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Despite advancements in treating cutaneous melanoma, patients with acral and mucosal (A/M) melanomas still have limited therapeutic options and poor prognoses. We analyzed 156 melanomas (101 cutaneous, 28 acral, and 27 mucosal) using the Foundation One cancer-gene specific clinical testing platform and identified new, potentially targetable genomic alterations (GAs) in specific anatomic sites of A/M melanomas. Using novel pre-clinical models of A/M melanoma, we demonstrate that several GAs and corresponding oncogenic pathways associated with cutaneous melanomas are similarly targetable in A/M melanomas. Other alterations, including MYC and CRKL amplifications, were unique to A/M melanomas and susceptible to indirect targeting using the BRD4 inhibitor JQ1 or Src/ABL inhibitor dasatinib, respectively. We further identified new, actionable A/M-specific alterations, including an inactivating NF2 fusion in a mucosal melanoma responsive to dasatinib in vivo. Our study highlights new molecular differences between cutaneous and A/M melanomas, and across different anatomic sites within A/M, which may change clinical testing and treatment paradigms for these rare melanomas.
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INTRODUCTION: For patients with stage III melanoma with occult lymph node metastasis, the use of adjuvant therapy is increasing, and completion lymph node dissection (CLND) is decreasing. We sought to evaluate the use of modern adjuvant therapy and outcomes for patients with stage III melanoma who did not undergo CLND. METHODS: Patients with a positive SLNB from 2015 to 2020 who did not undergo CLND were evaluated retrospectively. Nodal recurrence, recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and melanoma-specific survival were evaluated. RESULTS: Among 90 patients, 56 (62%) received adjuvant therapy and 34 (38%) underwent observation alone. Patients who received adjuvant therapy were younger (mean age: 53 vs. 65, p < 0.001) and had higher overall stage (Stage IIIb/c 75% vs. 54%, p = 0.041). Disease recurred in 12 of 34 patients (35%) in the observation group and 11 of 56 patients (20%) in the adjuvant therapy group. The most common first site of recurrence was distant recurrence alone (5/34 patients) in the observation group and nodal recurrence alone (8/90 patients) in the adjuvant therapy group. Despite more adverse nodal features in the adjuvant therapy group, 24-month nodal recurrence rate and RFS were not significantly different between the adjuvant and observation cohorts (nodal recurrence rate: 26% vs. 20%, p = 0.68; RFS: 75% vs. 61%, p = 0.39). Among patients with stage IIIb/c disease, adjuvant therapy was associated with a significantly improved 24-month DMFS (86% vs. 59%, p = 0.04). CONCLUSIONS: In this early report, modern adjuvant therapy in patients who forego CLND is associated with longer DMFS among patients with stage IIIb/c disease.
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Melanoma , Linfonodo Sentinela , Neoplasias Cutâneas , Humanos , Excisão de Linfonodo , Melanoma/cirurgia , Pessoa de Meia-Idade , Estudos Retrospectivos , Biópsia de Linfonodo Sentinela , Neoplasias Cutâneas/cirurgiaRESUMO
BACKGROUND: Adrenal gland metastases (AGMs) are common in advanced-stage melanoma, occurring in up to 50% of patients. The introduction of immune checkpoint inhibitors (ICIs) has markedly altered the outcome of patients with melanoma. However, despite significant successes, anecdotal evidence has suggested that treatment responses in AGMs are significantly lower than in other metastatic sites. We sought to investigate whether having an AGM is associated with altered outcomes and whether ICI responses are dampened in the adrenal glands. PATIENTS AND METHODS: We retrospectively compared ICI responses and overall survival (OS) in 68 patients with melanoma who were diagnosed with an AGM and a control group of 100 patients without AGMs at a single institution. Response was determined using RECIST 1.1. OS was calculated from time of ICI initiation, anti-PD-1 initiation, initial melanoma diagnosis, and stage IV disease diagnosis. Tumor-infiltrating immune cells were characterized in 9 resected AGMs using immunohistochemical analysis. RESULTS: Response rates of AGMs were significantly lower compared with other metastatic sites in patients with AGMs (16% vs 22%) and compared with those without AGMs (55%). Patients with AGMs also had significantly lower median OS compared with those without AGMs (3.1 years vs not reached, respectively). We further observed that despite this, AGMs exhibited high levels of tumor-infiltrating immune cells. CONCLUSIONS: In this cohort of patients with melanoma, those diagnosed with an AGM had lower ICI response rates and OS. These results suggest that tissue-specific microenvironments of AGMs present unique challenges that may require novel, adrenal gland-directed therapies or surgical resection.
