RESUMO
Drugs or cellular products that bind to gp100 are being investigated for treatment of cutaneous melanoma. The relative specificity of gp100 expression in melanocytes makes it an attractive target to harness for therapeutic intent. For example, Tebentafusp, a bispecific gp100 peptide-HLA-directed CD3 T cell engager, has generated significant enthusiasm in recent years due to its success in improving outcomes for uveal melanoma and is being studied in cutaneous melanoma. However, the extent and intensity of gp100 expression in advanced cutaneous melanoma has not been well studied. Here, we interrogated a large cohort of primary and metastatic melanomas for gp100 expression by immunohistochemistry. Expression in metastatic samples was globally higher and almost uniformly positive, however the degree of intensity was variable. Using a quantitative immunofluorescence method, we confirmed the variability in expression. As gp100-binding drugs are assessed in clinical trials, the association between activity of the drugs and the level of gp100 expression should be studied in order to potentially improve patient selection.
Assuntos
Melanoma , Neoplasias Cutâneas , Antígeno gp100 de Melanoma , Humanos , Melanoma/metabolismo , Melanoma/patologia , Antígeno gp100 de Melanoma/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Biomarcadores Tumorais/metabolismo , Melanoma Maligno Cutâneo , Imuno-HistoquímicaRESUMO
Microenvironment and transcriptional plasticity generate subpopulations within the tumor, and the use of BRAF inhibitors (BRAFis) contributes to the rise and selection of resistant clones. We stochastically isolated subpopulations (C1, C2, and C3) from naïve melanoma and found that the clones demonstrated distinct morphology, phenotypic, and functional profiles: C1 was less proliferative, more migratory and invasive, less sensitive to BRAFis, less dependent on OXPHOS, more sensitive to oxidative stress, and less pigmented; C2 was more proliferative, less migratory and invasive, more sensitive to BRAFis, less sensitive to oxidative stress, and more pigmented; and C3 was less proliferative, more migratory and invasive, less sensitive to BRAFis, more dependent on OXPHOS, more sensitive to oxidative stress, and more pigmented. Hydrogen peroxide plays a central role in oxidative stress and cell signaling, and PRDXs are one of its main consumers. The intrinsically resistant C1 and C3 clones had lower MITF, PGC-1α, and PRDX1 expression, while C1 had higher AXL and decreased pigmentation markers, linking PRDX1 to clonal heterogeneity and resistance. PRDX2 is depleted in acquired BRAFi-resistant cells and acts as a redox sensor. Our results illustrate that decreased pigmentation markers are related to therapy resistance and decreased antioxidant defense.
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Melanoma-associated leptomeningeal disease (M-LMD) occurs when circulating tumor cells (CTCs) enter into the cerebral spinal fluid (CSF) and colonize the meninges, the membrane layers that protect the brain and the spinal cord. Once established, the prognosis for M-LMD patients is dismal, with overall survival ranging from weeks to months. This is primarily due to a paucity in our understanding of the disease and, as a consequence, the availability of effective treatment options. Defining the underlying biology of M-LMD will significantly improve the ability to adapt available therapies for M-LMD treatment or design novel inhibitors for this universally fatal disease. A major barrier, however, lies in obtaining sufficient quantities of CTCs from the patient-derived CSF (CSF-CTCs) to conduct preclinical experiments, such as molecular characterization, functional analysis, and in vivo efficacy studies. Culturing CSF-CTCs ex vivo has also proven to be challenging. To address this, a novel protocol for the culture of patient-derived M-LMD CSF-CTCs ex vivo and in vivo is developed. The incorporation of conditioned media produced by human meningeal cells (HMCs) is found to be critical to the procedure. Cytokine array analysis reveals that factors produced by HMCs, such as insulin-like growth factor-binding proteins (IGFBPs) and vascular endothelial growth factor-A (VEGF-A), are important in supporting CSF-CTC survival ex vivo. Here, the usefulness of the isolated patient-derived CSF-CTC lines is demonstrated in determining the efficacy of inhibitors that target the insulin-like growth factor (IGF) and mitogen-activated protein kinase (MAPK) signaling pathways. In addition, the ability to intrathecally inoculate these cells in vivo to establish murine models of M-LMD that can be employed for preclinical testing of approved or novel therapies is shown. These tools can help unravel the underlying biology driving CSF-CTC establishment in the meninges and identify novel therapies to reduce the morbidity and mortality associated with M-LMD.
