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BACKGROUND: Although vulvar Paget's Disease (VPD) is a rare skin cancer associated with an excellent prognosis, high recurrence rates are associated with impaired quality of life. OBJECTIVES: Our objective was to investigate the epidemiological and clinical features of VPD diagnosed in a French administrative area (Franche Comté). METHODS: This retrospective study investigated clinical, histologic, therapeutic and follow-up data of patients with VPD diagnosed between 1981 and 2021, including data from the Doubs cancer registry. RESULTS: Among the 21 patients included (19 intra-epithelial and 2 invasive VPD), the median time to diagnosis was 24 months [0-110 months], with a median age of 72 years [38-88 years]. An associated cancer was present in 6 patients (29 %). At 5 years of follow-up, the recurrence rate was 26 %, but then increased to 42 % after a median follow-up of 145 months [31-503 months]. Among the 14 patients first surgically treated, incomplete resection (positive margins) was observed in all patients (100 %), associated with a postoperative recurrence rate of 86 % which was much higher than the rate observed in patients first topically treated (20 %). Postoperative adjuvant therapy (surgical revision, laser, imiquimod) significantly increased the recurrence-free survival (p < 0.001). CONCLUSIONS: Postoperative recurrence of VPD is frequent, mainly after 5 years, proving the importance of prolonged follow-up. Recurrence-free survival was significantly higher after postoperative adjuvant treatment.
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Immune-mediated sinusitis is poorly described and may easily go undiagnosed. We conducted a retrospective, multicenter, national study focusing on symptomatic immune-mediated sinusitis in patients receiving immune checkpoint inhibitors (ICIs) for melanoma treatment. Twelve patients were included (50% women, median age 58 years). Overall, the paraclinical assessment, the inefficacy of antibiotic/antihistaminic treatment, the improvement of symptoms on immunosuppressants and/or after ICI discontinuation, and the presence of multiple concomitant immune-related adverse-events, suggested a noninfectious etiology. Recognizing this toxicity is imperative for limitation of diagnostic wandering and appropriate treatment. However, additional epidemiological studies are needed to assess its prevalence as a potential immune-related adverse-event, and its prognostic value in patients treated with ICIs.
Immunotherapy is a type of cancer treatment that enhances the immune system's natural ability to target cancer cells. This immune response can sometimes become overstimulated or misdirected, causing side effects, known as immune-related adverse-events (IrAEs). IrAEs involving the nasal sinuses are rarely reported and often overlooked by medical oncologists. Herein, we report a series of twelve patients presenting a symptomatic sinusitis, occurring during immunotherapy for advanced melanoma. Our study shows that sinusitis, is an often-overlooked IrAE, that can become invalidating for patients, and even impair immunotherapy continuation. Therefore, recognizing this toxicity is crucial for appropriate patient care.
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Inibidores de Checkpoint Imunológico , Melanoma , Sinusite , Humanos , Melanoma/tratamento farmacológico , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Feminino , Pessoa de Meia-Idade , Masculino , Sinusite/tratamento farmacológico , Estudos Retrospectivos , Idoso , Adulto , Metástase NeoplásicaRESUMO
BACKGROUND: Currently, treatment options for patients with advanced melanoma who experience failed immunotherapy or targeted therapy are lacking. Recent studies suggest the antitumor activity of combined pembrolizumab and lenvatinib in patients with advanced melanoma progressing on immunotherapy. Herein, we report the clinical outcomes of combined lenvatinib and a programmed cell death protein-1 inhibitor (PD-1) in this population. MATERIALS AND METHODS: This French multicenter real-world study was conducted between September 2020 and July 2023. The primary endpoint was the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumours (version 1.1). Secondary variables were treatment-related adverse events (TRAEs), progression-free survival (PFS), overall survival (OS), and duration of response (DOR). RESULTS: Of the 67 patients included (median age, 69 years; median follow-up, 5.0 months), 85% had stage IV-M1c or M1d disease. The overall ORR was 28.4% (95% CI, 18%-41%), including 3 complete (4.5%) and 16 partial (23.9%) responses. Median DOR was 3.1 (interquartile range, 1.3-4.3) months. Median PFS and OS were 3.1 (95% CI, 2.5-3.7) and 9.8 (95% CI, 5.6-13.9) months, respectively. Grades 3-5 TRAEs occurred in 16 (24%) patients; common TRAEs were fatigue (43.3%), nausea/vomiting (26.8%), diarrhea (20.9%), and hypertension (20.9%). No treatment-related deaths occurred. CONCLUSION: Our real-world study demonstrates an interesting response rate and acceptable safety profile in a population with poor prognostic factors. Our data support this treatment option for refractory melanoma, as it is not approved by the Food and Drug Administration or European Medicines Agency, and highlight the need for new strategies.
