Ascierto, Paolo Antonio

مصطلحات موضوعية: Melanoma, molecular change, melanocytes

الوصف: The characterization of the molecular mechanisms involved in development and progression of melanoma could be helpful to identify the molecular profiles underlying aggressiveness, clinical behavior, and response to therapy as well as to better classify the subsets of melanoma patients with different prognosis and/or clinical outcome. Actually, some aspects regarding the main molecular changes responsible for the onset as well as the progression of melanoma toward a more aggressive phenotype have been described. Genes and molecules which control either cell proliferation, apoptosis, or cell senescence have been implicated. Here we provided an overview of the main molecular changes underlying the pathogenesis of melanoma. All evidence clearly indicates the existence of a complex molecular machinery that provides checks and balances in normal melanocytes. Progression from normal melanocytes to malignant metastatic cells in melanoma patients is the result of a combination of down- or up-regulation of various effectors acting on different molecular pathways.

العلاقة: info:eu-repo/semantics/altIdentifier/wos/WOS:000271531500001; volume:7; issue:86; firstpage:1; lastpage:17; journal:JOURNAL OF TRANSLATIONAL MEDICINE; http://hdl.handle.net/11388/264056Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-71149083533

الإتاحة: https://doi.org/10.1186/1479-5876-7-86Test
http://hdl.handle.net/11388/264056Test

المؤلفون: Spivey Tara L, De Giorgi Valeria, Zhao Yingdong, Bedognetti Davide, Pos Zoltan, Liu Qiuzhen, Tomei Sara, Ascierto Maria, Uccellini Lorenzo, Reinboth Jennifer, Chouchane Lotfi, Stroncek David F, Wang Ena, Marincola Francesco M

المصدر: BMC Genomics, Vol 13, Iss 1, p 156 (2012)

مصطلحات موضوعية: Melanoma, Melanoma genetics, Cancer, Tumor microenvironment, Biotechnology, TP248.13-248.65, Genetics, QH426-470

الوصف: Background The weight that gene copy number plays in transcription remains controversial; although in specific cases gene expression correlates with copy number, the relationship cannot be inferred at the global level. We hypothesized that genes steadily expressed by 15 melanoma cell lines (CMs) and their parental tissues (TMs) should be critical for oncogenesis and their expression most frequently influenced by their respective copy number. Results Functional interpretation of 3,030 transcripts concordantly expressed (Pearson's correlation coefficient p-value < 0.05) by CMs and TMs confirmed an enrichment of functions crucial to oncogenesis. Among them, 968 were expressed according to the transcriptional efficiency predicted by copy number analysis (Pearson's correlation coefficient p-value < 0.05). We named these genes, "genomic delegates" as they represent at the transcriptional level the genetic footprint of individual cancers. We then tested whether the genes could categorize 112 melanoma metastases. Two divergent phenotypes were observed: one with prevalent expression of cancer testis antigens, enhanced cyclin activity, WNT signaling, and a Th17 immune phenotype (Class A). This phenotype expressed, therefore, transcripts previously associated to more aggressive cancer. The second class (B) prevalently expressed genes associated with melanoma signaling including MITF , melanoma differentiation antigens, and displayed a Th1 immune phenotype associated with better prognosis and likelihood to respond to immunotherapy. An intermediate third class (C) was further identified. The three phenotypes were confirmed by unsupervised principal component analysis. Conclusions This study suggests that clinically relevant phenotypes of melanoma can be retraced to stable oncogenic properties of cancer cells linked to their genetic back bone, and offers a roadmap for uncovering novel targets for tailored anti-cancer therapy.

العلاقة: http://www.biomedcentral.com/1471-2164/13/156Test; https://doaj.org/toc/1471-2164Test; https://doaj.org/article/e21adb9af1974b2480f274cad75f9f93Test

الإتاحة: https://doi.org/10.1186/1471-2164-13-156Test
https://doaj.org/article/e21adb9af1974b2480f274cad75f9f93Test

المؤلفون: Spivey, Tara L, De Giorgi, Valeria, Zhao, Yingdong, Bedognetti, Davide, Pos, Zoltan, Liu, Qiuzhen, Tomei, Sara, Ascierto, Maria, Uccellini, Lorenzo, Reinboth, Jennifer, Chouchane, Lotfi, Stroncek, David F, Wang, Ena, Marincola, Francesco M