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Melanoma , Células Neoplásicas Circulantes , Humanos , Animais , Camundongos , Fator A de Crescimento do Endotélio Vascular , Encéfalo , Membrana CelularRESUMO
An effective cancer therapy requires killing cancer cells and targeting the tumor microenvironment (TME). Searching for molecules critical for multiple cell types in the TME, we identified NR4A1 as one such molecule that can maintain the immune suppressive TME. Here, we establish NR4A1 as a valid target for cancer immunotherapy and describe a first-of-its-kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 degrades NR4A1 within hours in vitro and exhibits long-lasting NR4A1 degradation in tumors with an excellent safety profile. NR-V04 inhibits and frequently eradicates established tumors. At the mechanistic level, NR-V04 induces the tumor-infiltrating (TI) B cells and effector memory CD8+ T (Tem) cells and reduces monocytic myeloid-derived suppressor cells (m-MDSC), all of which are known to be clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anticancer immune responses and offers a new avenue for treating various types of cancers such as melanoma.
Assuntos
Melanoma , Células Supressoras Mieloides , Humanos , Linhagem Celular Tumoral , Imunoterapia , Melanoma/patologia , Células Supressoras Mieloides/patologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Microambiente Tumoral , Quimera de Direcionamento de ProteóliseRESUMO
BACKGROUND: Resistance to BRAF and MEK inhibitors in BRAF V600-mutant melanoma is common. Multiple resistance mechanisms involve heat-shock protein 90 (HSP90) clients, and a phase 1 study of vemurafenib with the HSP90 inhibitor XL888 in patients with advanced melanoma showed activity equivalent to that of BRAF and MEK inhibitors. METHODS: Vemurafenib (960 mg orally twice daily) and cobimetinib (60 mg orally once daily for 21 of 28 days) with escalating dose cohorts of XL888 (30, 45, 60, or 90 mg orally twice weekly) was investigated in a phase 1 trial of advanced melanoma, with a modified Ji dose-escalation design. RESULTS: Twenty-five patients were enrolled. After two dose-limiting toxicities (DLTs) (rash and acute kidney injury) in the first cohort, lower doses of vemurafenib (720 mg) and cobimetinib (40 mg) were investigated with the same XL888 doses. Three DLTs (rash) were observed in 12 patients in the XL888 60-mg cohort, and this was determined as the maximum tolerated dose. Objective responses were observed in 19 patients (76%), and the median progression-free survival was 7.6 months, with a 5-year progression-free survival rate of 20%. The median overall survival was 41.7 months, with a 5-year overall survival rate of 37%. Single-cell RNA sequencing was performed on baseline and on-treatment biopsies; treatment was associated with increased immune cell influx (CD4-positive and CD8-positive T cells) and decreased melanoma cells. CONCLUSIONS: Combined vemurafenib and cobimetinib plus XL888 had significant toxicity, requiring frequent dose reductions, which may have contributed to the relatively low progression-free survival despite a high tumor response rate. Given overlapping toxicities, caution must be used when combining HSP90 inhibitors with BRAF and MEK inhibitors.
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Exantema , Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Vemurafenib , Proteínas Proto-Oncogênicas B-raf , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Exantema/induzido quimicamente , Exantema/tratamento farmacológico , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/uso terapêutico , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Mutação , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologiaRESUMO
Leptomeningeal disease (LMD) remains a major challenge in the clinical management of metastatic melanoma patients. Outcomes for patient remain poor, and patients with LMD continue to be excluded from almost all clinical trials. However, recent trials have demonstrated the feasibility of conducting prospective clinical trials in these patients. Further, new insights into the pathophysiology of LMD are identifying rational new therapeutic strategies. Here we present recent advances in the understanding of, and treatment options for, LMD from metastatic melanoma. We also annotate key areas of future focus to accelerate progress for this challenging but emerging field.