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Immune suppression is one of the 10 hallmarks of cancer. Interleukin-37 (IL-37), a member of the IL-1 family, inhibits both innate and adaptive immunity, and has been shown to modulate immune responses in various disease conditions. Yet, IL-37 has rarely been investigated in cancer patients, and its biological role in cancer remains to be elucidated. In this study, we investigated the gene expression of IL-37 in age- and sex-matched blood samples of healthy individuals and melanoma patients, and demonstrated upregulation of IL-37 messenger RNA (mRNA) in the blood samples of melanoma patients. By further analyzing immune cell subsets responsible for the upregulated IL-37 expression, we discovered that IL-37 mRNA was highly expressed in T cells and granulocytes, with the highest expression in regulatory T (Treg ) cells in healthy individuals, and that IL-37 mRNA was upregulated in lymphocytes (T, B, and natural killer cells) in melanoma patient blood. Among all cell subsets, Treg cells from melanoma patients exhibited the highest IL-37 gene expression levels. We provided evidence that melanoma-conditioned media induces IL-37 mRNA and protein expression in multiple lymphocyte populations, particularly in Treg cells. We further confirmed that the IL-1-mediated secretome from human melanoma cells, specifically transforming growth factor-ß, induces IL-37 mRNA expression in human Treg cells. Our results suggest a potential immunosuppressive role for IL-1 and IL-37 in melanoma tumorigenesis. Highly elevated IL-37 in specific lymphocyte populations could serve as a biomarker for tumor-induced immunosuppression.
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Interleucina-1/metabolismo , Melanoma/metabolismo , Linfócitos T Reguladores/metabolismo , Biomarcadores Tumorais/metabolismo , Células Cultivadas , Feminino , Humanos , Masculino , RNA Mensageiro/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Regulação para Cima/fisiologiaRESUMO
OBJECTIVE: To develop a nomogram to estimate the probability of positive sentinel lymph node (+SLN) for patients with thin melanoma and to characterize its potential impact on sentinel lymph node biopsy (SLNB) rates. METHODS: Patients diagnosed with thin (0.5-1.0 mm) melanoma were identified from the National Cancer Database 2012 to 2015. A multivariable logistic regression model was used to examine factors associated with +SLN, and a nomogram to predict +SLN was constructed. Nomogram performance was evaluated and diagnostic test statistics were calculated. RESULTS: Of the 21 971 patients included 10 108 (46.0%) underwent SLNB, with a 4.0% +SLN rate. On multivariable analysis, age, Breslow thickness, lymphovascular invasion, ulceration, and Clark level were significantly associated with SLN status. The area under the receiver operating curve was 0.67 (95% confidence interval, 0.65-0.70). While 15 249 (69.4%) patients had either T1b tumors or T1a tumors with at least one adverse feature, only 2846 (13.0%) had a nomogram predicted probability of a +SLN ≥5%. Using this cut-off, the indication for a SLNB in these patients would be reduced by 81.3% as compared to the American Joint Committee on Cancer 8th edition staging criteria. CONCLUSIONS: The risk predictions obtained from the nomogram allow for more accurate selection of patients who could benefit from SLNB.
