Research

12 pages, 2027 KiB

Open AccessArticle

TERT Expression Induces Resistance to BRAF and MEK Inhibitors in BRAF-Mutated Melanoma In Vitro

by Julie Delyon, Anaïs Vallet, Mélanie Bernard-Cacciarella, Isabelle Kuzniak, Coralie Reger de Moura, Baptiste Louveau, Fanélie Jouenne, Samia Mourah, Céleste Lebbé and Nicolas Dumaz

Cancers 2023, 15(11), 2888; https://doi.org/10.3390/cancers15112888 - 24 May 2023

Cited by 4 | Viewed by 1288

Abstract

Because BRAF-mutated melanomas are addicted to the Mitogen Activated Protein Kinase (MAPK) pathway they show a high response rate to BRAF and MEK inhibitors. However, the clinical responses to these inhibitors are often short-lived with the rapid onset of resistance to treatment. Deciphering [...] Read more.

Because BRAF-mutated melanomas are addicted to the Mitogen Activated Protein Kinase (MAPK) pathway they show a high response rate to BRAF and MEK inhibitors. However, the clinical responses to these inhibitors are often short-lived with the rapid onset of resistance to treatment. Deciphering the molecular mechanisms driving resistance has been the subject of intense research. Recent in vitro and clinical data have suggested a link between expression of telomerase and resistance to targeted therapy in melanoma. TERT promoter mutations are the main mechanism for the continuous upregulation of telomerase in melanoma and co-occur frequently with BRAF alterations. To understand how TERT promoter mutations could be associated with resistance to targeted therapy in melanoma, we conducted translational and in vitro studies. In a cohort of V600E-BRAF-mutated melanoma patients, we showed that the TERT promoter mutation status and TERT expression tended to be associated with response to BRAF and MEK inhibitors. We demonstrated that TERT overexpression in BRAF-mutated melanoma cells reduced sensitivity to BRAF and MEK independently of TERT’s telomer maintenance activity. Interestingly, inhibition of TERT reduced growth of BRAF-mutated melanoma including resistant cells. TERT expression in melanoma can therefore be a new biomarker for resistance to MAPK inhibitors as well as a novel therapeutic target. Full article

(This article belongs to the Special Issue Latest Development in Melanoma Research)

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21 pages, 6300 KiB

Open AccessArticle

Chick Chorioallantoic Membrane as a Patient-Derived Xenograft Model for Uveal Melanoma: Imaging Modalities for Growth and Vascular Evaluation

by Theodora Tsimpaki, Nikolaos E. Bechrakis, Berthold Seitz, Miriam M. Kraemer, Hongtao Liu, Sami Dalbah, Ekaterina Sokolenko, Utta Berchner-Pfannschmidt and Miltiadis Fiorentzis

Cancers 2023, 15(5), 1436; https://doi.org/10.3390/cancers15051436 - 24 Feb 2023

Cited by 2 | Viewed by 2216

Abstract

Background: Patient-derived tumor xenografts (PDXs) have emerged as valuable preclinical in vivo models in oncology as they largely retain the polygenomic architecture of the human tumors from which they originate. Although animal models are accompanied by cost and time constraints and a low [...] Read more.

