RESUMEN
Ovarian clear cell carcinoma (OCCC), which has unique clinical characteristics, arises from benign endometriotic cysts, forming an oxidative stress environment due to excess iron accumulation, and exhibits poor prognosis, particularly in advanced stages owing to resistance to conventional therapeutics. Ferroptosis is an iron-dependent form of programmed cell death induced by lipid peroxidation and controlled by Hippo signaling. We hypothesized that overcoming ferroptosis resistance is an attractive strategy because OCCC acquires oxidative stress resistance during its development and exhibits chemoresistant features indicative of ferroptosis resistance. This study aimed to determine whether OCCC is resistant to ferroptosis and clarify the mechanism underlying resistance. Unlike ovarian high-grade serous carcinoma cells, OCCC cells were exposed to oxidative stress. However, OCCC cells remained unaffected by lipid peroxidation. Cell viability assays revealed that OCCC cells exhibited resistance to the ferroptosis inducer erastin. Moreover, Samroc analysis showed that the Hippo signaling pathway was enriched in OCCC cell lines and clinical samples. Furthermore, patients with low expression of nuclear Yes-associated protein 1(YAP1) exhibited a significantly poor prognosis of OCCC. Moreover, YAP1 activation enhanced ferroptosis in OCCC cell lines. Furthermore, suppression of zinc finger DHHC-type palmitoyltransferase 7 (ZDHHC7) enhanced ferroptosis by activating YAP1 in OCCC cell lines. Mouse xenograft models demonstrated that ZDHHC7 inhibition suppressed tumor growth via YAP1 activation by erastin treatment. In conclusion, YAP1 activation regulated by ZDHHC7 enhanced ferroptosis in OCCC. Thus, overcoming ferroptosis resistance is a potential therapeutic strategy for OCCC.
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PURPOSE: Healthy lifestyle is related to quality of life (QOL) after cancer diagnosis and prognosis. However, there are few reports on patients conscious of healthy lifestyle and patients requiring medical providers' attention regarding healthy lifestyle. We aimed to develop a healthy lifestyle consciousness index (HLCI) for cancer patients and evaluated its validity in gynecological cancer patients. METHODS: The HLCI was designed to assess degree of healthy lifestyle consciousness, including items regarding "diet," "exercise," "body weight," and "sleep." Exploratory factor analysis was performed for dimensionality of the scale; Cronbach's alpha was calculated to assess internal-consistency reliability. For criterion-based validity, we calculated proportions of stage III/IV gynecological malignancies in those with categorized HLCI scores based on tertiles. Concurrent validity was evaluated between HLCI and other quality of life (QOL) scales including European Organization for Research and Treatment of Cancer QLQ-C30 in limited patients. RESULTS: HLCI comprised five 10-point items (0-45); higher values implied improved healthy lifestyle consciousness. Data from 108 gynecological malignancy patients at Kyoto University Hospital were analyzed. The mean age of subjects was 55.8 years; 36.1% of them had uterine corpus cancer; 34.3% were at stage III/IV of gynecological malignancy. The factor analysis revealed HLCI was unidimensional; the reliability based on Cronbach's alpha was satisfactory (0.88). The proportions of stage III/IV gynecological malignancies were 25.7%, 33.3%, and 44.4% in those with first (7-24 points), second (25-30 points), and third (31-46 points) tertiles of HLCI score, respectively. For patients with other QOL scales (n = 25), the mean scores of global health status of QLQ-C30 were 33.3, 50.0, and 83.3 for first, second, and third tertiles of HLCI score, respectively. CONCLUSION: HLCI was successfully validated; thus, patients with advanced stages or higher QOL might have strong consciousness regarding healthy lifestyle. HLCI may be useful in precision care for improved lifestyles and QOL.
