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OBJECTIVE: The objective is to determine how the COVID-19 pandemic affected care for patients undergoing thoracic surgery for cancer. BACKGROUND: The COVID-19 pandemic accelerated the adoption of telemedicine. METHODS: Characteristics and outcomes of new patients seen between March 1 and June 30, 2019, and the same period in 2020 were compared. Patients who did not undergo surgery were excluded. Patients who had a telemedicine visit (new and established) in the 2020 period were asked to complete a survey. RESULTS: In total, 624 new patients were seen in 2019 versus 299 in 2020 (52% reduction); 45% of patients (n=136) in 2020 were seen via telemedicine. There was no statistically significant difference in time to surgery, pathological upstaging, or postsurgical complications between 2019 and 2020. In total, 1085 patients (new and established) had a telemedicine visit in 2020; 239 (22%) completed the survey. A majority replied that telemedicine was equivalent to in-person care (77%), did not impair care quality (84%), resulted in less stress (69%) and shorter waits (86%), was more convenient (92%), saved money and commuting time (93%), and expanded who could attend visits (91%). Some patients regretted the loss of human interaction (71%). Most would opt for telemedicine after the pandemic (60%), although some would prefer in-person format for initial visits (55%) and visits with complex discussions (49%). Only 21% were uncomfortable with the telemedicine technology. CONCLUSIONS: Telemedicine enabled cancer care to continue during the COVID-19 pandemic without delays in surgery, cancer progression, or worsened postoperative morbidity and was generally well received.
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COVID-19 , Telemedicina , Procedimentos Cirúrgicos Torácicos , Humanos , Pandemias , COVID-19/epidemiologia , OncologiaRESUMO
INTRODUCTION: Tracheostomy in patients with COVID-19 is a controversial and difficult clinical decision. We hypothesized that a recently validated COVID-19 Severity Score (CSS) would be associated with survival in patients considered for tracheostomy. METHODS: We reviewed 77 mechanically ventilated COVID-19 patients evaluated for decision for percutaneous dilational tracheostomy (PDT) from March to June 2020 at a public tertiary care center. Decision for PDT was based on clinical judgment of the screening surgeons. The CSS was retrospectively calculated using mean biomarker values from admission to time of PDT consult. Our primary outcome was survival to discharge, and all patient charts were reviewed through August 31, 2021. ROC curve and Youden index were used to estimate an optimal cut-point for survival. RESULTS: The mean CSS for 42 survivors significantly differed from that of 35 nonsurvivors (CSS 52 versus 66, P = 0.003). The Youden index returned an optimal CSS of 55 (95% confidence interval 43-72), which was associated with a sensitivity of 0.8 and a specificity of 0.6. The median CSS was 40 (interquartile range 27, 49) in the lower CSS (<55) group and 72 (interquartile range 66, 93) in the high CSS (≥55 group). Eighty-seven percent of lower CSS patients underwent PDT, with 74% survival, whereas 61% of high CSS patients underwent PDT, with only 41% surviving. Patients with high CSS had 77% lower odds of survival (odds ratio = 0.2, 95% confidence interval 0.1-0.7). CONCLUSIONS: Higher CSS was associated with decreased survival in patients evaluated for PDT, with a score ≥55 predictive of mortality. The novel CSS may be a useful adjunct in determining which COVID-19 patients will benefit from tracheostomy. Further prospective validation of this tool is warranted.
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COVID-19 , Traqueostomia , Humanos , COVID-19/diagnóstico , COVID-19/terapia , Estudos RetrospectivosRESUMO
Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies.
