Outcome Of Melanoma Patients Research Articles

The Role of Digital Dermoscopy and Follow-Up in the Detection of Amelanotic/Hypomelanotic Melanoma in a Group of High-Risk Patients-Is It Useful?

The prognosis, outcome, and overall survival of melanoma patients improve with early diagnosis which has been facilitated in the past few decades with the introduction of dermoscopy. Further advancements in dermoscopic research, coupled with skilled, educated dermatologists in dermoscopy, have contributed to timely diagnoses. However, detecting amelanotic and hypomelanotic melanoma remains a challenge even to the most skilled experts because these melanomas can mimic inflammatory diseases, numerous benign lesions, and non-melanoma skin cancers. The list of the possible differential diagnoses can be long. Melanoma prediction without the pigment relies only on vascular criteria, and all classic dermoscopic algorithms have failed to fulfill our expectations. In fact, the diagnosis of amelanotic and hypomelanotic melanomas is very challenging, which is why every tool in detecting these lesions is of significance. This review aims to explore the current knowledge and the literature on the possibility of detecting amelanotic/hypomelanotic melanomas using sequential monitoring with digital dermoscopy and total body skin photography.

Immune Checkpoint Inhibitor Therapy for Metastatic Melanoma: What Should We Focus on to Improve the Clinical Outcomes?

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enhancing anti-tumour immune responses, demonstrating significant efficacy in various malignancies, including melanoma. However, over 50% of patients experience limited or no response to ICI therapy. Resistance to ICIs is influenced by a complex interplay of tumour intrinsic and extrinsic factors. This review summarizes current ICIs for melanoma and the factors involved in resistance to the treatment. We also discuss emerging evidence that the microbiota can impact ICI treatment outcomes by modulating tumour biology and anti-tumour immune function. Furthermore, microbiota profiles may offer a non-invasive method for predicting ICI response. Therefore, future research into microbiota manipulation could provide cost-effective strategies to enhance ICI efficacy and improve outcomes for melanoma patients.

Efficacy of anti PD-1 therapy in children and adolescent melanoma patients (MELCAYA study)

BackgroundData on the efficacy and safety of anti PD-1 antibodies in children and adolescents (CA) with melanoma are lacking. The aim of this study was to determine outcomes of CA melanoma patients receiving anti PD-1 antibodies. MethodsMelanoma patients ≤18 years treated with anti PD-1 were retrospectively retrieved from 15 academic centers. Information on histopathological diagnosis, surgical treatment, systemic therapy, objective response rate (ORR), safety profile was collected. Progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier method. ResultsBetween April 2016 and March 2024, 99 patients treated with systemic therapy were retrieved, 81 treated with anti PD-1 therapy. Median age was 14 years (range 2–18 years), 37 pts were ≤12 yrs. Overall, 38 CA patients received anti PD-1 in adjuvant setting, and the 3-year PFS and OS were 70.6 % and 81.1 %, respectively. Two patients received anti-PD-1 based neoadjuvant treatment, both had a pathologic complete response and remain disease free. Fifty-six received a systemic therapy for advanced disease and among them, 43 received anti PD-1-based therapy for advanced disease in 1st line, while 12 and 5 pts received a 2nd and 3rd line, respectively. Among patients receiving a 1st line therapy with anti PD-1 monotherapy the ORR was 25 %, and the 3-year OS was 34 %. Toxicities were consistent with previous studies in adult melanoma patients. ConclusionsOur study provides the first evidence of efficacy of anti PD-1 in CA melanoma patients and supports the use of anti PD-1 therapy in pts ≤18 years, included those <12 years.