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Melanoma , Compostos de Fenilureia , Quinolinas , Humanos , Quinolinas/uso terapêutico , Quinolinas/efeitos adversos , Melanoma/tratamento farmacológico , Melanoma/patologia , Melanoma/mortalidade , Masculino , Feminino , Idoso , Estudos Retrospectivos , Pessoa de Meia-Idade , Compostos de Fenilureia/uso terapêutico , Compostos de Fenilureia/efeitos adversos , Idoso de 80 Anos ou mais , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/mortalidade , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , França , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/farmacologia , Anticorpos Monoclonais HumanizadosRESUMO
BACKGROUND: Basal cell carcinoma (BCC) is the most frequent malignancy reported in populations with fair skin. In most countries, BCCs are only partially or not at all recorded, and incidence data are lacking. OBJECTIVES: This study assessed the current incidence rates and trends in the only two French départements where BCCs have been recorded for several decades. METHODS: This regional population-based study thus used data from two French cancer registries (Doubs and Haut-Rhin) where first-time BCC diagnoses were recorded. The European age-standardized incidence rates (EASR) were calculated per 100 000 person-years (PY). The trends and the annual percentages of change were assessed using joinpoint analysis. RESULTS: In all, 48 989 patients were diagnosed with a first BCC in the study period. The median age at diagnosis was 69â years and the BCCs were mainly located on the head and neck (68.8%). In the Doubs area between 1980 and 2016, the EASR of BCC increased from 59.9 to 183.1 per 100 000 PY. The annual increase for men was 5.73% before 1999 and 1.49% thereafter, and among women 4.56% before 2001 and 1.31% thereafter. In the Haut-Rhin area, the EASR increased from 139.2 in 1991 to 182.8 per 100 000 PY in 2019. Among men, the EASR increased annually by 2.31% before 2000, and by 0.29% after 2000; among women, it increased by 0.95% over the entire period (1991-2019). In the most recent period and for these two départements, the age-specific incidence rates of BCC for men and women were close before the age of 60â years, except for the 40-49-year age group, where the rates were significantly higher among women. For patients aged 60â years and over, men had much higher rates of BCC. CONCLUSIONS: BCC incidence has increased since 1980 and is still rising, particularly among men and the elderly. A slowing was observed from 2000, which could be explained by a shift in the management of BCCs and by the possible efficacy of prevention actions. This study provides insight into the BCC burden in France and highlights the need to maintain effective prevention strategies, as incidence is still increasing.
Basal cell carcinoma (BCC) is the most common malignant tumour reported among people with fair skin. BCC is a type of skin cancer that usually develops following prolonged exposure to sunlight. BCC typically grows slowly and is unlikely to spread to other parts of the body. However, if not treated, it can cause damage to nearby tissues and structures. In many countries, cases of BCC are not accurately recorded by cancer monitoring systems, leading to a lack of data on their frequency. Using population-based data, we aimed to determine the frequency of BCC occurrence and the changes in occurrence rates over time in two regions of France where BCC cases have been recorded consistently for many years. We collected information from two French cancer registries, in Doubs and Haut-Rhin, focusing on patients' first diagnosis of BCC. We calculated the incidence rates of BCC and the trends over time. We found that BCCs were diagnosed at a mean age of 68â years and that they were mainly located in the head and neck area. In recent years, we estimated that around 180 new cases were diagnosed each year for every 100 000 people. In both regions, the BCC occurrence rates increased significantly over time, with a slowing since 2000. Overall, the incidence of BCC has been rising since 1980 and is still increasing, especially among men and in older age groups. Our research points to the importance of promoting effective prevention strategies to limit the increase in BCC incidence in France.