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Antígenos de Neoplasias/imunologia , Proteínas de Bactérias/imunologia , Sobreviventes de Câncer , Reações Cruzadas/imunologia , Neoplasias Pancreáticas/imunologia , Linfócitos T Citotóxicos/imunologia , Adenocarcinoma/sangue , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Antígenos de Neoplasias/genética , Proteínas de Bactérias/sangue , Proteínas de Bactérias/genética , Antígeno Ca-125/genética , Antígeno Ca-125/imunologia , Simulação por Computador , Reações Cruzadas/genética , Humanos , Imunoterapia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/genética , Prognóstico , Análise de Sobrevida , Linfócitos T Citotóxicos/citologia , Sequenciamento do ExomaRESUMO
BACKGROUND AND OBJECTIVES: Metastasectomy for melanoma provides durable disease control in carefully selected patients. Similarly, BRAF-targeted and immune checkpoint inhibition has improved median overall survival (OS) in metastatic patients. We hypothesized that there is an increasing role for metastasectomy in melanoma patients responding to these therapies. METHODS: Retrospective analysis of a prospectively maintained database identified 128 patients with stage IV melanoma who received targeted molecular and/or checkpoint inhibitors at an academic institution from 2006 to 2017. Records were reviewed to characterize clinicopathologic characteristics, response to treatment, and intent of surgery for those who underwent metastasectomy. OS was analyzed by the Kaplan-Meier method. RESULTS: Median OS from stage IV diagnosis was 31.3 months. A total of 81 patients received checkpoint inhibitors, 11 received targeted inhibitors, and 36 received both. A total of 73 patients underwent metastasectomy. Indications for surgery included the intent to render disease-free (54%), palliation (34%), and diagnostic confirmation (11%). Responders to systemic therapy who underwent metastasectomy had improved OS compared to responders who did not (84.3 vs. 42.9 months, P = .018). CONCLUSIONS: Metastasectomy for melanoma is associated with improved OS in patients that respond to targeted molecular or immunotherapy. Resection should be strongly considered in this cohort as multimodality treatment results in excellent OS.
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Melanoma/secundário , Melanoma/terapia , Feminino , Humanos , Imunoterapia/métodos , Masculino , Melanoma/mortalidade , Melanoma/cirurgia , Metastasectomia , Terapia de Alvo Molecular/métodos , Estadiamento de Neoplasias , Estudos RetrospectivosRESUMO
γδ T cells are a rare but potent subset of T cells with pleiotropic functions. They commonly reside within tumors but the response of γδ T cells to tyrosine kinase inhibition is unknown. To address this, we studied a genetically engineered mouse model of gastrointestinal stromal tumor (GIST) driven by oncogenic Kit signaling that responds to the Kit inhibitor imatinib. At baseline, γδ T cells were antitumoral, as blockade of either γδ T-cell receptor or IL17A increased tumor weight and decreased antitumor immunity. However, imatinib therapy further stimulated intratumoral γδ T cells, as determined by flow cytometry and single-cell RNA sequencing (scRNA-seq). Imatinib expanded a highly activated γδ T-cell subset with increased IL17A production and higher expression of immune checkpoints and cytolytic effector molecules. Consistent with the mouse model, γδ T cells produced IL17A in fresh human GIST specimens, and imatinib treatment increased γδ T-cell gene signatures, as measured by bulk tumor RNA-seq. Furthermore, tumor γδ T cells correlated with survival in patients with GIST. Our findings highlight the interplay between tumor cell oncogene signaling and antitumor immune responses and identify γδ T cells as targets for immunotherapy in GIST.