The roles of genetic mutation and cytokines/chemokines in immune response and their association with uveal melanoma patient outcome

The impact of tumor mutations and the interplay of cytokines and chemokines on the immune response and clinical outcomes in uveal melanoma (UM) warrants further exploration. In our study, we delved into the correlation between genetic alterations and survival rates in a cohort of 188 UM patients, utilizing data from cBioPortal. We assessed the composition of immune cell populations within 80 UM tumors by examining RNA sequence-based gene expression data from The Cancer Genome Atlas (TCGA). Furthermore, we scrutinized the relationship between genetic mutations and the expression of cytokines and chemokines, as well as their influence on various immune cell subsets. Our investigation revealed a significant association between the presence of mutated GNAQ or SF3B1 genes and improved progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS) when compared to patients with non-mutated counterparts. In contrast, the presence of immune response gene mutations was associated with a detrimental effect on PFS, DSS, and OS. We also observed that the expression levels of cytokines and chemokines were positively linked to the infiltration of immune killer cells and inversely related to the populations of B cells and dendritic cells. Elevated expression levels of PDCD1, TNF, IL6, CXCL9, and CXCL10 were found to be correlated with reduced OS. Intriguingly, an increase in CD8+ T cell populations was associated with a poorer OS, a finding that warrants further investigation. These findings underscore the potential utility of cytokines/chemokines expression levels, immune cell subsets, and mutation status as critical biomarkers for the selection of patients who are most likely to benefit from immunotherapeutic interventions. Our research provides valuable insights that could guide the development of more targeted and effective treatment strategies for UM patients.

53664 Melanoma patient outcomes in a tertiary referral center compared with a VA medical center with shared providers

53664 Melanoma patient outcomes in a tertiary referral center compared with a VA medical center with shared providers

Non-coding RNAs in BRAF-mutant melanoma: targets, indicators, and therapeutic potential.

Melanoma, a highly aggressive skin cancer, is often driven by BRAF mutations, such as the V600E mutation, which promotes cancer growth through the MAPK pathway and contributes to treatment resistance. Understanding the role of non-coding RNAs (ncRNAs) in these processes is crucial for developing new therapeutic strategies. This review aims to elucidate the relationship between ncRNAs and BRAF mutations in melanoma, focusing on their regulatory roles and impact on treatment resistance. We comprehensively reviewed current literature to synthesize evidence on ncRNA-mediated regulation of BRAF-mutant melanoma and their influence on therapeutic responses. Key ncRNAs, including microRNAs and long ncRNAs, were identified as significant regulators of melanoma development and therapy resistance. MicroRNAs such as miR-15/16 and miR-200 families modulate critical pathways like Wnt signaling and melanogenesis. Long ncRNAs like ANRIL and SAMMSON play roles in cell growth, invasion, and drug susceptibility. Specific ncRNAs, such as BANCR and RMEL3, intersect with the MAPK pathway, highlighting their potential as therapeutic targets or biomarkers in BRAF-mutant melanoma. Additionally, ncRNAs involved in drug resistance, such as miR-579-3p and miR-1246, target processes like autophagy and immune checkpoint regulation. This review highlights the pivotal roles of ncRNAs in regulating BRAF-mutant melanoma and their contribution to drug resistance. These findings underscore the potential of ncRNAs as biomarkers and therapeutic targets, paving the way for innovative treatments to improve outcomes for melanoma patients.

Circulating interleukin-8 and osteopontin are promising biomarkers of clinical outcomes in advanced melanoma patients treated with targeted therapy