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Tomada de Decisões , Melanoma/patologia , Nomogramas , Medição de Risco/métodos , Linfonodo Sentinela/patologia , Neoplasias Cutâneas/patologia , Idoso , Bases de Dados Factuais , Feminino , Seguimentos , Humanos , Masculino , Melanoma/cirurgia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Linfonodo Sentinela/cirurgia , Biópsia de Linfonodo Sentinela , Neoplasias Cutâneas/cirurgiaRESUMO
BACKGROUND: Bilateral total knee arthroplasty (TKA) can be performed under a single-anesthetic (SA) or staged under a two-anesthetic (TA) technique. Recently, our institution began piloting a 2-surgeon team SA method for bilateral TKA. The purpose of this study was to compare the inpatient costs and clinical outcomes in the first 90 days after surgery between the team SA, single-surgeon SA, and single-surgeon TA approaches for bilateral TKA. METHODS: All primary TKAs performed from 2007 to 2017 by the 2 participating surgeons for each of the 3 groups of interest were identified: team SA (N = 42 patients; 84 knees), single-surgeon SA (N = 146 patients; 292 knees), single-surgeon TA (N = 242 patients; 484 knees). No patients were lost to follow-up. RESULTS: Median hospital cost (per TKA) for the episode(s) of care was as follows: team SA $20,962, single-surgeon SA $22,057, single-surgeon TA $31,145 (P < .001 overall; P = .0905 team SA vs single-surgeon SA). Rate of 90-day complications was 2.4% for team SA, 11.0% for single-surgeon SA, and 8.3% for single-surgeon TA (P = .2090). Discharge to skilled nursing facilities or rehab was as follows: team SA 31%, single-surgeon SA 53%, and single-surgeon TA after the second operation 34% (P < .001). CONCLUSION: This pilot project suggests that team SA bilateral TKA is a potentially cost-effective option with fewer complications compared to single-surgeon SA bilateral TKA. The less frequent disposition to skilled nursing facilities in the team SA group in conjunction with more efficient operating room utilization may further enhance the financial benefits.
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Artroplastia do Joelho/economia , Custos Hospitalares/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anestesia , Artroplastia do Joelho/métodos , Feminino , Humanos , Pacientes Internados , Masculino , Pessoa de Meia-Idade , Alta do Paciente , Projetos Piloto , Estudos Retrospectivos , Instituições de Cuidados Especializados de Enfermagem , Cirurgiões , Resultado do TratamentoRESUMO
Thoracic disc herniations are a relatively rare occurrence compared to disc herniations in the cervical or lumbar spine. Surgical management of these thoracic herniations can be technically difficult with a wide array of reported complications. In this study, we aim to describe the most common complications that can occur during or after surgical management of thoracic disc herniations. Furthermore, we describe tips and tricks for avoidance and, if necessary, management of surgical complications. Common complications addressed in this review include vertebral column instability, neurologic injury, cerebrospinal fluid leak/pleural fistula, thoracic viscera injury, wrong level surgery, incomplete disk resection, and intercostal neuralgia.
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Deslocamento do Disco Intervertebral , Vértebras Torácicas , Feminino , Humanos , Degeneração do Disco Intervertebral , Deslocamento do Disco Intervertebral/cirurgia , Vértebras Lombares/cirurgia , Região Lombossacral , Masculino , Pessoa de Meia-Idade , Vértebras Torácicas/cirurgiaRESUMO
A variety of analytical approaches have indicated that melanoma cell line UCLA-SO-M14 (M14) and breast carcinoma cell line MDA-MB-435 originate from a common donor. This indicates that at some point in the past, one of these cell lines became misidentified, meaning that it ceased to correspond to the reported donor and instead became falsely identified (through cross-contamination or other means) as a cell line from a different donor. Initial studies concluded that MDA-MB-435 was the misidentified cell line and M14 was the authentic cell line, although contradictory evidence has been published, resulting in further confusion. To address this question, we obtained early samples of the melanoma cell line (M14), a lymphoblastoid cell line from the same donor (ML14), and donor serum preserved at the originator's institution. M14 samples were cryopreserved in December 1975, before MDA-MB-435 cells were established in culture. Through a series of molecular characterizations, including short tandem repeat (STR) profiling and cytogenetic analysis, we demonstrated that later samples of M14 and MDA-MB-435 correspond to samples of M14 frozen in 1975, to the lymphoblastoid cell line ML14, and to the melanoma donor's STR profile, sex and blood type. This work demonstrates conclusively that M14 is the authentic cell line and MDA-MB-435 is misidentified. With clear provenance information and authentication testing of early samples, it is possible to resolve debates regarding the origins of problematic cell lines that are widely used in cancer research.