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Antineoplásicos , Tumores do Estroma Gastrointestinal , Camundongos , Animais , Humanos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Tumores do Estroma Gastrointestinal/patologia , Proteínas Proto-Oncogênicas c-kit/genética , Inibidores Enzimáticos/uso terapêutico , Transdução de Sinais , Linhagem Celular Tumoral , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/farmacologiaRESUMO
OBJECTIVE: Shape-sensing robotic-assisted bronchoscopy is an emerging technology for the sampling of pulmonary lesions. We seek to characterize the shape-sensing robotic-assisted bronchoscopy learning curve at an academic center. METHODS: Shape-sensing robotic-assisted bronchoscopy procedures performed by 9 proceduralists at a single institution were analyzed. Cumulative sum analyses were performed to examine diagnostic sampling and procedure time over each operator's first 50 cases, with the acceptable yield threshold set to 73%. RESULTS: During the study period, 442 patients underwent sampling of 551 lesions. Each operator sampled 61 lesions (interquartile range, 60-63 lesions). Lesion size was 1.90 cm (interquartile range, 1.33-2.80 cm). The median procedure time for single-target cases decreased from 62 minutes during the first 10 cases to 39 minutes after case 40 (P < .001). The overall diagnostic yield was 72% (range, 58%-83%). Six of 9 operators achieved proficiency over the study period. An aggregated cumulative sum analysis of those who achieved competency demonstrated a steep improvement between lesions 1 and 21 and crossing of the competency threshold by lesion 25. Temporal analysis of yield-related lesion characteristics demonstrated that at approximately lesion 20, more challenging lesions were increasingly targeted, as evidenced by smaller target size, higher rates of unfavorable radial endobronchial ultrasound views, and a negative bronchus sign. CONCLUSIONS: Skills acquisition in shape-sensing robotic-assisted bronchoscopy is variable. Approximately half of proceduralists become facile with the technology within 25 lesions. After the initial learning phase, operators increasingly target lesions with more challenging features. Overall, these findings can inform certification and competency standards and provide new users with expectations related to performance over time.
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Targeted therapy with a tyrosine kinase inhibitor (TKI) such as imatinib is effective in treating gastrointestinal stromal tumor (GIST), but it is rarely curative. Despite the presence of a robust immune CD8+ T-cell infiltrate, combining a TKI with immune-checkpoint blockade (ICB) in advanced GIST has achieved only modest effects. To identify limitations imposed by imatinib on the antitumor immune response, we performed bulk RNA sequencing (RNA-seq), single-cell RNA-seq, and flow cytometry to phenotype CD8+ T-cell subsets in a genetically engineered mouse model of GIST. Imatinib reduced the frequency of effector CD8+ T cells and increased the frequency of naïve CD8+ T cells within mouse GIST, which coincided with altered tumor chemokine production, CD8+ T-cell recruitment, and reduced CD8+ T-cell intracellular PI3K signaling. Imatinib also failed to induce intratumoral T-cell receptor (TCR) clonal expansion. Consistent with these findings, human GISTs sensitive to imatinib harbored fewer effector CD8+ T cells but more naïve CD8+ T cells. Combining an IL15 superagonist (IL15SA) with imatinib restored intratumoral effector CD8+ T-cell function and CD8+ T-cell intracellular PI3K signaling, resulting in greater tumor destruction. Combination therapy with IL15SA and ICB resulted in the greatest tumor killing and maintained an effector CD8+ T-cell population in the presence of imatinib. Our findings highlight the impact of oncogene inhibition on intratumoral CD8+ T cells and support the use of agonistic T-cell therapy during TKI and/or ICB administration.
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Tumores do Estroma Gastrointestinal , Animais , Linfócitos T CD8-Positivos , Linhagem Celular Tumoral , Quimiocinas , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Humanos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Inibidores de Checkpoint Imunológico , Interleucina-15/farmacologia , Camundongos , Fosfatidilinositol 3-Quinases , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/farmacologiaRESUMO
We present the case of a patient who developed esophageal adenocarcinoma after a previous laparoscopic sleeve gastrectomy. Bariatric surgery has emerged as the most effective treatment option for weight loss and obesity-related diseases; however, sleeve gastrectomy promotes gastroesophageal reflux and leads to Barrett's esophagus in a substantial portion of patients. The natural history of Barrett's esophagus in these patients is unknown, and active surveillance is recommended until the incidence of dysplasia and adenocarcinoma in this population is clarified. Management options for these patients include conversion to Roux-en-Y gastric bypass. Although esophagectomy in patients who have previously undergone sleeve gastrectomy may require an alternative conduit, the remnant stomach can be used in carefully selected patients. Here, we review the different weight loss procedures, their effect on gastroesophageal reflux disease and Barrett's esophagus, and the treatment options for patients with esophageal cancer after sleeve gastrectomy. We report the use of preoperative coil embolization as a means of vascular preconditioning before successful use of a gastric conduit.