BackgroundCirculating cytokines can represent non-invasive biomarkers to improve prediction of clinical outcomes of cancer patients. Here, plasma levels of IL-8, CCL4, osteopontin, LIF and BDNF were determined at baseline (T0), after 2 months of therapy (T2) and, when feasible, at progression (TP), in 70 melanoma patients treated with BRAF and MEK inhibitors. The association of baseline cytokine levels with clinical response, progression-free survival (PFS) and overall survival (OS) was evaluated.MethodsCytokine concentrations were measured using the xMAP technology. Their ability to discriminate between responding (Rs) and non-responding (NRs) patients was assessed by Receiver Operating Characteristics analysis. PFS and OS were estimated with the Kaplan–Meier method. The Cox proportional hazard model was used in the univariate and multivariate analyses to estimate crude and adjusted hazard ratios with 95% confidence intervals.ResultsCCL4 and LIF were undetectable in the majority of samples. The median osteopontin concentration at T0 and T2 was significantly higher in NRs than in Rs. The median T0 and T2 values of IL-8 were also higher in NRs than in Rs, although the statistical significance was not reached. No differences were detected for BDNF. In 39 Rs with matched T0, T2, and TP samples, osteopontin and IL-8 significantly decreased from T0 to T2 and rose again at TP, while BDNF levels remained unchanged. In NRs, none of the cytokines showed a significant decrease at T2. Only osteopontin demonstrated a good ability to discriminate between Rs and NRs. A high IL-8 T0 level was associated with significantly shorter PFS and OS and higher risk of progression and mortality, and remained an independent negative prognostic factor for OS in multivariate analysis. An elevated osteopontin T0 concentration was also significantly associated with worse OS and increased risk of death. Patients with high IL-8 and high osteopontin showed the lowest PFS and OS, and in multivariate analysis this cytokine combination remained independently associated with a three- to six-fold increased risk of mortality.ConclusionCirculating IL-8 and osteopontin appear useful biomarkers to refine prognosis evaluation of patients undergoing targeted therapy, and deserve attention as potential targets to improve its clinical efficacy.

Overcoming Vemurafenib Resistance in Metastatic Melanoma: Targeting Integrins to Improve Treatment Efficacy.

Metastatic melanoma, a deadly form of skin cancer, often develops resistance to the BRAF inhibitor drug vemurafenib, highlighting the need for understanding the underlying mechanisms of resistance and exploring potential therapeutic strategies targeting integrins and TGF-β signalling. In this study, the role of integrins and TGF-β signalling in vemurafenib resistance in melanoma was investigated, and the potential of combining vemurafenib with cilengitide as a therapeutic strategy was investigated. In this study, it was found that the transcription of PAI1 and p21 was induced by acquired vemurafenib resistance, and ITGA5 levels were increased as a result of this resistance. The transcription of ITGA5 was mediated by the TGF-β pathway in the development of vemurafenib resistance. A synergistic effect on the proliferation of vemurafenib-resistant melanoma cells was observed with the combination therapy of vemurafenib and cilengitide. Additionally, this combination therapy significantly decreased invasion and colony formation in these resistant cells. In conclusion, it is suggested that targeting integrins and TGF-β signalling, specifically ITGA5, ITGB3, PAI1, and p21, may offer promising approaches to overcoming vemurafenib resistance, thereby improving outcomes for metastatic melanoma patients.

Comprehensive insights on genetic alterations and immunotherapy prognosis in Chinese melanoma patients

Immune checkpoint inhibitors (ICI) have emerged as a promising therapeutic option for melanoma, which demonstrating improved clinical outcomes in melanoma patients regardless of specific genetic mutations. However, the identification of reliable biomarkers for predicting immunotherapy response and prognosis remains a challenge. In this study, we performed genetic profiling of the melanoma patients with different subtypes and evaluated the efficacy of ICI treatment. A total of 221 melanoma patients were included in our cohort, consisting primarily of acral lentiginous melanoma (ALM), cutaneous malignant melanoma (CMM), and mucosal malignant melanoma (MMM). Genetic analysis revealed BRAF mutations was predominant in CMM and NRAS mutations was prevalent in ALM. Copy number variants (CNVs) and structural variants (SV) were also detected, with CCND1 and CDK4 being the most affected genes in CNV and BRAF, ALK and RAF1 being the druggable targets in SV. Furthermore, NRAS mutations were associated with a poor prognosis in ALM, while TERT mutations were linked to unfavorable outcomes in CMM after receiving PD-1 therapy. Additionally, ALK expression exhibited improved outcomes in both ALM and CMM subtypes. Our study provides a comprehensive genomic and pathological profiling of Chinese melanoma patients, shedding light on the molecular landscape of the disease. Furthermore, numbers of gene mutations and ALK expression were identified as prognostic indicators. These findings contribute to the understanding of melanoma genetics in the Chinese population and have implications for personalized treatment approaches.