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Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Melanoma/patologia , Neoplasias da Mama/genética , DNA de Neoplasias/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Melanoma/genéticaRESUMO
BACKGROUND: Studies have demonstrated mixed results after humeral head replacement (HHR) for osteoarthritis at short- and medium-term follow-up intervals. The purpose of this study was to investigate the long-term outcomes (minimum 10 years) of HHR for the treatment of osteoarthritis. METHODS: This study included 44 shoulders in 42 patients who had been followed up for a minimum of 10 years, at a mean clinical follow-up of 17 years (range, 10-30 years). Of this group, 31 shoulders had radiographic follow-up beyond 5 years, at a mean of 11.1 years (range, 5-21 years). RESULTS: Patients experienced significant pain relief postoperatively that was maintained during the long-term follow-up (P < .01), with a subgroup of 11 patients reporting persistent moderate or severe pain. Patients maintained increases in shoulder abduction (<.01), external rotation (<.01) and modified Neer scores (<.01). Ten of 44 (22.7%) shoulders underwent revision surgery, predominantly for glenoid arthrosis (n = 9). In the 25 shoulders with 5 years of radiographic follow-up, Kaplan-Meier survival analysis demonstrated moderate to severe glenoid erosion in 50% at 5 years, which increased to 59% at 15 years and 88% at 20 years. CONCLUSIONS: HHR remains a successful operation for osteoarthritis at long-term follow-up. However, there is a substantive subgroup with continuing pain and a high rate of glenoid bone erosion after 10 years. Surgeons should carefully consider patients' needs and desires when judging the indications for HHR.
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Artroplastia do Ombro/métodos , Previsões , Cabeça do Úmero/cirurgia , Osteoartrite/cirurgia , Articulação do Ombro/cirurgia , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/diagnóstico , Radiografia , Reoperação , Articulação do Ombro/diagnóstico por imagem , Resultado do TratamentoRESUMO
To characterize the gene expression profile of regenerated melanocytes in the narrow band UVB (NBUVB)-treated vitiligo epidermis and their precursors in the hair follicle, we present here a strategy of RNA isolation from in situ melanocytes using human frozen skin. We developed a rapid immunostaining protocol using the NKI-beteb antibody, which labels differentiated and precursor melanocytes, followed by fluorescent laser capture microdissection. This technique enabled the direct isolation, from melanocyte and adjacent keratinocyte populations, of satisfactory quality RNA that was successfully amplified and analysed by qRT-PCR. The melanocyte-specific gene transcripts TYR, DCT, TYRP1 and PMEL were significantly upregulated in our NBUVB-treated melanocyte samples as compared with the keratinocyte samples, while keratinocyte-specific genes (KRT5 and KRT14) were expressed significantly higher in the keratinocyte samples as compared with the melanocyte samples. Furthermore, in both NBUVB-treated vitiligo skin and normal skin, when bulge melanocytes were compared with epidermal melanocytes, we found significantly lower expression of melanocyte-specific genes and significantly higher expression of three melanocytic stem cell genes (SOX9, WIF1 and SFRP1), while ALCAM and ALDH1A1 transcripts did not show significant variation. We found significantly higher expression of melanocyte-specific genes in the epidermis of NBUVB-treated vitiligo, as compared to the normal skin. When comparing bulge melanocyte samples from untreated vitiligo, NBUVB-treated vitiligo and normal skin, we did not find significant differences in the expression of melanocyte-specific genes or melanocytic stem cell genes. These techniques offer valuable opportunities to study melanocytes and their precursors in vitiligo and other pigmentation disorders.
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Microdissecção e Captura a Laser , Melanócitos/metabolismo , RNA/isolamento & purificação , Vitiligo/metabolismo , Estudos de Casos e Controles , Humanos , RNA/metabolismo , Vitiligo/radioterapiaRESUMO
The Castleman triad has been described in a select few patients presenting with a retroperitoneal mass, mucocutaneous pemphigus vulgaris, and bronchiolitis obliterans. Here, we describe the Castleman triad in a 19-year-old male with unicentric hyaline vascular type Castleman disease (HV-CD). This patient presented with an array of positive antibodies, including anti-cyclic citrullinated peptide, anti-double-stranded DNA, and Sjogren's IgG. Interestingly, the patient's rheumatologic symptoms resolved after tumor resection, while his antibody profile remained relatively unchanged. HV-CD, with a triad presentation, was thought to be from a paraneoplastic syndrome secondary to an underlying lymphoproliferative disorder. The findings presented here identify multiple autoantibodies potentially contributing to this patient's presentation with HV-CD.