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BACKGROUND: The COVID-19 pandemic overwhelmed New York City hospitals early in the pandemic. Shortages of ventilators and sedatives prompted tracheostomy earlier than recommended by professional societies. This study evaluates the impact of percutaneous dilational tracheostomy (PDT) in COVID+ patients on critical care capacity. METHODS: This is a single-institution prospective case series of mechanically ventilated COVID-19 patients undergoing PDT from April 1 to June 4, 2020 at a public tertiary care center. RESULTS: Fifty-five patients met PDT criteria and underwent PDT at a median of 13 days (IQR 10, 18) from intubation. Patient characteristics are found in Table 1. Intravenous midazolam, fentanyl, and cisatracurium equivalents were significantly reduced 48 hours post-PDT (Table 2). Thirty-five patients were transferred from the ICU and liberated from the ventilator. Median time from PDT to ventilator liberation and ICU discharge was 10 (IQR 4, 14) and 12 (IQR 8, 17) days, respectively. Decannulation occurred in 45.5% and 52.7% were discharged from acute inpatient care (Figure 1). Median follow-up for the study was 62 days. Four patients had bleeding complications postoperatively and 11 died during the study period. Older age was associated with increased odds of complication (OR 1.12, 95% CI 1.04, 1.23) and death (OR=1.15, 95% CI 1.05, 1.30). All operators tested negative for COVID-19 during the study period. CONCLUSION: These findings suggest COVID-19 patients undergoing tracheostomy within the standard time frame can improve critical care capacity in areas strained by the pandemic with low risk to operators. Long-term outcomes after PDT deserve further study.
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COVID-19/cirurgia , Cuidados Críticos/estatística & dados numéricos , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Traqueostomia/estatística & dados numéricos , Fatores Etários , COVID-19/epidemiologia , Feminino , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque/epidemiologia , Estudos Prospectivos , Respiração Artificial/estatística & dados numéricos , Fatores de Tempo , Traqueostomia/efeitos adversos , Traqueostomia/métodos , Resultado do Tratamento , Desmame do Respirador/estatística & dados numéricosRESUMO
Type I IFNs are implicated in tumor immunogenicity and response to systemic therapy, but their interaction with oncogene signaling is not well understood. Here, we studied oncogenic KIT, which drives gastrointestinal stromal tumor (GIST), the most common sarcoma. Using mouse models of GIST, we found that KIT inhibition reduced type I IFN production and signaling, which downregulated tumor MHC class I expression. Absence of type I IFN signaling increased tumor size, in part due to CD8+ T-cell impairment. Oncogenic KIT was required for GIST type I IFN signal transduction via STAT1. In human GIST cell lines and surgical specimens, type I IFN signaling contributed to human lymphocyte antigen class I expression and correlated with tumor immunogenicity. Augmenting the type I IFN response partially compensated for the immunosuppressive effects of KIT inhibition. Thus, KIT signaling contributes to type I IFN signaling, whereas KIT inhibition attenuates tumor immunogenicity and is partly rescued by innate immune stimulation.See related Spotlight on p. 489.