Real-world use and outcomes of targeted therapy and immunotherapy for adjuvant treatment of BRAF -mutated melanoma patients in the United States.

Using a customized, harmonized US electronic health record database, real-world prescription patterns of first-line adjuvant immunotherapy and targeted therapy were retrospectively assessed for BRAF V600-mutated melanoma. Adults with BRAF V600 mutation-positive stage IIIA-D cutaneous melanoma who received first-line adjuvant immunotherapy (nivolumab or pembrolizumab) or targeted therapy (dabrafenib plus trametinib) between 1 January 2014 and 30 August 2020 in the NOBLE database were included. Patients were followed from first-line adjuvant therapy initiation for at least 6 months, until death, progression, follow-up loss, or data cutoff. Primary endpoints were proportion of patients receiving either therapy in first-line and second-line, treatment switching, treatment timing, and status at the end of first-line therapy. Secondary endpoints included discontinuation rates, recurrence-free survival (RFS), and overall survival (OS). Of 318 patients evaluated, 67.6% received nivolumab, 14.2% pembrolizumab, and 18.2% targeted therapy as first-line adjuvant therapy. Median treatment duration was longest for nivolumab (292 days) and shortest for targeted therapy (115 days). Reason for discontinuation was recorded for 195 of 274 patients who discontinued first-line therapy; most common reasons were treatment completion and treatment-related toxicity [87/158 (55.0%) and 29/158 (18.4%), respectively, in immunotherapy-treated patients; 9/37 (24.3%) and 21/37 (56.8%) in targeted therapy-treated patients]. Median RFS and OS for targeted therapy and nivolumab were not reached and were 34.6 and 38.1 months, respectively, for pembrolizumab. These results inform on prescription preferences and clinical outcomes for BRAF V600-mutated melanoma patients in the first-line adjuvant setting.

Outcomes of adjuvant immune checkpoint inhibitor therapy in melanoma: a retrospective study

ABSTRACT Background Adjuvant treatment of malignant melanoma has improved the outcomes for patients. However, real-world data on efficacy and safety are limited. We investigated outcomes of melanoma patients treated with adjuvant immune checkpoint inhibitors (ICI) in the Ghent University Hospital. Methods Patients with melanoma (stage III-IV), who received at least one cycle of ICI as adjuvant treatment between 2018 and 2021 were included in this retrospective cohort study. Primary outcomes were recurrence-free (RFS) and overall survival (OS). Other outcomes of interest were relapse patterns and safety. Results 59 patients were included, with a median follow-up of 36 months. Disease recurrence or death of any cause was observed in 25/59 (42.4%) of the patients. The median RFS was 56.0 months (95%CI 36.1–75.9 months). At 48 months, RFS and OS were 55.9% and 84%, respectively. 9/23 (39%) recurrences were locoregional and 14/23 (60.9%) patients developed distant metastasis as first recurrence, including 2 (3.4%) with brain metastasis. Median time to recurrence was 9 months (range 2–56 months). 35/59 (59.3%) completed one year of adjuvant treatment, 12/59 (20.3%) stopped because of recurrence and 10/59 (16.9% because of toxicity. Immune-related adverse events wereseen in 29/59 (49.4%) patients, 10/59 (16.9%) developed grade 3-4 toxicity. Conclusion This study confirms the real-world efficacy and safety of adjuvant ICI for melanoma, achieving RFS and OS comparableto the pivotal clinical trials. About 40% of patients develop arelapse, mainly during the adjuvant treatment. The outcomes ofpatients progressing during adjuvant ICI are poor, emphasizing the need of prospective and real-world studies on optimal management after progression on (neo)adjuvant treatment.

The Effect of Body Mass Index on Melanoma Biology, Immunotherapy Efficacy, and Clinical Outcomes: A Narrative Review.