Background: Patient-derived tumor xenografts (PDXs) have emerged as valuable preclinical in vivo models in oncology as they largely retain the polygenomic architecture of the human tumors from which they originate. Although animal models are accompanied by cost and time constraints and a low engraftment rate, PDXs have primarily been established in immunodeficient rodent models for the in vivo assessment of tumor characteristics and of novel therapeutic cancer targets. The chick chorioallantoic membrane (CAM) assay represents an attractive alternative in vivo model that has long been used in the research of tumor biology and angiogenesis, and can overcome some of these limitations. Methods: In this study, we reviewed different technical approaches for the establishment and monitoring of a CAM-based uveal melanoma PDX model. Forty-six fresh tumor grafts were acquired after enucleation from six uveal melanoma patients and were implanted onto the CAM on ED7 with Matrigel and a ring (group 1), with Matrigel (group 2), or natively without Matrigel or a ring (group 3). Real-time imaging techniques, such as various ultrasound modalities, optical coherence tomography, infrared imaging, and imaging analyses with Image J for tumor growth and extension, as well as color doppler, optical coherence angiography, and fluorescein angiography for angiogenesis, were performed on ED18 as alternative monitoring instruments. The tumor samples were excised on ED18 for histological assessment. Results: There were no significant differences between the three tested experimental groups regarding the length and width of the grafts during the development period. A statistically significant increase in volume (p = 0.0007) and weight (p = 0.0216) between ED7 and ED18 was only documented for tumor specimens of group 2. A significant correlation of the results for the cross-sectional area, largest basal diameter, and volume was documented between the different imaging and measurement techniques and the excised grafts. The formation of a vascular star around the tumor and of a vascular ring on the base of the tumor was observed for the majority of the viable developing grafts as a sign of successful engraftment. Conclusion: The establishment of a CAM-PDX uveal melanoma model could elucidate the biological growth patterns and the efficacy of new therapeutic options in vivo. The methodological novelty of this study, investigating different implanting techniques and exploiting advances in real-time imaging with multiple modalities, allows precise, quantitative assessment in the field of tumor experimentation, underlying the feasibility of CAM as an in vivo PDX model. Full article

(This article belongs to the Special Issue Latest Development in Melanoma Research)

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12 pages, 10967 KiB

Open AccessArticle

Tolerability of BRAF and MEK Inhibitors for Metastasized Melanoma after Intra-Class Switch: A Multicenter, Retrospective Study

by Martin Salzmann, Alexander Wald, Henner Stege, Carmen Loquai, Lisa Zimmer, Kinan M. Hayani, Lucie Heinzerling, Ralf Gutzmer, Alexander H. Enk and Jessica C. Hassel

Cancers 2023, 15(5), 1426; https://doi.org/10.3390/cancers15051426 - 23 Feb 2023

Viewed by 1350

Abstract

Targeted therapy with BRAF and MEK inhibitors (BRAFi, MEKi) is one of the mainstays of melanoma treatment. When dose-limiting toxicity (DLT) is observed, an option represents the intra-class switch to a different BRAFi+MEKi combination. Currently, there is scarce evidence for this procedure. This [...] Read more.

Targeted therapy with BRAF and MEK inhibitors (BRAFi, MEKi) is one of the mainstays of melanoma treatment. When dose-limiting toxicity (DLT) is observed, an option represents the intra-class switch to a different BRAFi+MEKi combination. Currently, there is scarce evidence for this procedure. This is a multicenter, retrospective analysis from six German skin cancer centers of patients who received two different combinations of BRAFi and MEKi. In total, 94 patients were included: 38 patients (40%) were re-exposed with a different combination because of previous unacceptable toxicity, 51 (54%) were re-exposed after progression, and 5 (5%) were included for other reasons. Of the 44 patients with a DLT during their first BRAFi+MEKi combination, only five (11%) experienced the same DLT during their second combination. A new DLT was experienced by 13 patients (30%). Six patients (14%) had to discontinue the second BRAFi treatment due to its toxicity. Compound-specific adverse events were avoided in the majority of patients by switching to a different combination. Efficacy data were similar to historical cohorts of BRAFi+MEKi rechallenge, with an overall response rate of 31% for patients who had previously progressed to treatment. We conclude that switching to a different BRAFi+MEKi combination if dose-limiting toxicity occurs is a feasible and rational approach in patients with metastatic melanoma. Full article

(This article belongs to the Special Issue Latest Development in Melanoma Research)