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Anticorpos Monoclonais/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Interferon Tipo I/imunologia , Proteínas Proto-Oncogênicas c-kit/imunologia , Animais , Anticorpos Monoclonais/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and arises in the gastrointestinal tract. Most GISTs are caused by activating mutations in the KIT receptor tyrosine kinase, such as the exon 11 KIT V559Δ mutation. The small molecule imatinib inhibits KIT and has been a mainstay of therapy in GIST. Unfortunately, imatinib-treated patients typically relapse, most often due to clonal emergence of the resistance-associated KIT V654A mutation. To determine the biologic impact of this second-site mutation in vivo, we created a mouse model with the corresponding V558Δ;V653A Kit double mutation restricted (a) spatially to ETV1+ cells, which include the interstitial cells of Cajal (ICCs) from which GISTs presumably originate, and (b) temporally through tamoxifen treatment after birth. This resulted in the first in vivo model of the most common second-site mutation associated with imatinib resistance in GIST and the first in vivo demonstration that cell-autonomous expression of mutant KIT in the ICC lineage leads to GIST. GISTs driven by the V558Δ;V653A Kit double mutation were resistant to imatinib, while cabozantinib was more effective in overcoming resistance than sunitinib. Compared to control mice with a single V558Δ Kit mutation, mice with a double V558Δ; V653A Kit mutation had increased tumor oncogenesis and associated KIT-dependent STAT activation. Our findings demonstrate that the biologic consequences of a second-site mutation in an oncogenic driver may include not only a mechanism for drug resistance, but changes in tumor oncogenic potential and differential activation of signaling pathways.
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Carcinogênese/genética , Neoplasias Gastrointestinais/genética , Tumores do Estroma Gastrointestinal/genética , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Fatores de Transcrição STAT/metabolismo , Animais , Modelos Animais de Doenças , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/patologia , Humanos , Camundongos , Proteínas Proto-Oncogênicas c-kit/metabolismo , Transdução de Sinais/genética , Microambiente Tumoral/genéticaRESUMO
Patients with pancreatic ductal adenocarcinoma do not benefit from checkpoint blockade. However, human tumors harbor evidence of adaptive immunity in clonally expanded T-cell populations. Immune intact modeling of human tumors identifies stromal sequestration as a mechanism of immune escape. Targeting the stroma combined with checkpoint blockade unleashes antitumor immunity.See related article by Seo et al., p. 3934.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Imunidade Adaptativa , Humanos , Pâncreas , Linfócitos TRESUMO
Gastrointestinal stromal tumor (GIST) is the most common human sarcoma, frequently characterized by an oncogenic mutation in the KIT or platelet-derived growth factor receptor alpha (PDGFRA) genes. We performed RNA sequencing of 75 human GIST tumors from 75 patients, comprising the largest cohort of GISTs sequenced to date, in order to discover differences in the immune infiltrates of KIT and PDGFRA-mutant GIST. Through bioinformatics, immunohistochemistry, and flow cytometry, we found that PDGFRA-mutant GISTs harbored more immune cells with increased cytolytic activity when compared to KIT-mutant GISTs. PDGFRA-mutant GISTs expressed many chemokines, such as CXCL14, at a significantly higher level when compared to KIT-mutant GISTs and exhibited more diverse driver-derived neoepitope:HLA binding, both of which may contribute to PDGFRA-mutant GIST immunogenicity. Through machine learning, we generated gene expression-based immune profiles capable of differentiating KIT and PDGFRA-mutant GISTs, and also identified additional immune features of high PD-1 and PD-L1 expressing tumors across all GIST mutational subtypes, which may provide insight into immunotherapeutic opportunities and limitations in GIST.
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Análise Mutacional de DNA , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/imunologia , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Quimiocinas CXC/genética , Biologia Computacional , Epitopos/imunologia , Feminino , Perfilação da Expressão Gênica , Humanos , Sistema Imunitário , Aprendizado de Máquina , Masculino , Mutação , Análise de Componente Principal , Estudos Prospectivos , Análise de Sequência de RNARESUMO
Gastrointestinal stromal tumor (GIST) is driven by an activating mutation in the KIT proto-oncogene. Using a mouse model of GIST and human specimens, we show that intratumoral murine CD103+CD11b- dendritic cells (DCs) and human CD141+ DCs are associated with CD8+ T cell infiltration and differentiation. In mice, the antitumor effect of the Kit inhibitor imatinib is partially mediated by CD103+CD11b- DCs, and effector CD8+ T cells initially proliferate. However, in both mice and humans, chronic imatinib therapy decreases intratumoral DCs and effector CD8+ T cells. The mechanism in our mouse model depends on Kit inhibition, which reduces intratumoral GM-CSF, leading to the accumulation of Batf3-lineage DC progenitors. GM-CSF is produced by γδ T cells via macrophage IL-1ß. Stimulants that expand and mature DCs during imatinib treatment improve antitumor immunity. Our findings identify the importance of tumor cell oncogene activity in modulating the Batf3-dependent DC lineage and reveal therapeutic limitations for combined checkpoint blockade and tyrosine kinase inhibition.