Recent studies indicate that a higher body mass index (BMI) might correlate with improved responses to melanoma treatment, especially with immune checkpoint inhibitors (ICIs), despite the general association of obesity with an increased risk of cancer and higher mortality rates. This review examines the paradoxical relationship between BMI and clinical outcomes in melanoma patients by exploring molecular links, the efficacy of immunotherapy, and patient survival outcomes. Our comprehensive literature search across the PubMed and Embase databases revealed a consistent pattern: increased BMI is associated with a better prognosis in melanoma patients undergoing ICI treatment. This "obesity paradox" might be explained by the metabolic and immunological changes in obesity, which could enhance the effectiveness of immunotherapy in treating melanoma. The findings highlight the complexity of the interactions between obesity and melanoma, suggesting that adipose tissue may modulate the immune response and treatment sensitivity favorably. Our review highlights the need for personalized treatment strategies that consider the metabolic profiles of patients and calls for further research to validate BMI as a prognostic factor in clinical settings. This nuanced approach to the obesity paradox in melanoma could significantly impact treatment planning and patient management.

Risk score stratification of cutaneous melanomas based on whole slide images using deep learning.

e21573 Background: Predictive and prognostic biomarkers represent the cornerstone of clinical oncology. Improving the prognostication of melanoma is needed to select patients for effective adjuvant therapies. Taking into account that tumor tissue contains a large amount of clinically relevant hidden information that is not fully exploited, we applied a weakly-supervised deep-learning approach on H&amp;E-stained whole-slide image (WSI) to directly predict 5-year survival outcomes in melanoma patients. Methods: We designed a deep neural (DL) network that extracts features from no-padding patches of WSI (tiles of size 512x512 pixels) using a self-supervised learning framework as well as from the tumor region. These features are then fed along with survival information into the deep learning fusion network assigning a survival risk score to each WSI. The model was trained and validated on 195 cases of primary melanoma diagnosed between 2015 and 2017 originating from the IHP Group and the French RICMel melanoma database. Performance was evaluated using a cross-validation and cross-testing framework as well as on an external set of 238 cases from the TCGA database. Concordance index (c-index) was used as a metric to assess the performance of the proposed algorithm. Results: For the prediction of survival, the proposed pipeline yielded c-index of 0.76 and 0.66 for the IHP Group cohort and TCGA dataset respectively. Furthermore, the model is able to significantly discriminate between the 2 groups of patients, with a good and a poor prognosis in terms of overall survival (p-value &lt; 0.001 for IHP and p-value = 0.01 for TCGA). Also, the proposed score is statistically significant when added to a multivariate cox model incorporating the classic prognosis factors (p-value &lt; 0.005) and allows to reach a c-index of 0.81 over the discovery cohort. Conclusions: This infrequent weakly-supervised deep-learning approach to HE images analysis has the advantage of leaving the feature selection entirely to the deep network, and so discover new morphological biomarkers. By this way, it could have in the near future the potential to accelerate and improve the clinical decision-making process in the field of melanoma. Also, these findings will undoubtedly open room for substantial applications with economic and treatment delay fallouts.

Serum multiplex analysis of checkpoint proteins in association with immune-related adverse events in patients with melanoma receiving adjuvant anti-PD-1 therapy.