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Melanoma , Radiocirurgia , Humanos , Melanoma/secundário , Estudos Prospectivos , Radiocirurgia/efeitos adversosRESUMO
BACKGROUND: Although the anti-PD-1+LAG-3 and the anti-PD-1+CTLA-4 combinations are effective in advanced melanoma, it remains unclear whether their mechanisms of action overlap. METHODS: We used single cell (sc) RNA-seq, flow cytometry and IHC analysis of responding SM1, D4M-UV2 and B16 melanoma flank tumors and SM1 brain metastases to explore the mechanism of action of the anti-PD-1+LAG-3 and the anti-PD-1+CTLA-4 combination. CD4+ and CD8+ T cell depletion, tetramer binding assays and ELISPOT assays were used to demonstrate the unique role of CD4+T cell help in the antitumor effects of the anti-PD-1+LAG-3 combination. RESULTS: The anti-PD-1+CTLA-4 combination was associated with the infiltration of FOXP3+regulatory CD4+ cells (Tregs), fewer activated CD4+T cells and the accumulation of a subset of IFNγ secreting cytotoxic CD8+T cells, whereas the anti-PD-1+LAG-3 combination led to the accumulation of CD4+T helper cells that expressed CXCR4, TNFSF8, IL21R and a subset of CD8+T cells with reduced expression of cytotoxic markers. T cell depletion studies showed a requirement for CD4+T cells for the anti-PD-1+LAG-3 combination, but not the PD-1-CTLA-4 combination at both flank and brain tumor sites. In anti-PD-1+LAG-3 treated tumors, CD4+T cell depletion was associated with fewer activated (CD69+) CD8+T cells and impaired IFNγ release but, conversely, increased numbers of activated CD8+T cells and IFNγ release in anti-PD-1+CTLA-4 treated tumors. CONCLUSIONS: Together these studies suggest that these two clinically relevant immune checkpoint inhibitor (ICI) combinations have differential effects on CD4+T cell polarization, which in turn, impacted cytotoxic CD8+T cell function. Further insights into the mechanisms of action/resistance of these clinically-relevant ICI combinations will allow therapy to be further personalized.
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Neoplasias Encefálicas , Melanoma Experimental , Animais , Humanos , Linfócitos T CD4-Positivos , Antígeno CTLA-4 , Linfócitos T Citotóxicos/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismoRESUMO
Acral melanoma is a rare subtype of melanoma that arises on the non-hair bearing skin of the nail bed, palms of the hand and soles of the feet. It is unique among melanomas in not being linked to ultraviolet radiation (UVR) exposure from the sun, and, as such, its incidence is similar across populations who are of Asian, Hispanic, African and European origin. Although research into acral melanoma has lagged behind that of sun-exposed cutaneous melanoma, recent studies have begun to address the unique genetics and immune features of acral melanoma. In this review we will discuss the latest progress in understanding the biology of acral melanoma across different ethnic populations and will outline how these new discoveries can help to guide the therapeutic management of this rare tumor.
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Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/genética , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/tratamento farmacológico , Raios Ultravioleta/efeitos adversos , Genômica , Melanoma Maligno CutâneoRESUMO
Melanomas can adopt multiple transcriptional states. Little is known about the epigenetic drivers of these cell states, limiting our ability to regulate melanoma heterogeneity. Here, we identify stress-induced HDAC8 activity as driving melanoma brain metastasis development. Exposure of melanocytes and melanoma cells to multiple stresses increases HDAC8 activation leading to a neural crest-stem cell transcriptional state and an amoeboid, invasive phenotype that increases seeding to the brain. Using ATAC-Seq and ChIP-Seq we show that increased HDAC8 activity alters chromatin structure by increasing H3K27ac and enhancing accessibility at c-Jun binding sites. Functionally, HDAC8 deacetylates the histone acetyltransferase EP300, causing its enzymatic inactivation. This, in turn, increases binding of EP300 to Jun-transcriptional sites and decreases binding to MITF-transcriptional sites. Inhibition of EP300 increases melanoma cell invasion, resistance to stress and increases melanoma brain metastasis development. HDAC8 is identified as a mediator of transcriptional co-factor inactivation and chromatin accessibility that drives brain metastasis.