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15 pages, 4721 KiB

Open AccessArticle

Head-to-Head Comparison of BRAF/MEK Inhibitor Combinations Proposes Superiority of Encorafenib Plus Trametinib in Melanoma

by Alexander Schulz, Jennifer Raetz, Paula C. Karitzky, Lisa Dinter, Julia K. Tietze, Isabell Kolbe, Theresa Käubler, Bertold Renner, Stefan Beissert, Friedegund Meier and Dana Westphal

Cancers 2022, 14(19), 4930; https://doi.org/10.3390/cancers14194930 - 08 Oct 2022

Cited by 7 | Viewed by 2983

Abstract

BRAFV600 mutations in melanoma are targeted with mutation-specific BRAF inhibitors in combination with MEK inhibitors, which have significantly increased overall survival, but eventually lead to resistance in most cases. Additionally, targeted therapy for patients with NRASmutant melanoma is difficult. Our own studies showed [...] Read more.

BRAFV600 mutations in melanoma are targeted with mutation-specific BRAF inhibitors in combination with MEK inhibitors, which have significantly increased overall survival, but eventually lead to resistance in most cases. Additionally, targeted therapy for patients with NRASmutant melanoma is difficult. Our own studies showed that BRAF inhibitors amplify the effects of MEK inhibitors in NRASmutant melanoma. This study aimed at identifying a BRAF and MEK inhibitor combination with superior anti-tumor activity to the three currently approved combinations. We, thus, assessed anti-proliferative and pro-apoptotic activities of all nine as well as resistance-delaying capabilities of the three approved inhibitor combinations in a head-to-head comparison in vitro. The unconventional combination encorafenib/trametinib displayed the highest activity to suppress proliferation and induce apoptosis, acting in an additive manner in BRAFmutant and in a synergistic manner in NRASmutant melanoma cells. Correlating with current clinical studies of approved inhibitor combinations, encorafenib/binimetinib prolonged the time to resistance most efficiently in BRAFmutant cells. Conversely, NRASmutant cells needed the longest time to establish resistance when treated with dabrafenib/trametinib. Together, our data indicate that the most effective combination might not be currently used in clinical settings and could lead to improved overall responses. Full article

(This article belongs to the Special Issue Latest Development in Melanoma Research)

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14 pages, 1846 KiB

Open AccessArticle

N-Acetylcysteine Promotes Metastatic Spread of Melanoma in Mice

by Elena Obrador, Rosario Salvador-Palmer, Rafael López-Blanch, María Oriol-Caballo, Paz Moreno-Murciano and José M. Estrela

Cancers 2022, 14(15), 3614; https://doi.org/10.3390/cancers14153614 - 25 Jul 2022

Cited by 5 | Viewed by 8140

Abstract

N-acetylcysteine (NAC) is a direct Cys donor and a promoter of glutathione (GSH) synthesis. GSH regulates melanoma growth and NAC has been suggested to increase melanoma metastases in mice. We found that high therapeutic doses of NAC do not increase the growth of [...] Read more.

N-acetylcysteine (NAC) is a direct Cys donor and a promoter of glutathione (GSH) synthesis. GSH regulates melanoma growth and NAC has been suggested to increase melanoma metastases in mice. We found that high therapeutic doses of NAC do not increase the growth of melanoma xenografts, but can cause metastatic spread and distant metastases. Nevertheless, this is not due to an antioxidant effect since NAC, in fact, increases the generation of reactive oxygen species in the growing metastatic melanoma. Trolox, an antioxidant vitamin E derivative, administered in vivo, decreased metastatic growth. Metastatic cells isolated from NAC-treated mice showed an increase in the nuclear translocation of Nrf2, as compared to controls. Nrf2, a master regulator of the antioxidant response, controls the expression of different antioxidant enzymes and of the γ-glutamylcysteine ligase (the rate-limiting step in GSH synthesis). Cystine uptake through the xCT cystine-glutamate antiporter (generating intracellular Cys) and the γ-glutamylcysteine ligase activity are key to control metastatic growth. This is associated to an increase in the utilization of L-Gln by the metastatic cells, another metastases promoter. Our results demonstrate the potential of NAC as an inducer of melanoma metastases spread, and suggest that caution should be taken when administering GSH promoters to cancer patients. Full article