9588 Background: Immune checkpoint inhibitors have significantly improved melanoma (MEL) patient (PT) outcomes. Immune-related adverse events (irAEs) may cause significant morbidity, rarely including death. Soluble immune checkpoints have been identified as biomarkers of autoimmune activity and potential off-target pathology. Understanding their relationship to pathologic outcomes may assist in the identification of PTs at highest risk of irAEs. Methods: PTs with resectable stage IIB-IV MEL who received adjuvant anti-programmed-death-1 (PD-1) therapy were identified from the University of Pittsburgh’s MEL Center biospecimen repository (N=273). MILLIPLEX Human Immuno-Oncology Checkpoint Protein Panel 2 was used to study serum levels of immunomodulatory proteins. Mean pretreatment serum levels in PTs with and without irAEs were compared using a two-sample t-test after performing Box-Cox transformation for non-normally distributed data. Results: Sera from 43 PTs were analyzed. The cohort included 28 (65.1%) male, mean age at diagnosis (62), including MEL stage IIIA = 7 (16.3%), IIIB = 16(37.2%) and IIIC = 20(46.5%). The most common irAEs (n=24, 55.8%) were thyroiditis (n=9, 20.9%), dermatitis (n=8, 18.6%), and adrenal insufficiency (n=9, 21.0%). Multiple irAEs were observed amongst 22 (51.2%) PTs with ≥3 irAEs and 6 (13.9%) with 5 irAEs. Visceral irAEs included Hepatitis (n=3, 7.0%), pneumonitis (n=2, 4.7%), and colitis (n=5, 11.6%). Seven of 8 patients with visceral irAEs required corticosteroids. Siglec-7 (mean 23.4 vs 3.51 pg/mL, p=0.018) and siglec-9 (mean 77.0 vs 33.1 pg/mL, p=0.049) were significantly elevated in the PTs who developed any irAE. After stratifying for each individual irAE, PTs with thyroiditis had elevated Nectin-4 (mean 2785.5 vs 494.7 pg/mL, p&lt;0.001) and serum arginase (mean 2437.5 vs 1383.1 pg/mL, p= 0.046) was elevated in PTs who developed colitis. PTs with hepatitis demonstrated increased galectin-3 (mean 10103.9 vs 9915.3 pg/mL, p=0.045) and decreased levels of CD40L (mean 2869.2 vs 9496.9 pg/mL, p=0.033). In PTs with dermatitis B7-H3 (mean 2503.3 vs 732.4 pg/mL, p=0.009) and MHC class I polypeptide-related sequence B (mean 1598.0 vs 259.1 pg/mL, p=0.048) were elevated. Conclusions: We have demonstrated unique serum checkpoint protein profiles related to specific irAEs in melanoma patients receiving adjuvant anti-PD1. Further studies are warranted to confirm and validate the utility of these irAE predictors during adjuvant anti-PD-1.

Loss of p14 diminishes immunogenicity in melanoma via non-canonical Wnt signaling by reducing the peptide surface density.

Immunotherapy has achieved tremendous success in melanoma. However, only around 50% of advanced melanoma patients benefit from immunotherapy. Cyclin-dependent kinase inhibitor 2A (CDKN2A), encoding the two tumor-suppressor proteins p14ARF and p16INK4a, belongs to the most frequently inactivated gene loci in melanoma and leads to decreased Tcell infiltration. While the role of p16INK4a has been extensively investigated, knowledge about p14ARF in melanoma is scarce. In this study, we elucidate the impact of reduced p14ARF expression on melanoma immunogenicity. Knockdown of p14ARF in melanoma cell lines diminished their recognition and killing by melanoma differentiation antigen (MDA)-specific Tcells. Resistance was caused by a reduction of the peptide surface density of presented MDAs. Immunopeptidomic analyses revealed that antigen presentation via human leukocyte antigen class I (HLA-I) molecules was enhanced upon p14ARF downregulation in general, but absolute and relative expression of cognate peptides was decreased. However, this phenotype is associated with a favorable outcome for melanoma patients. Limiting Wnt5a signaling reverted this phenotype, suggesting an involvement of non-canonical Wnt signaling. Taken together, our data indicate a new mechanism limiting MDA-specific Tcell responses by decreasing both absolute and relative MDA-peptide presentation in melanoma.