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Carcinoma Basocelular , Sistema de Registros , Neoplasias Cutâneas , Humanos , Carcinoma Basocelular/epidemiologia , Masculino , França/epidemiologia , Feminino , Neoplasias Cutâneas/epidemiologia , Incidência , Sistema de Registros/estatística & dados numéricos , Idoso , Pessoa de Meia-Idade , Distribuição por Sexo , Idoso de 80 Anos ou mais , Distribuição por Idade , Adulto , Adulto JovemRESUMO
Although generally well tolerated compared with chemotherapy, molecular targeted therapy used in metastatic melanoma may be associated with life-threatening toxicity. We report the case of a patient with metastatic melanoma treated by dabrafenib plus trametinib who developed intracranial hemorrhage. Physicians should be aware of this rare but life-threatening adverse event of B-rapidly accelerated fibrosarcoma (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors. However, they should be also careful about the bleeding origin, which can prove to be a new onset of melanoma metastasis or anticoagulation overdose, or even an uncontrolled arterial hypertension.
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Protocolos de Quimioterapia Combinada Antineoplásica , Hemorragias Intracranianas , Melanoma , Humanos , Masculino , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Imidazóis/uso terapêutico , Hemorragias Intracranianas/induzido quimicamente , Melanoma/tratamento farmacológico , Melanoma/complicações , Oximas/uso terapêutico , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologiaRESUMO
Data regarding elderly melanoma patients treated with anti-PD-1 or anti-CTLA-4 antibodies are in favor of tolerability outcomes that are similar to those of younger counterparts. However, there are very few studies focusing on elderly patients receiving nivolumab combined with ipilimumab (NIVO + IPI). Here, we ask what are the current prescribing patterns of NIVO + IPI in the very elderly population and analyze the tolerance profile. This French multicenter retrospective study was conducted on 60 melanoma patients aged 80 years and older treated with NIVO + IPI between January 2011 and June 2022. The mean age at first NIVO + IPI administration was 83.7 years (range: 79.3-93.3 years). Fifty-five patients (92%) were in good general condition and lived at home. Two dosing regimens were used: NIVO 1 mg/kg + IPI 3 mg/kg Q3W (NIVO1 + IPI3) in 27 patients (45%) and NIVO 3 mg/kg + IPI 1 mg/kg Q3W (NIVO3 + IPI1) in 33 patients (55%). NIVO + IPI was a first-line treatment in 39 patients (65%). The global prevalence of immune-related adverse events was 63% (38/60), with 27% (16/60) being of grade 3 or higher. Grade ≥ 3 adverse events were less frequent in patients treated with NIVO3 + IPI1 compared with those treated with NIVO1 + IPI3 (12% versus 44%, p = 0.04). In conclusion, the prescribing patterns of NIVO + IPI in very elderly patients are heterogeneous in terms of the dosing regimen and line of treatment. The safety profile of NIVO + IPI is reassuring; whether or not the low-dose regimen NIVO3 + IPI1 should be preferred over NIVO1 + IPI3 in patients aged 80 years or older remains an open question.