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Immune checkpoint inhibitors (ICIs) are now the first-line treatment for patients with advanced melanoma. Despite promising clinical results, many patients fail to respond to these therapies. BH3 mimetics, a novel class of small molecule inhibitors that bind and inhibit anti-apoptotic members of the BCL2 family proteins such as BCL2 or MCL1, have been very successful in treating hematologic malignancies. However, there are limited studies on the immunomodulatory role of the BH3 mimetics. Several factors contribute to ICI resistance including myeloid-derived suppressor cells (MDSCs) that exert immunosuppressive effects through direct and indirect inhibition of antitumor immunity. Thus, targeting MDSCs to enhance antitumor immunity has the potential to enhance the efficacy of ICIs. In this study, we show that the MCL1 inhibitor S64315 reduces melanoma tumor growth in an immune cell-dependent manner in mice. Specifically, S64315 enhances antitumor immunity by reducing MDSC frequency and by promoting the activity of CD8+T cells. Additionally, human MDSCs are 10 times more sensitive to S64315 than cutaneous melanoma lines. Further, we found that a higher expression of MCL1 is associated with poor survival for patients treated with anti-PD-1. Finally, combining S64315 and anti-PD-1 significantly slowed tumor growth compared to either agent alone. Together, this proof-of-concept study demonstrates the potential of combining an MCL1 inhibitor with anti-PD-1 in the treatment of melanoma. It justifies the further development of next generation MCL1 inhibitors to improve efficacy of ICIs in treating malignant melanoma.
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Antineoplásicos , Melanoma , Células Supressoras Mieloides , Neoplasias Cutâneas , Humanos , Animais , Camundongos , Inibidores de Checkpoint Imunológico/farmacologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Melanoma/tratamento farmacológico , Antineoplásicos/farmacologia , Linfócitos T CD8-Positivos/metabolismo , Células Supressoras Mieloides/metabolismoRESUMO
We have discovered that human vitiligo patients treated with narrow-band UVB (NBUVB) demonstrated localized resistance to repigmentation in skin sites characterized by distinct cellular and molecular pathways. Using immunostaining studies, discovery-stage RNA-Seq analysis, and confirmatory in situ hybridization, we analyzed paired biopsies collected from vitiligo lesions that did not repigment after 6 months of NBUVB treatment (non-responding) and compared them with repigmented (responding) lesions from the same patient. Non-responding lesions exhibited acanthotic epidermis, had low number of total, proliferative, and differentiated melanocyte (MC) populations, and increased number of senescent keratinocytes (KCs) and of cytotoxic CD8+ T cells as compared with responding lesions. The abnormal response in the non-responding lesions was driven by a dysregulated cAMP pathway and of upstream activator PDE4B, and of WNT/ß-catenin repigmentation pathway. Vitiligo-responding lesions expressed high levels of WNT10B ligand, a molecule that may prevent epidermal senescence induced by NBUVB, and that in cultured melanoblasts prevented the pro-melanogenic effect of α-MSH. Understanding the pathways that govern lack of NBUVB-induced vitiligo repigmentation has a great promise in guiding the development of new therapeutic strategies for vitiligo.