The Fight Tumour Blindness Registry: Efficient capture of high-quality real-world data in uveal melanoma

ObjectifDécrire la création d'un outil de cueillette de données accessible en ligne servant à suivre la prise en charge du mélanome de l'uvée et les résultats des traitements. NatureDescription d'un registre clinique. ParticipantsPatients présentant un mélanome de l'uvée. MéthodesUn groupe d'oncologues oculaires a fait équipe avec des médecins d'autres spécialités pertinentes et des experts dans l’élaboration de registres pour mettre au point un ensemble minimal de données à recueillir afin de suivre l'issue clinique réelle du mélanome de l'uvée. Cet ensemble de données a servi à créer le registre Fight Tumour Blindness! (FTB!) chapeauté par les registres australiens Save Sight Registries. RésultatsLes données à recueillir sont les suivantes : caractéristiques démographiques des patients, antécédents médicaux, visite initiale, visite de suivi, traitement de la tumeur, détermination du stade et surveillance de la tumeur, examens anatomopathologiques et auto-questionnaires des patients. On y décrit les mécanismes intégrés afin d'assurer une cueillette complète et efficiente des données. ConclusionsLe registre FTB! peut servir à surveiller les résultats des traitements chez les patients qui présentent un mélanome de l'uvée. Il permet d’étalonner les résultats et de les comparer d'une clinique à l'autre et d'un pays à l'autre.

The Circadian Clock Component RORA Increases Immunosurveillance in Melanoma by Inhibiting PD-L1 Expression.

Circadian clock perturbation frequently occurs in cancer and facilitates tumor progression by regulating malignant growth and shaping the immune microenvironment. Emerging evidence has indicated that clock genes are disrupted in melanoma and linked to immune escape. Herein, we found that the expression of retinoic acid receptor-related orphan receptor-α (RORA) is downregulated in melanoma patients and that patients with higher RORA expression have a better prognosis after immunotherapy. Additionally, RORA was significantly positively correlated with T-cell infiltration and recruitment. Overexpression or activation of RORA stimulated cytotoxic T-cell-mediated antitumor responses. RORA bound to the CD274 promoter and formed an inhibitory complex with HDAC3 to suppress PD-L1 expression. In contrast, the DEAD-box helicase family member DDX3X competed with HDAC3 for binding to RORA, and DDX3X overexpression promoted RORA release from the suppressive complex and thereby increased PD-L1 expression to generate an inhibitory immune environment. The combination of a RORA agonist with an anti-CTLA4 antibody synergistically increased T-cell antitumor immunity in vivo. A score based on the combined expression of HDAC3, DDX3X, and RORA correlated with immunotherapy response in melanoma patients. Together, this study elucidates a mechanism of clock component-regulated antitumor immunity, which will help inform the use of immunotherapy and lead to improved outcomes for melanoma patients receiving combined therapeutic treatments. Significance: RORA forms a corepressor complex to inhibit PD-L1 expression and activate antitumor T-cell responses, indicating that RORA is a potential target and predictive biomarker to improve immunotherapy response in melanoma patients.

Effect of glucocorticoids for the management of immune-related adverse events on outcome in melanoma patients treated with immunotherapy—a retrospective and biomarker study

Immune-related adverse events (IRAEs) during therapy with immune checkpoint inhibitors (ICIs) are common, and their management sometimes requires glucocorticoids (GCs). Predictors for development of IRAEs and data about the impact of GCs on clinical outcome are missing. We evaluated the impact of GCs to treat IRAEs on clinical outcome, and plasmatic inflammatory proteins as predictors for IRAEs. Patients with melanoma (n= 98) treated with ICIs at Karolinska University Hospital were included. Clinical information and data regarding prescription of systemic GCs were collected. Baseline plasma samples (n= 57) were analyzed for expression of 92 inflammatory proteins. Forty-four patients developed at least one IRAE requiring systemic GCs and the most common was hypocortisolemia (n= 11). A median overall survival of 72.8 months for patients developing IRAEs requiring GCs, 17.7 months for those who did not, and 1.4 months for individuals receiving GCs at baseline was observed in Kaplan-Meier curves (P= 0.001). In immortal time bias adjusted analysis, patients receiving steroids to treat IRAE survived slightly longer, even though this time trend was not statistically significant. The median overall survival was 29 months for those treated with GCs within 60 days after ICIs start and was not reached for patients receiving GCs later. The number of ICI cycles was higher in subjects receiving GCs after 60 days (P= 0.0053). Hypocortisolemia occurred mainly in males (10/11) and correlated with favorable outcome. Male patients with hypocortisolemia had lower expression of interleukin 8, transforming growth factor-α, and fibroblast growth factor 5 and higher expression of Delta/Notch-like epidermal growth factor-related receptor. GCs may be used to treat IRAEs without major concern. GCs early during ICIs may, however, impact clinical outcome negatively. The prognostic value of hypocortisolemia and inflammation proteins as biomarkers should be further investigated.