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BACKGROUND: The long-term effectiveness of immune checkpoint inhibitor (ICI) rechallenge for progressive or recurrent advanced melanoma following previous disease control induced by ICI has not been thoroughly described in the literature. PATIENTS AND METHODS: In this retrospective multicenter national real-life study, we enrolled patients who had been rechallenged with an ICI after achieving disease control with a first course of ICI, which was subsequently interrupted. The primary objective was to evaluate tumor response, while the secondary objectives included assessing the safety profile, identifying factors associated with tumor response, and evaluating survival outcomes. RESULTS: A total of 85 patients from 12 centers were included in the study. These patients had advanced (unresectable stage III or stage IV) melanoma that had been previously treated and controlled with a first course of ICI before undergoing rechallenge with ICI. The rechallenge treatments consisted of pembrolizumab (n = 44, 52%), nivolumab (n = 35, 41%), ipilimumab (n = 2, 2%), or ipilimumab plus nivolumab (n = 4, 5%). The best overall response rate was 54%. The best response was a complete response in 30 patients (35%), a partial response in 16 patients (19%), stable disease in 18 patients (21%) and progressive disease in 21 patients (25%). Twenty-eight adverse events (AEs) were reported in 23 patients (27%), including 18 grade 1-2 AEs in 14 patients (16%) and 10 grade 3-4 AEs in nine patients (11%). The median progression-free survival (PFS) was 21 months, and the median overall survival (OS) was not reached at the time of analysis. Patients who received another systemic treatment (chemotherapy, targeted therapy or clinical trial) between the two courses of ICI had a lower response to rechallenge (p = 0.035) and shorter PFS (p = 0.016). CONCLUSION: Rechallenging advanced melanoma patients with ICI after previous disease control induced by these inhibitors resulted in high response rates (54%) and disease control (75%). Therefore, ICI rechallenge should be considered as a relevant therapeutic option.
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BACKGROUND: With more than 15,000 new cases /year in France and 2,000 deaths, cutaneous melanoma represents approximately 4% of incidental cancers and 1.2% of cancer related deaths. In locally advanced (stage III) or resectable metastatic (stage IV) melanomas, medical adjuvant treatment is proposed and recent advances had shown the benefit of anti-PD1/PDL1 and anti-CTLA4 immunotherapy as well as anti-BRAF and anti-MEK targeted therapy in BRAF V600 mutated tumors. However, the recurence rate at one year is approximately 30% and justify extensive research of predictive biomarkers. If in metastatic disease, the follow-up of circulating tumor DNA (ctDNA) has been demonstrated, its interest in adjuvant setting remains to be precised, especially because of a lower detection rate. Further, the definition of a molecular response could prove useful to personalized treatment. METHODS: PERCIMEL is an open prospective multicentric study executed through collaboration of the Institut de Cancérologie de Lorraine (non-profit comprehensive cancer center) and 6 French university and community hospitals. A total of 165 patients with resected stage III and IV melanoma, eligible to adjuvant imunotherapy or anti-BRAF/MEK kinase inhibitors will be included. The primary endpoint is the presence of ctDNA, 2 to 3 weeks after surgery, defined as mutated ctDNA copy number calculated as the allelic fraction of a clonal mutation relative to total ctDNA. Secondary endpoints are recurrence-free survival, distant metastasis-free survival and specific survival. We will follow ctDNA along treatment, quantitatively through ctDNA mutated copy number variation, qualitatively through the presence of cfDNA and its clonal evolution. Relative and absolute variations of ctDNA during follow-up will be also analyzed. PERCIMEL study aims at provide scientific evidence that ctDNA quantitative and qualitative variations can be used to predict the recurrence of patients with melanoma treated with adjuvant immunotherapy or kinase inhibitors, thus defining the notion of molecular recurrence.