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Epiderme , Melanócitos , Pigmentação da Pele , Vitiligo , Vitiligo/patologia , Vitiligo/radioterapia , Vitiligo/metabolismo , Humanos , Epiderme/patologia , Epiderme/metabolismo , Epiderme/efeitos da radiação , Pigmentação da Pele/efeitos da radiação , Melanócitos/patologia , Melanócitos/metabolismo , Melanócitos/efeitos da radiação , Terapia Ultravioleta/métodos , Queratinócitos/metabolismo , Queratinócitos/patologia , Queratinócitos/efeitos da radiação , Raios Ultravioleta , Feminino , Masculino , Via de Sinalização Wnt , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genéticaRESUMO
A better understanding of human melanocyte (MC) and MC stem cell biology is essential for treating MC-related diseases. This study employed an inherited pigmentation disorder carrying the SASH1S519N variant in a Hispanic family to investigate SASH1 function in the MC lineage and the underlying mechanism for this disorder. We used a multidisciplinary approach, including clinical examinations, human cell assays, yeast 2-hybrid screening, and biochemical techniques. Results linked early hair graying to the SASH1S519N variant, a previously unrecognized clinical phenotype in hyperpigmentation disorders. In vitro, we identified SASH1 as a regulator in MC stem cell maintenance and discovered that TNKS2 is crucial for SASH1's role. In addition, the S519N variant is located in one of multiple tankyrase-binding motifs and alters the binding kinetics and affinity of the interaction. In summary, this disorder links both gain and loss of pigmentation in the same individual, hinting to accelerated aging in human MC stem cells. The findings offer insights into the roles of SASH1 and TNKS2 in MC stem cell maintenance and the molecular mechanisms of pigmentation disorders. We propose that a comprehensive clinical evaluation of patients with MC-related disorders should include an assessment and history of hair pigmentation loss.
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Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Histiocitose Sinusal/diagnóstico , Histiocitose Sinusal/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Histiocitose Sinusal/metabolismo , Humanos , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Although the concept of cancer stem cells (CSCs) is well-accepted for many tumors, the existence of such cells in human melanoma has been the subject of debate. In this study, we demonstrate the existence of human melanoma cells that fulfill the criteria for CSCs (self-renewal and differentiation) by serially xenotransplanting cells into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. These cells possess high aldehyde dehydrogenase (ALDH) activity with ALDH1A1 and ALDH1A3 being the predominant ALDH isozymes. ALDH-positive melanoma cells are more tumorigenic than ALDH-negative cells in both NOD/SCID mice and NSG mice. Biological analyses of the ALDH-positive melanoma cells reveal the ALDH isozymes to be key molecules regulating the function of these cells. Silencing ALDH1A by siRNA or shRNA leads to cell cycle arrest, apoptosis, decreased cell viability in vitro, and reduced tumorigenesis in vivo. ALDH-positive melanoma cells are more resistant to chemotherapeutic agents and silencing ALDH1A by siRNA sensitizes melanoma cells to drug-induced cell death. Furthermore, we, for the first time, examined the molecular signatures of ALDH-positive CSCs from patient-derived tumor specimens. The signatures of melanoma CSCs include retinoic acid (RA)-driven target genes with RA response elements and genes associated with stem cell function. These findings implicate that ALDH isozymes are not only biomarkers of CSCs but also attractive therapeutic targets for human melanoma. Further investigation of these isozymes and genes will enhance our understanding of the molecular mechanisms governing CSCs and reveal new molecular targets for therapeutic intervention of cancer.
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Aldeído Desidrogenase/genética , Transformação Celular Neoplásica/genética , Melanoma/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias Cutâneas/genética , Aldeído Desidrogenase/antagonistas & inibidores , Família Aldeído Desidrogenase 1 , Aldeído Oxirredutases , Animais , Apoptose/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Melanoma/enzimologia , Melanoma/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Neoplasias , Células-Tronco Neoplásicas/enzimologia , Células-Tronco Neoplásicas/patologia , RNA Interferente Pequeno/genética , Elementos de Resposta , Retinal Desidrogenase , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/patologia , Temozolomida , Tretinoína/química , Tretinoína/farmacologiaRESUMO
Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is an immune checkpoint expressed in regulatory T (Treg) cells and activated T lymphocytes. Despite its potential as a treatment strategy for melanoma, CTLA-4 inhibition has limited efficacy. Using data from The Cancer Genome Atlas (TCGA) melanoma database and another dataset, we found that decreased CTLA4 mRNA was associated with a poorer prognosis in metastatic melanoma. To investigate further, we measured blood CTLA4 mRNA in 273 whole-blood samples from an Australian cohort and found that it was lower in metastatic melanoma than in healthy controls and associated with worse patient survival. We confirmed these findings using Cox proportional hazards model analysis and another cohort from the US. Fractionated blood analysis revealed that Treg cells were responsible for the downregulated CTLA4 in metastatic melanoma patients, which was confirmed by further analysis of published data showing downregulated CTLA-4 surface protein expression in Treg cells of metastatic melanoma compared to healthy donors. Mechanistically, we found that secretomes from human metastatic melanoma cells downregulate CTLA4 mRNA at the post-transcriptional level through miR-155 while upregulating FOXP3 expression in human Treg cells. Functionally, we demonstrated that CTLA4 expression inhibits the proliferation and suppressive function of human Treg cells. Finally, miR-155 was found to be upregulated in Treg cells from metastatic melanoma patients compared to healthy donors. Our study provides new insights into the underlying mechanisms of reduced CTLA4 expression observed in melanoma patients, demonstrating that post-transcriptional silencing of CTLA4 by miRNA-155 in Treg cells may play a critical role. Since CTLA-4 expression is downregulated in non-responder melanoma patients to anti-PD-1 immunotherapy, targeting miRNA-155 or other factors involved in regulating CTLA4 expression in Treg cells without affecting T cells could be a potential strategy to improve the efficacy of immunotherapy in melanoma. Further research is needed to understand the molecular mechanisms regulating CTLA4 expression in Treg cells and identify potential therapeutic targets for enhancing immune-based therapies.