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Calidad de Vida , Neoplasias Uterinas , Estado de Conciencia , Femenino , Estilo de Vida Saludable , Humanos , Persona de Mediana Edad , Psicometría , Reproducibilidad de los Resultados , Encuestas y CuestionariosRESUMEN
Tertiary lymphoid structures (TLS) are transient ectopic lymphoid aggregates whose formation might be caused by chronic inflammation states, such as cancer. However, how TLS are induced in the tumor microenvironment (TME) and how they affect patient survival are not well understood. We investigated TLS distribution in relation to tumor infiltrating lymphocytes (TILs) and related gene expression in high-grade serous ovarian cancer (HGSC) specimens. CXCL13 gene expression correlated with TLS presence and the infiltration of T cells and B cells, and it was a favorable prognostic factor for patients with HGSC. Coexistence of CD8+ T cells and B cell lineages in the TME significantly improved the prognosis of HGSC and was correlated with the presence of TLS. CXCL13 expression was predominantly coincident with CD4+ T cells in TLS and CD8+ T cells in TILs, and it shifted from CD4+ T cells to CD21+ follicular DCs as TLS matured. In a mouse ovarian cancer model, recombinant CXCL13 induced TLS and enhanced survival by the infiltration of CD8+ T cells. These results suggest that TLS formation was associated with CXCL13-producing CD4+ T cells and that TLS facilitated the coordinated antitumor response of cellular and humoral immunity in ovarian cancer.
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Neoplasias Ováricas , Estructuras Linfoides Terciarias , Animales , Linfocitos T CD4-Positivos/patología , Quimiocina CXCL13/metabolismo , Femenino , Humanos , Linfocitos Infiltrantes de Tumor , Ratones , Neoplasias Ováricas/patología , Pronóstico , Estructuras Linfoides Terciarias/patología , Microambiente TumoralRESUMEN
Serous carcinoma of the uterus (USC) is a pathological subtype of high-grade endometrial cancers, with no effective treatment for advanced cases. Since such refractory tumors frequently harbor antitumor immune tolerance, many immunotherapies have been investigated for various malignant tumors using immuno-competent animal models mimicking their local immunities. In this study, we established an orthotopic mouse model of high-grade endometrial cancer and evaluated the local tumor immunity to explore the efficacy of immunotherapies against USC. A multivariate analysis of 62 human USC cases revealed that the tumor-infiltrating cell status, few CD8+ cells and abundant myeloid-derived suppressor cells (MDSCs), was an independent prognostic factor (P < 0.005). A murine endometrial cancer cell (mECC) was obtained from C57BL/6 mice via endometrium-specific deletion of Pten and Tp53, and another high-grade cell (HPmECC) was established by further overexpressing Myc in mECCs. HPmECCs exhibited higher capacities of migration and anchorage-independent proliferation than mECCs (P < 0.01, P < 0.0001), and when both types of cells were inoculated into the uterus of C57BL/6 mice, the prognosis of mice bearing HPmECC-derived tumors was significantly poorer (P < 0.001). Histopathological analysis of HPmECC orthotopic tumors showed serous carcinoma-like features with prominent tumor infiltration of MDSCs (P < 0.05), and anti-Gr-1 antibody treatment significantly prolonged the prognosis of HPmECC-derived tumor-bearing mice (P < 0.05). High CCL7 expression was observed in human USC and HPmECC, and MDSCs migration was promoted in a CCL7 concentration-dependent manner. These results indicate that antitumor immunity is suppressed in USC due to increased number of tumor-infiltrating MDSCs via CCL signal.