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Ácidos Nucleicos Livres , Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/genética , Melanoma/terapia , Melanoma/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Estudos Prospectivos , Seguimentos , Variações do Número de Cópias de DNA , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas B-raf/genética , Mutação , Melanoma Maligno CutâneoRESUMO
Merkel cell carcinoma (MCC) is an aggressive skin cancer for which Merkel cell polyomavirus integration and expression of viral oncogenes small T and Large T have been identified as major oncogenic determinants. Recently, a component of the PRC2 complex, the histone methyltransferase enhancer of zeste homolog 2 (EZH2) that induces H3K27 trimethylation as a repressive mark has been proposed as a potential therapeutic target in MCC. Because divergent results have been reported for the levels of EZH2 and trimethylation of lysine 27 on histone 3, we analyzed these factors in a large MCC cohort to identify the molecular determinants of EZH2 activity in MCC and to establish MCC cell lines' sensitivity to EZH2 inhibitors. Immunohistochemical expression of EZH2 was observed in 92% of MCC tumors (156 of 170), with higher expression levels in virus-positive than virus-negative tumors (P = 0.026). For the latter, we showed overexpression of EZHIP, a negative regulator of the PRC2 complex. In vitro, ectopic expression of the large T antigen in fibroblasts led to the induction of EZH2 expression, whereas the knockdown of T antigens in MCC cell lines resulted in decreased EZH2 expression. EZH2 inhibition led to selective cytotoxicity on virus-positive MCC cell lines. This study highlights the distinct mechanisms of EZH2 induction between virus-negative and -positive MCC.
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Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Neoplasias Cutâneas , Humanos , Carcinoma de Célula de Merkel/patologia , Histonas/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Neoplasias Cutâneas/patologia , Poliomavírus das Células de Merkel/genética , Antígenos Virais de Tumores/genética , Antígenos Virais de Tumores/metabolismoRESUMO
BACKGROUND: Our objective was to describe the clinical, histological characteristics, and disease outcome of a cohort of mycosis fungoides (MF) diagnosed during childhood including disease status at adulthood. METHODS: This is a retrospective multicentre survey of patients aged under 18 years at diagnosis with histologically confirmed MF. Patients' clinical and histological characteristics, treatments, and disease outcome (for patients followed for more than 12 months) were analysed. RESULTS: Forty-six patients were included (median age at diagnosis: 11 years; M:F sex ratio: 3:1) with 39 (85%) followed for at least 12 months. Thirty-nine patients (85%) had stage I MF. Hypopigmented patches were observed in 48% and folliculotropism in 43% patients. Immunophenotype of the skin infiltrate was predominantly CD8+ in 17% of patients. Initial management included a wait-and-see strategy in 6/39 (15%), skin-directed treatment in 27 (69%), and systemic treatment in 6 (15%) patients, respectively, with partial or complete clinical response (PR or CR) observed in 28 patients (72%). 14/39 patients (36%) relapsed after initial response. After a median follow-up period of 54 months, disease status at last news was PR or CR in 31/39 (79%), stable disease in 6 (15%), and progression in 2 (5%) patients. Histological transformation was observed in 3/39 (8%). Of the 15 patients followed until adulthood, 13 (87%) had persistent MF. DISCUSSION: This survey confirms the high frequency of hypopigmented and folliculotropic lesions and of CD8+ immunophenotype compared to adult MF patients. The long-term course is usually indolent but transformation may occur sometimes long after disease onset and the disease may persist during adulthood.
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Hipopigmentação , Micose Fungoide , Neoplasias Cutâneas , Adulto , Humanos , Criança , Adolescente , Idoso , Neoplasias Cutâneas/diagnóstico , Micose Fungoide/diagnóstico , Estudos Retrospectivos , Hipopigmentação/tratamento farmacológico , Hipopigmentação/patologia , Administração CutâneaRESUMO
Introduction: Adverse events (AEs) of immune checkpoint inhibitors (ICIs) are frequent and mainly due to an overactivity of the immune system leading to excessive inflammatory responses (immune-related AE) that can affect any organ of the body. Beside the most frequent AEs, there are rare AEs whose diagnosis and treatment can be challenging. We report here a singular case of capillary leak syndrome (CLS) associated with chylothorax occurring in a patient who has been treated with adjuvant nivolumab (anti-PD1) for resected AJCC stage IIB primary melanoma. Case presentation: A 43-year-old woman was diagnosed with a nodular stage IIB melanoma of her left thigh, according to the AJCC 8th edition (T3bN0M0). The woman was treated with adjuvant nivolumab. She stopped the treatment after 4 infusions due to thrombopenia. Three months later, she developed facial and leg edema and ascites due to capillary leak syndrome. The CLS was associated with chylothorax and elevated vascular endothelial growth factor. The patient was initially treated with several pleural puncturing and steroids. CLS and chylothorax progressively decreased with intravenous immunoglobulins and fat-free diet without recurrence of melanoma at one-year follow-up. Conclusion: CLS is a rare and potentially life-threatening AE of ICIs such as anti-PD1. This AE may be associated with chylothorax probably related to lymphatic permeability induced by anti-PD1.