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Melanoma , MicroRNAs , Segunda Neoplasia Primária , Humanos , Linfócitos T Reguladores , Antígeno CTLA-4 , Austrália , Prognóstico , MicroRNAs/metabolismoRESUMO
PURPOSE: A phase Ib/II clinical trial was conducted to evaluate the safety and efficacy of the combination of all-trans retinoic acid (ATRA) with pembrolizumab in patients with stage IV melanoma. PATIENTS AND METHODS: Anti-PD-1 naïve patients with stage IV melanoma were treated with pembrolizumab plus supplemental ATRA for three days surrounding each of the first four pembrolizumab infusions. The primary objective was to establish the MTD and recommended phase II dose (RP2D) of the combination. The secondary objectives were to describe the safety and toxicity of the combined treatment and to assess antitumor activity in terms of (i) the reduction in circulating myeloid-derived suppressor cell (MDSC) frequency and (ii) progression-free survival (PFS). RESULTS: Twenty-four patients were enrolled, 46% diagnosed with M1a and 29% with M1c stage disease at enrollment. All patients had an ECOG status ≤1, and 75% had received no prior therapies. The combination was well tolerated, with the most common ATRA-related adverse events being headache, fatigue, and nausea. The RP2D was established at 150 mg/m2 ATRA + 200 mg Q3W pembrolizumab. Median PFS was 20.3 months, and the overall response rate was 71%, with 50% of patients experiencing a complete response, and the 1-year overall survival was 80%. The combination effectively lowered the frequency of circulating MDSCs. CONCLUSIONS: With a favorable tolerability and high response rate, this combination is a promising frontline treatment strategy for advanced melanoma. Targeting MDSCs remains an attractive mechanism to enhance the efficacy of immunotherapies, and this combination merits further investigation. See related commentary by Olson and Luke, p. 1167.
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Melanoma , Células Supressoras Mieloides , Segunda Neoplasia Primária , Humanos , Células Supressoras Mieloides/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Melanoma/patologia , Tretinoína/efeitos adversos , Segunda Neoplasia Primária/tratamento farmacológicoRESUMO
Both aging spots (hyperpigmentation) and hair graying (lack of pigmentation) are associated with aging, two seemingly opposite pigmentation phenotypes. It is not clear how they are mechanistically connected. This study investigated the underlying mechanism in a family with an inherited pigmentation disorder. Clinical examinations identified accelerated hair graying and skin dyspigmentation (intermixed hyper and hypopigmentation) in the family members carrying the SASH1 S519N variant. Cell assays indicated that SASH1 promoted stem-like characteristics in human melanocytes, and SASH1 S519N was defective in this function. Multiple assays showed that SASH1 binds to tankyrase 2 (TNKS2), which is required for SASH1's promotion of stem-like function. Further, the SASH1 S519N variant is in a bona fide Tankyrase-binding motif, and SASH1 S519N alters the binding kinetics and affinity. Results here indicate SASH1 as a novel protein regulating the appropriate balance between melanocyte stem cells (McSC) and mature melanocytes (MCs), with S519N variant causing defects. We propose that dysfunction of McSC maintenance connects multiple aging-associated pigmentation phenotypes in the general population.