(This article belongs to the Special Issue Latest Development in Melanoma Research)

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18 pages, 3248 KiB

Open AccessArticle

Sarcoid-like Granulomatosis Associated with Immune Checkpoint Inhibitors in Melanoma

by Audrey Melin, Émilie Routier, Séverine Roy, Pauline Pradere, Jerome Le Pavec, Thibaut Pierre, Noémie Chanson, Jean-Yves Scoazec, Olivier Lambotte and Caroline Robert

Cancers 2022, 14(12), 2937; https://doi.org/10.3390/cancers14122937 - 14 Jun 2022

Cited by 8 | Viewed by 2531

Abstract

We aimed to review the clinical and biological presentation of granulomatosis associated with immune-checkpoint inhibitors (ICI) in patients with melanoma and to explore its association with classical sarcoidosis as well as with cancer response to ICI. To this end, a retrospective study on [...] Read more.

We aimed to review the clinical and biological presentation of granulomatosis associated with immune-checkpoint inhibitors (ICI) in patients with melanoma and to explore its association with classical sarcoidosis as well as with cancer response to ICI. To this end, a retrospective study on 18 melanoma patients with histologically proven ICI-induced granulomatosis over a 12-year period in a single center, as well as on 67 similar cases reported in the literature, was conducted. Results indicate ICI-induced granulomatosis is an early side effect (median time to onset: 2 months). Its clinical presentation, with predominant (90%) thoracic involvement, histopathological appearance and supposed underlying biology (involving the mTOR pathway in immune cells, Th17 polarization and TReg dysfunction) are indistinguishable from those of sarcoidosis. Moreover, it appears to be associated with ICI benefit (>65% objective response rate). Evolution is generally favorable, and symptomatic steroid treatment and/or ICI discontinuation are rarely necessary. ICI-associated granulomatosis is critical to explore for several reasons. Practically, it is essential to differentiate it from cancer progression. Secondly, this “experimental” sarcoidosis brings new elements that may help to address sarcoidosis origin and pathophysiology. Its association with ICI efficacy must be confirmed on a larger scale but could have significant impacts on patient management and biomarker definition. Full article

(This article belongs to the Special Issue Latest Development in Melanoma Research)

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17 pages, 4831 KiB

Open AccessArticle

Differential Effects on the Translation of Immune-Related Alternatively Polyadenylated mRNAs in Melanoma and T Cells by eIF4A Inhibition

by Biswendu Biswas, Ramdane Guemiri, Mandy Cadix, Céline M. Labbé, Alina Chakraborty, Martin Dutertre, Caroline Robert and Stéphan Vagner

Cancers 2022, 14(5), 1177; https://doi.org/10.3390/cancers14051177 - 24 Feb 2022

Cited by 5 | Viewed by 2887

Abstract

Targeting the translation initiation complex eIF4F, which binds the 5′ cap of mRNAs, is a promising anti-cancer approach. Silvestrol, a small molecule inhibitor of eIF4A, the RNA helicase component of eIF4F, inhibits the translation of the mRNA encoding the signal transducer and activator [...] Read more.