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BACKGROUND: Despite the poor prognosis associated with melanoma brain metastases (BM), data concerning these patients and their inclusion in clinical trials remains scarce. We report here the efficacy results of a subgroup analysis in patients with BRAFV600-mutant melanoma and BM treated with BRAF and MEK inhibitors dabrafenib (D) and trametinib (T). PATIENTS AND METHODS: This phase IIIb single-arm, open-label, multicenter, French study included patients with unresectable stage IIIc or IV BRAFV600-mutant melanoma with or without BM. The present analysis focuses on patients with BM. Response rates were determined clinically and/or radiologically as per standard clinical practice. Progression-free survival (PFS) was estimated using the Kaplan Meier analysis and modelled with multivariate Cox regression model. Risk subgroups were identified using an exponential regression tree analysis. Significance was set at p < 0.05. RESULTS: Between March 2015 and November 2016, 856 patients were included and 275 (32%) patients had BM. Median PFS was 5.68 months (95% confidence interval [CI], 5.29-6.87). Significant independent factors associated with shorter PFS were ECOG ≥1, elevated serum lactate dehydrogenase (LDH), ≥3 metastatic sites, and non-naïve status. The binary-split classification and regression tree modelling identified baseline LDH and ECOG status as major prognostic factors. CONCLUSION: This is to date the largest, close to real-world, study in advanced BRAFV600-mutant melanoma patients with BM treated with D+T. ECOG >1, ≥3 metastatic sites and elevated LDH were associated with shorter PFS, a finding previously demonstrated only in patients without BM. Further studies are warranted to determine the optimal treatment sequence in this population.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Encefálicas , Melanoma , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Humanos , Imidazóis , Lactato Desidrogenases , Masculino , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Quinases de Proteína Quinase Ativadas por Mitógeno , Mutação , Oximas/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/uso terapêutico , PirimidinonasAssuntos
Carcinoma de Células Escamosas , Neoplasias Cutâneas , Xeroderma Pigmentoso , Humanos , Xeroderma Pigmentoso/complicações , Xeroderma Pigmentoso/tratamento farmacológico , Xeroderma Pigmentoso/genética , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Carcinoma de Células Escamosas/complicações , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Anticorpos Monoclonais Humanizados/uso terapêuticoRESUMO
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immune suppressive cells detected in several human cancers. In this study, we investigated the features and immune suppressive function of a novel subset of monocytic MDSC overexpressing TIE-2 (TIE-2+ M-MDSC), the receptor for the pro-angiogenic factor angiopoietin 2 (ANGPT2). We showed that patients with melanoma exhibited a higher circulating rate of TIE-2+ M-MDSCs, especially in advanced stages, as compared to healthy donors. The distribution of the TIE-2+ M-MDSC rate toward the melanoma stage correlated with the serum level of ANGPT2. TIE-2+ M-MDSC from melanoma patients overexpressed immune suppressive molecules such as PD-L1, CD73, TGF-ß, and IL-10, suggesting a highly immunosuppressive phenotype. The exposition of these cells to ANGPT2 increased the expression of most of these molecules, mainly Arginase 1. Hence, we observed a profound impairment of melanoma-specific T-cell responses in patients harboring high levels of TIE-2+ M-MDSC along with ANGPT2. This was confirmed by in vitro experiments indicating that the addition of ANGPT2 increased the ability of TIE-2+ M-MDSC to suppress antitumor T-cell function. Furthermore, by using TIE-2 kinase-specific inhibitors such as regorafenib or rebastinib, we demonstrated that an active TIE-2 signaling was required for optimal suppressive activity of these cells after ANGPT2 exposition. Collectively, these results support that TIE-2+ M-MDSC/ANGPT2 axis represents a potential immune escape mechanism in melanoma.