مصطلحات موضوعية: Melanoma, Melanoma genetics, Cancer, Tumor microenvironment

الوصف: Background The weight that gene copy number plays in transcription remains controversial; although in specific cases gene expression correlates with copy number, the relationship cannot be inferred at the global level. We hypothesized that genes steadily expressed by 15 melanoma cell lines (CMs) and their parental tissues (TMs) should be critical for oncogenesis and their expression most frequently influenced by their respective copy number. Results Functional interpretation of 3,030 transcripts concordantly expressed (Pearson's correlation coefficient p-value < 0.05) by CMs and TMs confirmed an enrichment of functions crucial to oncogenesis. Among them, 968 were expressed according to the transcriptional efficiency predicted by copy number analysis (Pearson's correlation coefficient p-value < 0.05). We named these genes, "genomic delegates" as they represent at the transcriptional level the genetic footprint of individual cancers. We then tested whether the genes could categorize 112 melanoma metastases. Two divergent phenotypes were observed: one with prevalent expression of cancer testis antigens, enhanced cyclin activity, WNT signaling, and a Th17 immune phenotype (Class A). This phenotype expressed, therefore, transcripts previously associated to more aggressive cancer. The second class (B) prevalently expressed genes associated with melanoma signaling including MITF , melanoma differentiation antigens, and displayed a Th1 immune phenotype associated with better prognosis and likelihood to respond to immunotherapy. An intermediate third class (C) was further identified. The three phenotypes were confirmed by unsupervised principal component analysis. Conclusions This study suggests that clinically relevant phenotypes of melanoma can be retraced to stable oncogenic properties of cancer cells linked to their genetic back bone, and offers a roadmap for uncovering novel targets for tailored anti-cancer therapy.

العلاقة: http://www.biomedcentral.com/1471-2164/13/156Test

الإتاحة: http://www.biomedcentral.com/1471-2164/13/156Test

المؤلفون: Ascierto, Maria Libera, Melero, Ignacio, Ascierto, Paolo Antonio, Sala, Arturo, Vigneri, Paolo Giovanni

المصدر: Frontiers in Oncology; Jul2015, p1-7, 7p

مصطلحات موضوعية: MELANOMA immunotherapy, SURGICAL complications, MONOCLONAL antibodies

مستخلص: After Coley's observation in 1891 of tumor regression in a patient who developed a postoperative infection, the field of immunotherapy is finally reborn. Avoiding immune destruction is now considered a hallmark of cancer, and the immunotherapy arena has exploded with the recent advances demonstrating an improvement in survival and a durability of response in patients with different cancer types, which translates into improved overall survival benefit. Here, we provide an overview of the main immune-oncology treatment strategies that, either alone or in combination, are undergoing clinical development. Namely, we will refer to those immunotherapeutic strategies that include adoptive transfer of ex vivo activated T cells, immunomodulatory monoclonal antibodies, and cancer vaccines. Our major focus will be to describe these approaches in melanoma, a cancer type transformed by immunotherapy into a potentially curable disease. [ABSTRACT FROM AUTHOR]

: Copyright of Frontiers in Oncology is the property of Frontiers Media S.A. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Tomei, Sara, Bedognetti, Davide, De Giorgi, Valeria, Sommariva, Michele, Civini, Sara, Reinboth, Jennifer, Al Hashmi, Muna, Ascierto, Maria Libera, Liu, Qiuzhen, Ayotte, Ben D., Worschech, Andrea, Uccellini, Lorenzo, Ascierto, Paolo A., Stroncek, David, Palmieri, Giuseppe, Chouchane, Lotfi, Wang, Ena, Marincola, Francesco M.

المصدر: Molecular Oncology; Jan2015, Vol. 9 Issue 1, p93-104, 12p

مستخلص: Background : The existence of a dichotomy between immunologically active and quiescent tumor phenotypes has been recently recognized in several types of cancer. The activation of a Th1 type of immune signature has been shown to confer better prognosis and likelihood to respond to immunotherapy. However, whether such dichotomy depends on the genetic make-up of individual cancers is not known yet. BRAF and NRAS mutations are commonly acquired during melanoma progression. Here we explored the role of BRAF and NRAS mutations in influencing the immune phenotype based on a classification previously identified by our group. Methods One-hundred-thirteen melanoma metastases underwent microarray analysis and BRAF and NRAS genotyping. Allele-specific PCR was also performed in order to exclude low-frequency mutations. Results Comparison between BRAF and NRAS mutant versus wild type samples identified mostly constituents or regulators of MAPK and related pathways. When testing gene lists discriminative of BRAF, NRAS and MAPK alterations, we found that 112 BRAF-specific transcripts were able to distinguish the two immune-related phenotypes already described in melanoma, with the poor phenotype associated mostly with BRAF mutation. Noteworthy, such association was stronger in samples displaying low BRAF mRNA expression. However, when testing NRAS mutations, we were not able to find the same association. Conclusion This study suggests that BRAF mutation-related specific transcripts associate with a poor phenotype in melanoma and provide a nest for further investigation. [ABSTRACT FROM AUTHOR]