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Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Carcinogênese/patologia , Células Dendríticas/metabolismo , Tumores do Estroma Gastrointestinal/imunologia , Tumores do Estroma Gastrointestinal/patologia , Imunidade , Inibidores de Proteínas Quinases/farmacologia , Proteínas Repressoras/metabolismo , Animais , Antígenos CD/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Carcinogênese/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Fatores Quimiotáticos/farmacologia , Células Dendríticas/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Mesilato de Imatinib/farmacologia , Imunidade/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Monitorização Imunológica , Oncogenes , Proto-Oncogene Mas , Receptores de Antígenos de Linfócitos T gama-delta/metabolismoRESUMO
Purpose: Imatinib dramatically reduces gastrointestinal stromal tumor (GIST) 18F-FDG uptake, providing an early indicator of treatment response. Despite decreased glucose internalization, many GIST cells persist, suggesting that alternative metabolic pathways are used for survival. The role of mitochondria in imatinib-treated GIST is largely unknown.Experimental Design: We quantified the metabolic activity of several human GIST cell lines. We treated human GIST xenografts and genetically engineered KitV558del/+ mice with the mitochondrial oxidative phosphorylation inhibitor VLX600 in combination with imatinib and analyzed tumor volume, weight, histology, molecular signaling, and cell cycle activity. In vitro assays on human GIST cell lines were also performed.Results: Imatinib therapy decreased glucose uptake and downstream glycolytic activity in GIST-T1 and HG129 cells by approximately half and upregulated mitochondrial enzymes and improved mitochondrial respiratory capacity. Mitochondrial inhibition with VLX600 had a direct antitumor effect in vitro while appearing to promote glycolysis through increased AKT signaling and glucose transporter expression. When combined with imatinib, VLX600 prevented imatinib-induced cell cycle escape and reduced p27 expression, leading to increased apoptosis when compared to imatinib alone. In KitV558del/+ mice, VLX600 alone did not induce tumor cell death, but had a profound antitumor effect when combined with imatinib.Conclusions: Our findings show that imatinib alters the metabolic phenotype of GIST, and this may contribute to imatinib resistance. Our work offers preclinical proof of concept of metabolic targeting as an effective strategy for the treatment of GIST. Clin Cancer Res; 24(4); 972-84. ©2017 AACR.
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Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mesilato de Imatinib/farmacologia , Redes e Vias Metabólicas/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/metabolismo , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/metabolismo , Humanos , Hidrazonas/administração & dosagem , Hidrazonas/farmacologia , Mesilato de Imatinib/administração & dosagem , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Mitocôndrias/genética , Mitocôndrias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Resultado do Tratamento , Triazóis/administração & dosagem , Triazóis/farmacologia , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Tyrosine kinase inhibition of gastrointestinal stromal tumors (GIST) is effective but typically culminates in resistance and is rarely curative. Immunotherapy has potential application to GIST, as we previously showed that T-cell checkpoint blockade increases the antitumor effects of imatinib. Here, we showed that ligation of CD40 using an agonistic antibody (anti-CD40) activated tumor-associated macrophages (TAMs) in vivo in a knock-in mouse model of GIST harboring a germline mutation in Kit exon 11. Activated TAMs had greater TNFα production and NFκB signaling and directly inhibited tumor cells in vitro Anti-CD40 required concomitant therapy with imatinib for efficacy and depended on TAMs, and to a lesser extent CD8+ T cells, but not on CD4+ T cells or B cells. In an analysis of 50 human GIST specimens by flow cytometry, we found that CD40 was expressed on human TAMs and tumor cells yet was downregulated after response to imatinib. CD40 ligation did not have a direct inhibitory effect on human GIST cells. Our findings provide the rationale for combining anti-CD40 and tyrosine kinase inhibition to treat human GIST. Cancer Immunol Res; 6(4); 434-47. ©2018 AACR.