Targeting the translation initiation complex eIF4F, which binds the 5′ cap of mRNAs, is a promising anti-cancer approach. Silvestrol, a small molecule inhibitor of eIF4A, the RNA helicase component of eIF4F, inhibits the translation of the mRNA encoding the signal transducer and activator of transcription 1 (STAT1) transcription factor, which, in turn, reduces the transcription of the gene encoding one of the major immune checkpoint proteins, i.e., programmed death ligand-1 (PD-L1) in melanoma cells. A large proportion of human genes produce multiple mRNAs differing in their 3′-ends through the use of alternative polyadenylation (APA) sites, which, when located in alternative last exons, can generate protein isoforms, as in the STAT1 gene. Here, we provide evidence that the STAT1α, but not STAT1β protein isoform generated by APA, is required for silvestrol-dependent inhibition of PD-L1 expression in interferon-γ-treated melanoma cells. Using polysome profiling in activated T cells we find that, beyond STAT1, eIF4A inhibition downregulates the translation of some important immune-related mRNAs, such as the ones encoding TIM-3, LAG-3, IDO1, CD27 or CD137, but with little effect on the ones for BTLA and ADAR-1 and no effect on the ones encoding CTLA-4, PD-1 and CD40-L. We next apply RT-qPCR and 3′-seq (RNA-seq focused on mRNA 3′ ends) on polysomal RNAs to analyze in a high throughput manner the effect of eIF4A inhibition on the translation of APA isoforms. We identify about 150 genes, including TIM-3, LAG-3, AHNAK and SEMA4D, for which silvestrol differentially inhibits the translation of APA isoforms in T cells. It is therefore crucial to consider 3′-end mRNA heterogeneity in the understanding of the anti-tumor activities of eIF4A inhibitors. Full article

(This article belongs to the Special Issue Latest Development in Melanoma Research)

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Review

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14 pages, 657 KiB

Open AccessReview

The Cross Talk between Cellular Senescence and Melanoma: From Molecular Pathogenesis to Target Therapies

by Jiahua Liu, Runzi Zheng, Yanghuan Zhang, Shuting Jia, Yonghan He and Jing Liu

Cancers 2023, 15(9), 2640; https://doi.org/10.3390/cancers15092640 - 06 May 2023

Cited by 5 | Viewed by 2617

Abstract

Melanoma is a malignant skin tumor that originates from melanocytes. The pathogenesis of melanoma involves a complex interaction that occurs between environmental factors, ultraviolet (UV)-light damage, and genetic alterations. UV light is the primary driver of the skin aging process and development of [...] Read more.

Melanoma is a malignant skin tumor that originates from melanocytes. The pathogenesis of melanoma involves a complex interaction that occurs between environmental factors, ultraviolet (UV)-light damage, and genetic alterations. UV light is the primary driver of the skin aging process and development of melanoma, which can induce reactive oxygen species (ROS) production and the presence of DNA damage in the cells, and results in cell senescence. As cellular senescence plays an important role in the relationship that exists between the skin aging process and the development of melanoma, the present study provides insight into the literature concerning the topic at present and discusses the relationship between skin aging and melanoma, including the mechanisms of cellular senescence that drive melanoma progression, the microenvironment in relation to skin aging and melanoma factors, and the therapeutics concerning melanoma. This review focuses on defining the role of cellular senescence in the process of melanoma carcinogenesis and discusses the targeting of senescent cells through therapeutic approaches, highlighting the areas that require more extensive research in the field. Full article

(This article belongs to the Special Issue Latest Development in Melanoma Research)

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23 pages, 1725 KiB

Open AccessReview

Melanoma Tumour Vascularization and Tissue-Resident Endothelial Progenitor Cells

by Ghazaleh Hashemi, James Dight, Kiarash Khosrotehrani and Laura Sormani

Cancers 2022, 14(17), 4216; https://doi.org/10.3390/cancers14174216 - 30 Aug 2022

Cited by 4 | Viewed by 2665

Abstract

The aggressiveness of solid cancers, such as melanoma, relies on their metastatic potential. It has become evident that this key cause of mortality is largely conferred by the tumour-associated stromal cells, especially endothelial cells. In addition to their essential role in the formation [...] Read more.