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المؤلفون: Tomei, Sara, Adams, Sharon, Uccellini, Lorenzo, Bedognetti, Davide, De Giorgi, Valeria, Erdenebileg, Narnygerel, Ascierto, Maria, Reinboth, Jennifer, Liu, Qiuzhen, Bevilacqua, Generoso, Wang, Ena, Mazzanti, Chiara, Marincola, Francesco

المصدر: Medical Oncology; Dec2012, Vol. 29 Issue 5, p3456-3461, 6p

مستخلص: HRAS belongs to the RAS genes superfamily. RAS genes are important players in several human tumors and the single-nucleotide polymorphism rs12628 has been shown to contribute to the risk of bladder, colon, gastrointestinal, oral, and thyroid carcinoma. We hypothesized that this SNP may affect the risk of cutaneous melanoma as well. HRAS gene contains a polymorphic region (rs112587690), a repeated hexanucleotide -GGGCCT- located in intron 1. Three alleles of this region, P1, P2, and P3, have been identified that contain two, three, and four repeats of the hexanucleotide, respectively. We investigated the clinical impact of these polymorphisms in a case-control study. A total of 141 melanoma patients and 118 healthy donors from the North America Caucasian population were screened for rs12628 and rs112587690 polymorphisms. Genotypes were assessed by capillary sequencing or fragment analysis, respectively, and rs12628 CC and rs112587690 P1P1 genotypes significantly associated with increased melanoma risk (OR = 3.83, p = 0.003; OR = 11.3, p = 0.033, respectively), while rs112587690 P1P3 frequency resulted significantly higher in the control group (OR = 0.5, p = 0.017). These results suggest that rs12628 C homozygosis may be considered a potential risk factor for melanoma development in the North American population possibly through the linkage to rs112587690. [ABSTRACT FROM AUTHOR]

: Copyright of Medical Oncology is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Carretero, Rafael, Wang, Ena, Rodriguez, Ana I., Reinboth, Jennifer, Ascierto, Maria L., Engle, Alyson M., Liu, Hui, Camacho, Francisco M., Marincola, Francesco M., Garrido, Federico, Cabrera, Teresa

المصدر: International Journal of Cancer; Jul2012, Vol. 131 Issue 2, p387-395, 9p

مستخلص: We present the results of a comparative gene expression analysis of 15 metastases (10 regressing and 5 progressing) obtained from 2 melanoma patients with mixed response following different forms of immunotherapy. Whole genome transcriptional analysis clearly indicate that regression of melanoma metastases is due to an acute immune rejection mediated by the upregulation of genes involved in antigen presentation and interferon mediated response (STAT-1/IRF-1) in all the regressing metastases from both patients. In contrast, progressing metastases showed low transcription levels of genes involved in these pathways. Histological analysis showed T cells and HLA-DR positive infiltrating cells in the regressing but not in the progressing metastases. Quantitative expression analysis of HLA-A,B and C genes on microdisected tumoral regions indicate higher HLA expression in regressing than in progressing metastases. The molecular signature obtained in melanoma rejection appeared to be similar to that observed in other forms of immune-mediated tissue-specific rejection such as allograft, pathogen clearance, graft versus host or autoimmune disease, supporting the immunological constant of rejection. We favor the idea that the major factor determining the success or failure of immunotherapy is the nature of HLA Class I alterations in tumor cells and not the type of immunotherapy used. If the molecular alteration is reversible by the immunotherapy, the HLA expression will be upregulated and the lesion will be recognized and rejected. In contrast, if the defect is structural the MHC Class I expression will remain unchanged and the lesion will progress. [ABSTRACT FROM AUTHOR]

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المؤلفون: Uccellini, Lorenzo, De Giorgi, Valeria, Yingdong Zhao, Tumaini, Barbara, Erdenebileg, Narnygerel, Dudley, Mark E., Tomei, Sara, Bedognetti, Davide, Libera Ascierto, Maria, Qiuzhen Liu, Simon, Richard, Kottyan, Leah, Kaufman, Kenneth M., Harley, John B., Ena Wang, Rosenberg, Steven A., Marincola, Francesco M.