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Cistadenocarcinoma Seroso , Neoplasias Endometriales , Células Supresoras de Origen Mieloide , Animales , Línea Celular Tumoral , Quimiocina CCL7 , Cistadenocarcinoma Seroso/patología , Neoplasias Endometriales/patología , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Microambiente TumoralRESUMEN
New approaches beyond PD-1/PD-L1 inhibition are required to target the immunologically diverse tumor microenvironment (TME) in high-grade serous ovarian cancer (HGSOC). In this study, we explored the immunosuppressive effect of B7-H3 (CD276) via the CCL2-CCR2-M2 macrophage axis and its potential as a therapeutic target. Transcriptome analysis revealed that B7-H3 is highly expressed in PD-L1-low, nonimmunoreactive HGSOC tumors, and its expression negatively correlated with an IFNγ signature, which reflects the tumor immune reactivity. In syngeneic mouse models, B7-H3 (Cd276) knockout (KO) in tumor cells, but not in stromal cells, suppressed tumor progression, with a reduced number of M2 macrophages and an increased number of IFNγ+CD8+ T cells. CCL2 expression was downregulated in the B7-H3 KO tumor cell lines. Inhibition of the CCL2-CCR2 axis partly negated the effects of B7-H3 suppression on M2 macrophage migration and differentiation, and tumor progression. In patients with HGSOC, B7-H3 expression positively correlated with CCL2 expression and M2 macrophage abundance, and patients with B7-H3-high tumors had fewer tumoral IFNγ+CD8+ T cells and poorer prognosis than patients with B7-H3-low tumors. Thus, B7-H3 expression in tumor cells contributes to CCL2-CCR2-M2 macrophage axis-mediated immunosuppression and tumor progression. These findings provide new insights into the immunologic TME and could aid the development of new therapeutic approaches against the unfavorable HGSOC phenotype.
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Antígenos B7/inmunología , Linfocitos T CD8-positivos/inmunología , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/terapia , Animales , Antígenos B7/genética , Linfocitos T CD8-positivos/patología , Línea Celular Tumoral , Quimiocina CCL2/genética , Femenino , Humanos , Tolerancia Inmunológica , Linfocitos Infiltrantes de Tumor/inmunología , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Receptores CCR2/genética , Factores de Transcripción/metabolismo , Microambiente Tumoral/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Immunotherapy has experienced remarkable growth recently. Tertiary lymphoid structures (TLSs) and B cells may play a key role in the immune response and have a survival benefit in some solid tumors, but there have been no reports about their role in endometrial cancer (EC). We investigated the clinicopathological and pathobiological characteristics of the tumor microenvironment (TME) in EC. Patients with EC at Kyoto University Hospital during 2006-2011 were retrospectively included. In 104 patients with EC who met study inclusion criteria, 81 (77.9%) had TLSs, which consisted of areas rich in CD20+ B cells, CD8+ T cells, CD4+ T cells, and CD38+ plasma cells. The absence of TLS was independently associated with tumor progression (HR, 0.154; 95% CI, 0.044-0.536; P = 0.003). Patients with TLSs that included CD23+ germinal centers had better PFS. All tumor infiltrating lymphocytes were counted in the intratumor site. The number of CD20+ B cells was significantly larger in patients with TLSs than in those without TLS (P < 0.001). CD20+ B cells numbers were positively correlated with other TLSs. The larger number of CD20+ B cell was associated with better PFS (P = 0.015). TLSs and B cell infiltration into tumors are associated with favorable survival outcomes in patients with EC. They may represent an active immune reaction of the TME in endometrial cancer.
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Neoplasias Endometriales , Estructuras Linfoides Terciarias , Antígenos CD20 , Linfocitos T CD8-positivos/patología , Neoplasias Endometriales/patología , Femenino , Humanos , Linfocitos Infiltrantes de Tumor , Pronóstico , Estudios Retrospectivos , Microambiente TumoralRESUMEN
Based on our previous phase II clinical trial of anti-programmed death-1 (PD-1) antibody nivolumab for platinum-resistant ovarian cancer (n = 19, UMIN000005714), we aimed to identify the biomarkers predictive of response. Tumor gene expression was evaluated by proliferative, mesenchymal, differentiated, and immunoreactive gene signatures derived from high-grade serous carcinomas and a signature established prior for ovarian clear cell carcinoma. Resulting signature scores were statistically assessed with both univariate and multivariate approaches for correlation to clinical response. Analyses were performed to identify pathways differentially expressed by either the complete response (CR) or progressive disease (PD) patient groups. The clear cell gene signature was scored significantly higher in the CR group, and the proliferative gene signature had significantly higher scores in the PD group where nivolumab was not effective (respective p values 0.005 and 0.026). Combinations of gene signatures improved correlation with response, where a visual projection of immunoreactive, proliferative, and clear cell signatures differentiated clinical response. An applicable clinical response prediction formula was derived. Ovarian cancer-specific gene signatures and related pathway scores provide a robust preliminary indicator for ovarian cancer patients prior to anti-PD-1 therapy decisions.