The aggressiveness of solid cancers, such as melanoma, relies on their metastatic potential. It has become evident that this key cause of mortality is largely conferred by the tumour-associated stromal cells, especially endothelial cells. In addition to their essential role in the formation of the tumour vasculature, endothelial cells significantly contribute to the establishment of the tumour microenvironment, thus enabling the dissemination of cancer cells. Melanoma tumour vascularization occurs through diverse biological processes. Vasculogenesis is the formation of de novo blood vessels from endothelial progenitor cells (EPCs), and recent research has shown the role of EPCs in melanoma tumour vascularization. A more detailed understanding of the complex role of EPCs and how they contribute to the abnormal vessel structures in tumours is of importance. Moreover, anti-angiogenic drugs have a limited effect on melanoma tumour vascularization, and the role of these drugs on EPCs remains to be clarified. Overall, targeting cancer vasculature remains a challenge, and the role of anti-angiogenic drugs and combination therapies in melanoma, a focus of this review, is an area of extensive exploration. Full article

(This article belongs to the Special Issue Latest Development in Melanoma Research)

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22 pages, 1726 KiB

Open AccessReview

The Role of Extracellular Vesicles in Melanoma Progression

by Evelyn Lattmann and Mitchell P. Levesque

Cancers 2022, 14(13), 3086; https://doi.org/10.3390/cancers14133086 - 23 Jun 2022

Cited by 15 | Viewed by 3229

Abstract

Cutaneous melanoma arises from a malignant transformation of the melanocytes in the skin. It is the deadliest form of skin cancer owing to its potential to metastasize. While recent advances in immuno-oncology have been successful in melanoma treatment, not all the patients respond [...] Read more.

Cutaneous melanoma arises from a malignant transformation of the melanocytes in the skin. It is the deadliest form of skin cancer owing to its potential to metastasize. While recent advances in immuno-oncology have been successful in melanoma treatment, not all the patients respond to the treatment equally, thus individual pre-screening and personalized combination therapies are essential to stratify and monitor patients. Extracellular vesicles (EVs) have emerged as promising biomarker candidates to tackle these challenges. EVs are ~50–1000-nm-sized, lipid bilayer-enclosed spheres, which are secreted by almost all cell types, including cancer cells. Their cargo, such as nucleic acids, proteins, lipids, amino acids, and metabolites, can be transferred to target cells. Thanks to these properties, EVs can both provide a multiplexed molecular fingerprint of the cell of origin and thus serve as potential biomarkers, or reveal pathways important for cancer progression that can be targeted pharmaceutically. In this review we give a general overview of EVs and focus on their impact on melanoma progression. In particular, we shed light on the role of EVs in shaping the tumor–stroma interactions that facilitate metastasis and summarize the latest findings on molecular profiling of EV-derived miRNAs and proteins that can serve as potential biomarkers for melanoma progression. Full article

(This article belongs to the Special Issue Latest Development in Melanoma Research)

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19 pages, 981 KiB

Open AccessReview

Heterogeneity in Melanoma

by Mei Fong Ng, Jacinta L. Simmons and Glen M. Boyle

Cancers 2022, 14(12), 3030; https://doi.org/10.3390/cancers14123030 - 20 Jun 2022

Cited by 10 | Viewed by 2353

Abstract

There is growing evidence that tumour heterogeneity has an imperative role in cancer development, evolution and resistance to therapy. Continuing advancements in biomedical research enable tumour heterogeneity to be observed and studied more critically. As one of the most heterogeneous human cancers, melanoma [...] Read more.