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Neoplasias Encefálicas , Proteína p300 Associada a E1A , Histona Desacetilases , Melanoma , Humanos , Neoplasias Encefálicas/secundário , Cromatina/metabolismo , Proteína p300 Associada a E1A/genética , Proteína p300 Associada a E1A/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Melanócitos/metabolismo , Melanoma/patologia , Proteínas Repressoras/metabolismo , Fatores de Transcrição/metabolismoRESUMO
Despite the successes of immunotherapy, melanoma remains one of the deadliest cancers, therefore, the need for innovation remains high. We previously reported anti-melanoma compounds that work by downregulating spliceosomal proteins hnRNPH1 and H2. In a separate study, we reported that these compounds were non-toxic to Balb/C mice at 50 mg/kg suggesting their utility in in vivo studies. In the present study, we aimed to assess the efficacy of these compounds by testing them in A375 cell-line xenograft in nude athymic mice. Animals were randomized into four groups (n = 12/group): 10 mg/kg vemurafenib, and 25 mg/kg 2155-14 and 2155-18 thrice a week for 15 days along with a control group. The results revealed that both 2155-14 and 2155-18 significantly decreased the growth of A375 tumors, which was comparable to vemurafenib. These results were confirmed by tumor volume, weight, and histopathological examination. In conclusion, these results demonstrate the therapeutic potential of targeting spliceosomal proteins hnRNPH1 and H2.
Assuntos
Melanoma , Camundongos , Animais , Humanos , Vemurafenib/farmacologia , Vemurafenib/uso terapêutico , Camundongos Nus , Xenoenxertos , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Melanoma/patologia , Proliferação de CélulasRESUMO
BACKGROUND: Combination BRAF and MEK inhibitor therapy is an active regimen in patients who have BRAF V600E-mutated tumors; however, the clinical efficacy of this therapy is limited by resistance. Preclinically, the addition of heat shock protein 90 (HSP90) inhibition improves the efficacy of BRAF inhibitor therapy in both BRAF inhibitor-sensitive and BRAF inhibitor-resistant mutant cell lines. METHODS: Cancer Therapy Evaluation Program study 9557 (ClinicalTrials.gov identifier NCT02097225) is a phase 1 study that was designed to assess the safety and efficacy of the small-molecule HSP90 inhibitor, AT13387, in combination with dabrafenib and trametinib in BRAF V600E/K-mutant solid tumors. Correlative analyses evaluated the expression of HSP90 client proteins and chaperones. RESULTS: Twenty-two patients with metastatic, BRAF V600E-mutant solid tumors were enrolled using a 3 + 3 design at four dose levels, and 21 patients were evaluable for efficacy assessment. The most common tumor type was colorectal cancer (N = 12). Dose-limiting toxicities occurred in one patient at dose level 3 and in one patient at dose level 4; specifically, myelosuppression and fatigue, respectively. The maximum tolerated dose was oral dabafenib 150 mg twice daily, oral trametinib 2 mg once daily, and intravenous AT13387 260 mg/m2 on days 1, 8, and 15. The best response was a partial response in two patients and stable disease in eight patients, with an overall response rate of 9.5% (90% exact confidence interval [CI], 2%-27%), a disease control rate of 47.6% (90% CI, 29%-67%), and a median overall survival of 5.1 months (90% CI, 3.4-7.6 months). There were no consistent proteomic changes associated with response or resistance, although responders did have reductions in BRAF expression, and epidermal growth factor receptor downregulation using HSP90 inhibition was observed in one patient who had colorectal cancer. CONCLUSIONS: HSP90 inhibition combined with BRAF/MEK inhibition was safe and produced evidence of modest disease control in a heavily pretreated population. Additional translational work may identify tumor types and resistance mechanisms that are most sensitive to this approach.