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Melanoma , Células Supressoras Mieloides , Angiopoietina-2/metabolismo , Humanos , Linfócitos TRESUMO
MCC (Merkel cell carcinoma) is an aggressive neuroendocrine cutaneous neoplasm. Integration of the Merkel cell polyomavirus (MCPyV) is observed in about 80% of the cases, while the remaining 20% are related to UV exposure. Both MCPyV-positive and -negative MCCs-albeit by different mechanisms-are associated with RB1 inactivation leading to overexpression of SOX2, a major contributor to MCC biology. Moreover, although controversial, loss of RB1 expression seems to be restricted to MCPyV-negative cases.The aim of the present study was to assess the performances of RB1 loss and SOX2 expression detected by immunohistochemistry to determine MCPyV status and to diagnose MCC, respectively.Overall, 196 MCC tumors, 233 non-neuroendocrine skin neoplasms and 70 extra-cutaneous neuroendocrine carcinomas (NEC) were included. SOX2 and RB1 expressions were assessed by immunohistochemistry in a tissue micro-array. Diagnostic performances were determined using the likelihood ratio (LHR).RB1 expression loss was evidenced in 27% of the MCC cases, 12% of non-neuroendocrine skin tumors and 63% of extra-cutaneous NEC. Importantly, among MCC cases, RB1 loss was detected in all MCPyV(-) MCCs, while MCPyV( +) cases were consistently RB1-positive (p < 0.001). SOX2 diffuse expression was observed in 92% of the MCC cases and almost never observed in non-neuroendocrine skin epithelial neoplasms (2%, p < 0.0001, LHR + = 59). Furthermore, SOX2 diffuse staining was more frequently observed in MCCs than in extra-cutaneous NECs (30%, p < 0.001, LHR + = 3.1).These results confirm RB1 as a robust predictor of MCC viral status and further suggest SOX2 to be a relevant diagnostic marker of MCC.
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Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Infecções por Polyomavirus , Neoplasias Cutâneas , Infecções Tumorais por Vírus , Carcinoma de Célula de Merkel/diagnóstico , Carcinoma de Célula de Merkel/patologia , Humanos , Poliomavírus das Células de Merkel/metabolismo , Infecções por Polyomavirus/complicações , Infecções por Polyomavirus/metabolismo , Proteínas de Ligação a Retinoblastoma , Fatores de Transcrição SOXB1/metabolismo , Neoplasias Cutâneas/patologia , Infecções Tumorais por Vírus/complicações , Ubiquitina-Proteína LigasesRESUMO
Exosomes, as potential circulated biomarkers, have recently become a topic of interest in the field of oncology. Immune checkpoint molecule PD-L1 has recently been detected in circulating exosomes from cancer patients. The purpose of this work was to evaluate PD-L1 levels in circulating exosomes (Exo-PD-L1) isolated from patients' plasma suffering from Merkel cell carcinoma (MCC). We conducted a prospective bicentric cohort study. PD-L1 was analysed in circulating exosomes from plasma samples of patients suffering from MCC stage I to IV (according to the AJCC 8). Exosomes from 34 patients corresponding to 66 samples were analysed. PD-L1 was identified in circulating exosomes of MCC patients. Exo-PD-L1 levels of MCC patients were similar to healthy donors and lower than other cancers such as melanoma. Exo-PD-L1 levels tended to be higher in MCC patients with distant metastases. Furthermore, Exo-PD-L1 levels did not significantly vary over the course of the disease whatever the disease course or the response to treatment. This study assessed the presence of PD-L1 in circulating exosomes of MCC patients. The low levels of Exo-PD-L1 and small changes over the course of the disease may be due to the metastatic dissemination of MCC, which is mainly through the skin and lymph nodes rather than blood. PD-L1 was identified in circulating exosomes of MCC patients and tends to be higher in advanced disease. This preliminary study is a proof of concept of PD-L1 detection in circulating exosomes of MCC patients.