There is growing evidence that tumour heterogeneity has an imperative role in cancer development, evolution and resistance to therapy. Continuing advancements in biomedical research enable tumour heterogeneity to be observed and studied more critically. As one of the most heterogeneous human cancers, melanoma displays a high level of biological complexity during disease progression. However, much is still unknown regarding melanoma tumour heterogeneity, as well as the role it plays in disease progression and treatment response. This review aims to provide a concise summary of the importance of tumour heterogeneity in melanoma. Full article

(This article belongs to the Special Issue Latest Development in Melanoma Research)

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24 pages, 2060 KiB

Open AccessEditor’s ChoiceReview

Immune Checkpoints in Cancers: From Signaling to the Clinic

by Céline Pisibon, Amira Ouertani, Corine Bertolotto, Robert Ballotti and Yann Cheli

Cancers 2021, 13(18), 4573; https://doi.org/10.3390/cancers13184573 - 12 Sep 2021

Cited by 32 | Viewed by 3481

Abstract

The immune system is known to help fight cancers. Ten years ago, the first immune checkpoint inhibitor targeting CTLA4 was approved by the FDA to treat patients with metastatic melanoma. Since then, immune checkpoint therapies have revolutionized the field of oncology and the [...] Read more.

The immune system is known to help fight cancers. Ten years ago, the first immune checkpoint inhibitor targeting CTLA4 was approved by the FDA to treat patients with metastatic melanoma. Since then, immune checkpoint therapies have revolutionized the field of oncology and the treatment of cancer patients. Numerous immune checkpoint inhibitors have been developed and tested, alone or in combination with other treatments, in melanoma and other cancers, with overall clear benefits to patient outcomes. However, many patients fail to respond or develop resistance to these treatments. It is therefore essential to decipher the mechanisms of action of immune checkpoints and to understand how immune cells are affected by signaling to be able to understand and overcome resistance. In this review, we discuss the signaling and effects of each immune checkpoint on different immune cells and their biological and clinical relevance. Restoring the functionality of T cells and their coordination with other immune cells is necessary to overcome resistance and help design new clinical immunotherapy strategies. In this respect, NK cells have recently been implicated in the resistance to anti-PD1 evoked by a protein secreted by melanoma, ITGBL1. The complexity of this network will have to be considered to improve the efficiency of future immunotherapies and may lead to the discovery of new immune checkpoints. Full article

(This article belongs to the Special Issue Latest Development in Melanoma Research)

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Other

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11 pages, 742 KiB

Open AccessSystematic Review

Burden and Risk Factors of Brain Metastases in Melanoma: A Systematic Literature Review

by Xiang-Lin Tan, Amy Le, Huilin Tang, Madeline Brown, Emilie Scherrer, Jiali Han, Ruixuan Jiang, Scott J. Diede and Irene M. Shui

Cancers 2022, 14(24), 6108; https://doi.org/10.3390/cancers14246108 - 12 Dec 2022

Cited by 2 | Viewed by 1295

Abstract

Melanoma can frequently metastasize to the brain with severe consequences. However, variation of melanoma brain metastases (MBM) development among populations is not well studied, and underlying mechanisms and risk factors for MBM development are not consistently documented. We conducted a systematic literature review [...] Read more.

Melanoma can frequently metastasize to the brain with severe consequences. However, variation of melanoma brain metastases (MBM) development among populations is not well studied, and underlying mechanisms and risk factors for MBM development are not consistently documented. We conducted a systematic literature review (SLR) including a total of 39 articles to evaluate the proportion of melanoma patients who are diagnosed with, or develop, brain metastases, and summarize the risk factors of MBM. The average proportion of MBM was calculated and weighted by the sample size of each study. Meta-analyses were conducted for the selected risk factors using a random-effects model. The proportion of MBM at diagnosis was 33% (975 with MBM out of 2948 patients) among patients with cutaneous melanoma (excluding acral) and 23% (651/2875) among patients with cutaneous mixed with other types of melanoma. The proportion at diagnosis was lower among populations with mucosal (9/96, 9%) or uveal (4/184, 2%) melanoma and among populations outside the United States and Europe. Meta-analysis demonstrated that male vs. female gender and left-sided tumors vs. right-sided were significantly associated with increased risk of melanoma brain metastases. These data may help clinicians to assess an individual patient’s risk of developing melanoma brain metastases. Full article

(This article belongs to the Special Issue Latest Development in Melanoma Research)

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