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Neoplasias Colorretais , Melanoma , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Proteômica , Piridonas/uso terapêutico , Pirimidinonas , Oximas/efeitos adversos , Melanoma/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinases de Proteína Quinase Ativadas por Mitógeno , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Mutação , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosAssuntos
Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Proteínas de Membrana/genética , GTP Fosfo-Hidrolases/genéticaRESUMO
Despite the recent advances in melanoma therapy, the need for new targets and novel approaches to therapy is urgent. We previously reported melanoma actives that work via binding and downregulating spliceosomal proteins hnRNPH1 and H2. Given the lack of knowledge about the side effects of using spliceosomal binders in humans, an acute toxicity study was conducted to evaluate these compounds in mice. Male and female mice were treated with compounds 2155-14 and 2155-18 at 50 mg/kg/day via subcutaneous injections, and the clinical signs of distress were monitored for 21 days and compared with control mice. Additionally, the effect of the leads on blood chemistry, blood cell counts, and organs was evaluated. No significant changes were observed in the body weight, blood cell count, blood chemistry, or organs of the mice following the compound treatment. The results show that our compounds, 2155-14 and 2155-18, are not toxic for the study period of three weeks.
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Melanoma , Humanos , Camundongos , Masculino , Feminino , AnimaisRESUMO
Patients with metastatic melanoma who are overweight or obese have improved outcomes when treated with immunotherapies or targeted therapies. A recent study provides the first evidence that the host metabolic state influences the tumor metabolic phenotype, with implications for tumor progression and therapeutic response. See related article by Hahn et al., p. 154.
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Melanoma , Segunda Neoplasia Primária , Humanos , Melanoma/terapia , Melanoma/tratamento farmacológico , Obesidade/complicações , SobrepesoRESUMO
Although immune checkpoint inhibition (ICI) has revolutionized the treatment of advanced melanoma, reliable predictive biomarkers are still lacking. In this issue of Cancer Research, Antoranz and colleagues used RNA sequencing and multiplexed IHC to study the spatial immune landscape of pretreatment melanoma specimens from patients who either responded or did not respond to antiprogrammed death protein 1 (PD-1) therapy. The authors identified the spatial interaction between cytotoxic T cells and M1-like macrophages expressing PD-L1 at the tumor boundary as predictive of responses to immune checkpoint inhibition. These studies pave the way for the development of new spatial biomarkers to identify patients most likely to benefit from ICI therapy. See related article by Antoranz et al., p. 3275.
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Melanoma , Segunda Neoplasia Primária , Antígeno B7-H1 , Comunicação Celular , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Fatores Imunológicos , Imunoterapia , Melanoma/tratamento farmacológico , Melanoma/genética , Receptor de Morte Celular Programada 1RESUMO
Although substantial progress has been made in treating patients with advanced melanoma with targeted and immuno-therapies, de novo and acquired resistance is commonplace. After treatment failure, therapeutic options are very limited and novel strategies are urgently needed. Combination therapies are often more effective than single agents and are now widely used in clinical practice. Thus, there is a strong need for a comprehensive computational resource to define rational combination therapies. We developed a Shiny app, DRepMel to provide rational combination treatment predictions for melanoma patients from seventy-three thousand combinations based on a multi-omics drug repurposing computational approach using whole exome sequencing and RNA-seq data in bulk samples from two independent patient cohorts. DRepMel provides robust predictions as a resource and also identifies potential treatment effects on the tumor microenvironment (TME) using single-cell RNA-seq data from melanoma patients. Availability: DRepMel is accessible online.