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Antineoplásicos Inmunológicos/farmacología , Carcinoma Epitelial de Ovario , Nivolumab/farmacología , Neoplasias Ováricas , Receptor de Muerte Celular Programada 1/metabolismo , Biomarcadores de Tumor/genética , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/genética , Femenino , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genéticaRESUMEN
BACKGROUND: The mechanism of resistance development to anti-VEGF therapy in ovarian cancer is unclear. We focused on the changes in tumour immunity post anti-VEGF therapy. METHODS: The frequencies of immune cell populations and hypoxic conditions in the resistant murine tumours and clinical samples were examined. The expression profiles of both the proteins and genes in the resistant tumours were analysed. The impact of granulocyte-monocyte colony-stimulating factor (GM-CSF) expression on myeloid-derived suppressor cell (MDSC) function in the resistant tumours was evaluated. RESULTS: We found a marked increase and reduction in the number of Gr-1 + MDSCs and CD8 + lymphocytes in the resistant tumour, and the MDSCs preferentially infiltrated the hypoxic region. Protein array analysis showed upregulation of GM-CSF post anti-VEGF therapy. GM-CSF promoted migration and differentiation of MDSCs, which inhibited the CD8 + lymphocyte proliferation. Anti-GM-CSF therapy improved the anti-VEGF therapy efficacy, which reduced the infiltrating MDSCs and increased CD8 + lymphocytes. In immunohistochemical analysis of clinical samples, GM-CSF expression and MDSC infiltration was enhanced in the bevacizumab-resistant case. CONCLUSIONS: The anti-VEGF therapy induces tumour hypoxia and GM-CSF expression, which recruits MDSCs and inhibits tumour immunity. Targeting the GM-CSF could help overcome the anti-VEGF therapy resistance in ovarian cancers.
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Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Células Supresoras de Origen Mieloide/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Neoplasias Ováricas/patologíaRESUMEN
Side population (SP) cells harbor malignant phenotypes in cancer. The aim of this study was to identify genes that modulate the proportion of ovarian cancer SP cells. Using a shRNA library targeting 15,000 genes, a functional genomics screen was performed to identify genes whose suppression increased the SP percentage. The biological effects caused by alteration of those identified genes were investigated in vitro and in vivo. We found that suppression of MSL3, ZNF691, VPS45, ITGB3BP, TLE2, and ZNF498 increased the proportion of SP cells. Newly generated SP cells exhibit greater capacity for sphere formation, single cell clonogenicity, and in vivo tumorigenicity. On the contrary, overexpression of MSL3, VPS45, ITGB3BP, TLE2, and ZNF498 decreased the proportion of SP cells, sphere formation capacity and single cell clonogenicity. In ovarian cancer cases, low expression of MSL3, ZNF691 and VPS45 was related to poor prognosis. Suppression of these six genes enhanced activity of the hedgehog pathway. Cyclopamine, a hedgehog pathway inhibitor, significantly decreased the number of SP cells and their sphere forming ability. Our results provide new information regarding molecular mechanisms favoring SP cells and suggest that Hedgehog signaling may provide a viable target for ovarian cancer.