Identification of Plasma Lipid Alterations Associated with Melanoma Metastasis.

The aim of this study was to apply a state-of-the-art quantitative lipidomic profiling platform to uncover lipid alterations predictive of melanoma progression. Our study included 151 melanoma patients; of these, 83 were without metastasis and 68 with metastases. Plasma samples were analyzed using a targeted Lipidyzer™ platform, covering 13 lipid classes and over 1100 lipid species. Following quality control filters, 802 lipid species were included in the subsequent analyses. Total plasma lipid contents were significantly reduced in patients with metastasis. Specifically, levels of two out of the thirteen lipid classes (free fatty acids (FFAs) and lactosylceramides (LCERs)) were significantly decreased in patients with metastasis. Three lipids (CE(12:0), FFA(24:1), and TAG47:2-FA16:1) were identified as more effective predictors of melanoma metastasis than the well-known markers LDH and S100B. Furthermore, the predictive value substantially improved upon combining the lipid markers. We observed an increase in the cumulative levels of five lysophosphatidylcholines (LPC(16:0); LPC(18:0); LPC(18:1); LPC(18:2); LPC(20:4)), each individually associated with an elevated risk of lymph node metastasis but not cutaneous or distant metastasis. Additionally, seventeen lipid molecules were linked to patient survival, four of which (CE(12:0), CE(14:0), CE(15:0), SM(14:0)) overlapped with the lipid panel predicting metastasis. This study represents the first comprehensive investigation of the plasma lipidome of melanoma patients to date. Our findings suggest that plasma lipid profiles may serve as important biomarkers for predicting clinical outcomes of melanoma patients, including the presence of metastasis, and may also serve as indicators of patient survival.

Survival and treatment outcomes in patients with leptomeningeal disease from metastatic melanoma.

Melanoma leptomeningeal disease (LMD) has a poor prognosis. However, the management of patients with advanced melanoma has evolved with time, including those with LMD. We reviewed a large cohort of melanoma LMD patients to assess factors associated with survival. Retrospective clinical data was collected on patients diagnosed with LMD at MD Anderson Cancer Center from 2015 to 2020. Overall survival (OS) was determined from LMD diagnosis to date of death or last follow-up. The Kaplan-Meier method and log-rank test were used to estimate OS and to assess univariate group differences, respectively. Multivariable associations of survival with variables of interest were determined using Cox proportional hazards regression models. A total of 172 patients were identified. The median age at LMD diagnosis was 53 (range 20-79) years, and all patients had radiographic evidence of LMD on magnetic resonance imaging of either brain or spine. In total 143 patients previously received systemic therapy (83%), with a median of 2 prior treatments (range 0-5). 81 patients (47%) had concurrent uncontrolled systemic disease and 80 patients (53%) had elevated serum LDH at the time of diagnosis. With a median follow-up of 4.0 months (range 0.1-65.3 months), median OS for all patients from LMD diagnosis was 4.9 months. Patients (n = 45) who received intrathecal therapy or systemic immunotherapy for LMD had a median OS of 8.0 months and 10.2 months, respectively. On multivariable analysis, decreased performance status, positive CSF cytology, elevated LDH, and whole brain radiation were associated with worse OS. Despite many advances in therapeutic options, the outcomes of melanoma patients with LMD remains poor. However, a subset of patients appears to derive benefit from LMD-directed treatment.