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Antígenos CD40/antagonistas & inibidores , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Tumores do Estroma Gastrointestinal/imunologia , Tumores do Estroma Gastrointestinal/metabolismo , Mesilato de Imatinib/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Animais , Biomarcadores , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Quimiotaxia de Leucócito/efeitos dos fármacos , Quimiotaxia de Leucócito/imunologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/patologia , Expressão Gênica , Humanos , Imunofenotipagem , Imunoterapia , Macrófagos/metabolismo , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Carga Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Gastrointestinal stromal tumor (GIST) is the most common sarcoma, often resulting from a KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutation. The lineage transcription factor ETV1 is expressed similarly in GISTs regardless of malignant potential. Although the related transcription factor ETV4 has been associated with metastasis and tumor progression in other cancers, its role in GIST is unknown. In this study, we found that ETV4 levels were high in a subset of human GISTs and correlated with high mitotic rate. Through Gene Set Enrichment Analysis in selected human GISTs, we identified a relationship between ETV4 levels and ß-catenin signaling, especially in advanced GISTs. GIST specimens with high ETV4 levels overexpressed cell cycle regulating genes and had aberrant activation of the canonical Wnt pathway. In human GIST cell lines, ETV4 RNA interference suppressed cell cycle genes and Wnt/ß-catenin signaling. ETV4 knockdown also reduced tumor cell proliferation, invasion, and tumor growth in vivo. Conversely, ETV4 overexpression increased cyclin D1 expression and Wnt/ß-catenin signaling. Moreover, we determined that ETV4 knockdown destabilized nuclear ß-catenin and increased its degradation via COP1, an E3 ligase involved in both ETV4 and ß-catenin turnover. Aberrant accumulation of ETV4 and nuclear ß-catenin was found in patient derived xenografts created from metastatic GISTs that became resistant to tyrosine kinase inhibitors. Collectively, our findings highlight the significance of ETV4 expression in GIST and identify ETV4 as a biomarker in human GISTs.
RESUMO
PURPOSE: Tyrosine kinase inhibitors are effective in gastrointestinal stromal tumors (GISTs) but often are of transient benefit as resistance commonly develops. Immunotherapy, particularly blockade of the inhibitory receptor programmed death 1 (PD-1) or the ligand programmed death ligand 1 (PD-L1), has shown effectiveness in a variety of cancers. The functional effects of PD-1/PD-L1 blockade are unknown in GISTs. EXPERIMENTAL DESIGN: We analyzed tumor and matched blood samples from 85 patients with GISTs and determined the expression of immune checkpoint molecules using flow cytometry. We investigated the combination of imatinib with PD-1/PD-L1 blockade in KitV558Δ/+ mice that develop GISTs. RESULTS: The inhibitory receptors PD-1, lymphocyte activation gene 3, and T-cell immunoglobulin mucin-3 were upregulated on tumor-infiltrating T cells compared with T cells from matched blood. PD-1 expression on T cells was highest in imatinib-treated human GISTs. Meanwhile, intratumoral PD-L1 expression was variable. In human GIST cell lines, treatment with imatinib abrogated the IFNγ-induced upregulation of PD-L1 via STAT1 inhibition. In KitV558Δ/+ mice, imatinib downregulated IFNγ-related genes and reduced PD-L1 expression on tumor cells. PD-1 and PD-L1 blockade in vivo each had no efficacy alone but enhanced the antitumor effects of imatinib by increasing T-cell effector function in the presence of KIT and IDO inhibition. CONCLUSIONS: PD-1/PD-L1 blockade is a promising strategy to improve the effects of targeted therapy in GISTs. Collectively, our results provide the rationale to combine these agents in human GISTs. Clin Cancer Res; 23(2); 454-65. ©2016 AACR.