المصدر: Journal of Translational Medicine; 2012, Vol. 10 Issue 1, p170-177, 8p, 3 Color Photographs, 3 Charts

مصطلحات موضوعية: INTERFERON regulatory factors, TRANSCRIPTION factors, MELANOMA, AUTOIMMUNITY, SINGLE nucleotide polymorphisms, LYMPHOCYTES

مستخلص: Background: Interferon regulatory factor (IRF)-5 is a transcription factor involved in type I interferon signaling whose germ line variants have been associated with autoimmune pathogenesis. Since relationships have been observed between development of autoimmunity and responsiveness of melanoma to several types of immunotherapy, we tested whether polymorphisms of IRF5 are associated with responsiveness of melanoma to adoptive therapy with tumor infiltrating lymphocytes (TILs). Methods: 140 TILs were genotyped for four single nucleotide polymorphisms (rs10954213, rs11770589, rs6953165, rs2004640) and one insertion-deletion in the IRF5 gene by sequencing. Gene-expression profile of the TILs, 112 parental melanoma metastases (MM) and 9 cell lines derived from some metastases were assessed by Affymetrix Human Gene ST 1.0 array. Results: Lack of A allele in rs10954213 (G > A) was associated with non-response (p < 0.005). Other polymorphisms in strong linkage disequilibrium with rs10954213 demonstrated similar trends. Genes differentially expressed in vitro between cell lines carrying or not the A allele could be applied to the transcriptional profile of 112 melanoma metastases to predict their responsiveness to therapy, suggesting that IRF5 genotype may influence immune responsiveness by affecting the intrinsic biology of melanoma. Conclusions: This study is the first to analyze associations between melanoma immune responsiveness and IRF5 polymorphism. The results support a common genetic basis which may underline the development of autoimmunity and melanoma immune responsiveness. [ABSTRACT FROM AUTHOR]

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المؤلفون: Qiuzhen Liu^1,2 liuqiuzhen@126.gov, Tomei, Sara³, Ascierto, Maria Libera¹, De Giorgi, Valeria¹, Bedognetti, Davide¹, Cuilian Dai⁴, Uccellini, Lorenzo⁵, Spivey, Tara⁶, Pos, Zoltan^7,8, Thomas, Jaime¹, Reinboth, Jennifer¹, Murtas, Daniela¹, Qianbing Zhang², Chouchane, Lotfi³, Weiss, Geoffrey R.⁹, Slingluff Jr., Craig L.⁹, Lee, Peter P.¹⁰, Rosenberg, Steven A.¹¹, Alter, Harvey¹, Kaitai Yao²

المصدر: Journal of Clinical Investigation. May2014, Vol. 124 Issue 5, p2147-2159. 13p. 4 Color Photographs, 1 Chart, 2 Graphs.

مصطلحات موضوعية: *MELANOMA, *GENE expression, *CELLULAR signal transduction, *INTERFERONS, *PHOSPHORYLATION, *CANCER immunology, *GENETICS

مستخلص: In multiple forms of cancer, constitutive activation of type I IFN signaling is a critical consequence of immune surveillance against cancer; however, PBMCs isolated from cancer patients exhibit depressed STAT1 phosphorylation in response to IFN-α, suggesting IFN signaling dysfunction. Here, we demonstrated in a coculture system that melanoma cells differentially impairs the IFN-α response in PBMCs and that the inhibitory potential of a particular melanoma cell correlates with NOS1 expression. Comparison of gene transcription and array comparative genomic hybridization (aCGH) between melanoma cells from different patients indicated that suppression of IFN-α signaling correlates with an amplification of the NOS1 locus within segment 12q22-24. Evaluation of NOS1 levels in melanomas and IFN responsiveness of purified PBMCs from patients indicated a negative correlation between NOS1 expression in melanomas and the responsiveness of PBMCs to IFN-α. Furthermore, in an explorative study, NOS1 expression in melanoma metastases was negatively associated with patient response to adoptive T cell therapy. This study provides a link between cancer cell phenotype and IFN signal dysfunction in circulating immune cells. [ABSTRACT FROM AUTHOR]