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Melanoma , Microambiente Tumoral , Combinação de Medicamentos , Reposicionamento de Medicamentos , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , RNA-SeqRESUMO
Activation of unfolded protein responses (UPRs) in cancer cells undergoing endoplasmic reticulum (ER) stress promotes survival. However, how UPR in tumor cells impacts anti-tumor immune responses remains poorly described. Here, we investigate the role of the UPR mediator pancreatic ER kinase (PKR)-like ER kinase (PERK) in cancer cells in the modulation of anti-tumor immunity. Deletion of PERK in cancer cells or pharmacological inhibition of PERK in melanoma-bearing mice incites robust activation of anti-tumor T cell immunity and attenuates tumor growth. PERK elimination in ER-stressed malignant cells triggers SEC61ß-induced paraptosis, thereby promoting immunogenic cell death (ICD) and systemic anti-tumor responses. ICD induction in PERK-ablated tumors stimulates type I interferon production in dendritic cells (DCs), which primes CCR2-dependent tumor trafficking of common-monocytic precursors and their intra-tumor commitment into monocytic-lineage inflammatory Ly6C+CD103+ DCs. These findings identify how tumor cell-derived PERK promotes immune evasion and highlight the potential of PERK-targeting therapies in cancer immunotherapy.
Assuntos
Interferon Tipo I , Neoplasias , Animais , Estresse do Retículo Endoplasmático , Interferon Tipo I/metabolismo , Camundongos , Transdução de Sinais , Linfócitos T/metabolismo , Resposta a Proteínas não Dobradas , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismoRESUMO
Uveal melanoma (UM) is the most common primary cancer of the eye and is associated with a high rate of metastatic death. UM can be stratified into two main classes based on metastatic risk, with class 1 UM having a low metastatic risk and class 2 UM having a high metastatic risk. Class 2 UM have a distinctive genomic, transcriptomic, histopathologic, and clinical phenotype characterized by biallelic inactivation of the BAP1 tumor-suppressor gene, an immune-suppressive microenvironment enriched for M2-polarized macrophages, and poor response to checkpoint-inhibitor immunotherapy. To identify potential mechanistic links between BAP1 loss and immune suppression in class 2 UM, we performed an integrated analysis of UM samples, as well as genetically engineered UM cell lines and uveal melanocytes (UMC). Using RNA sequencing (RNA-seq), we found that the most highly upregulated gene associated with BAP1 loss across these datasets was PROS1, which encodes a ligand that triggers phosphorylation and activation of the immunosuppressive macrophage receptor MERTK. The inverse association between BAP1 and PROS1 in class 2 UM was confirmed by single-cell RNA-seq, which also revealed that MERTK was upregulated in CD163+ macrophages in class 2 UM. Using ChIP-seq, BAP1 knockdown in UM cells resulted in an accumulation of H3K27ac at the PROS1 locus, suggesting epigenetic regulation of PROS1 by BAP1. Phosphorylation of MERTK in RAW 264.7 monocyte-macrophage cells was increased upon coculture with BAP1-/- UMCs, and this phosphorylation was blocked by depletion of PROS1 in the UMCs. These findings were corroborated by multicolor immunohistochemistry, where class 2/BAP1-mutant UMs demonstrated increased PROS1 expression in tumor cells and increased MERTK phosphorylation in CD163+ macrophages compared with class 1/BAP1-wildtype UMs. Taken together, these findings provide a mechanistic link between BAP1 loss and the suppression of the tumor immune microenvironment in class 2 UMs, and they implicate the PROS1-MERTK pathway as a potential target for immunotherapy in UM.
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Brain metastases are the most common brain malignancy. This review discusses the studies presented at the third annual meeting of the Melanoma Research Foundation in the context of other recent reports on the biology and treatment of melanoma brain metastases (MBM). Although symptomatic MBM patients were historically excluded from immunotherapy trials, efforts from clinicians and patient advocates have resulted in more inclusive and even dedicated clinical trials for MBM patients. The results of checkpoint inhibitor trials were discussed in conversation with current standards of care for MBM patients, including steroids, radiotherapy, and targeted therapy. Advances in the basic scientific understanding of MBM, including the role of astrocytes and metabolic adaptations to the brain microenvironment, are exposing new vulnerabilities which could be exploited for therapeutic purposes. Technical advances including single-cell omics and multiplex imaging are expanding our understanding of the MBM ecosystem and its response to therapy. This unprecedented level of spatial and temporal resolution is expected to dramatically advance the field in the coming years and render novel treatment approaches that might improve MBM patient outcomes.