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Neoplasias Ováricas/patología , Células de Población Lateral/patología , Antineoplásicos/farmacología , Línea Celular Tumoral , Forma de la Célula , Células Clonales , Regulación hacia Abajo , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Biblioteca de Genes , Genes Relacionados con las Neoplasias , Proteínas Hedgehog/genética , Humanos , Concentración 50 Inhibidora , Estimación de Kaplan-Meier , Neoplasias Ováricas/genética , Fenotipo , Pronóstico , ARN Mensajero/genética , ARN Neoplásico/genética , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/farmacología , Células de Población Lateral/química , Transducción de Señal , Esferoides Celulares , TransfecciónRESUMEN
Uterine serous carcinoma (USC) is a highly aggressive histological subtype of endometrial cancers harboring highly metastatic and chemoresistant features. Our previous study showed that STAT1 is highly expressed in USC and acts as a key molecule that is positively correlated with tumor progression, but it remains unclear whether STAT1 is relevant to the malicious chemorefractory nature of USC. In the present study, we investigated the regulatory role of STAT1 toward platinum-cytotoxicity in USC. STAT1 suppression sensitized USC cells to increase cisplatin-mediated apoptosis (p < 0.001). Furthermore, phosphorylation of STAT1 was prominently observed on serine-727 (pSTAT1-Ser727), but not on tyrosine-701, in the nucleus of USC cells treated with cisplatin. Mechanistically, the inhibition of pSTAT1-Ser727 by dominant-negative plasmid elevated cisplatin-mediated apoptosis by increasing intracellular accumulation of cisplatin through upregulation of CTR1 expression. TBB has an inhibitory effect on casein kinase 2 (CK2), which phosphorylate STAT1 at serine residues. Sequential treatment with TBB and cisplatin on USC cells greatly reduced nuclear pSTAT1-Ser727, enhanced intracellular accumulation of cisplatin, and subsequently increased apoptosis. Tumor load was significantly reduced by combination therapy of TBB and cisplatin in in vivo xenograft models (p < 0.001). Our results collectively suggest that pSTAT1-Ser727 may play a key role in platinum resistance as well as tumor progression in USC. Thus, targeting the STAT1 pathway via CK2 inhibitor can be a novel method for attenuating the chemorefractory nature of USC.
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Antineoplásicos/uso terapéutico , Cisplatino/uso terapéutico , Cistadenocarcinoma Seroso/tratamiento farmacológico , Factor de Transcripción STAT1/metabolismo , Serina/metabolismo , Neoplasias Uterinas/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quimioterapia Adyuvante , Cisplatino/farmacología , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patología , Resistencia a Antineoplásicos , Femenino , Xenoinjertos , Humanos , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Fosforilación , Factor de Transcripción STAT1/química , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologíaRESUMEN
BACKGROUND: V-domain Ig suppressor of T cell activation (VISTA) is a novel inhibitory immune-checkpoint protein. VISTA expression on tumour cells and the associated regulatory mechanisms remain unclear. We investigated VISTA expression and function in tumour cells, and evaluated its mechanism and activity. METHODS: VISTA in tumour cells was assessed by tissue microarray analysis, immunohistochemical staining and western blot. A series of in vitro assays were used to determine the function of tumour-expressed VISTA. In vivo efficacy was evaluated in syngeneic models. RESULTS: VISTA was highly expressed in human ovarian and endometrial cancers. Upregulation of VISTA in endometrial cancer was related to the methylation status of the VISTA promoter. VISTA in tumour cells suppressed T cell proliferation and cytokine production in vitro, and decreased the tumour-infiltrating CD8+ T cells in vivo. Anti-VISTA antibody prolonged the survival of tumour-bearing mice. CONCLUSIONS: This is the first demonstration that VISTA is highly expressed in human ovarian and endometrial cancer cells, and that anti-VISTA antibody treatment significantly prolongs the survival of mice bearing tumours expressing high levels of VISTA. The data suggest that VISTA is a novel immunosuppressive factor within the tumour microenvironment, as well as a new target for cancer immunotherapy.
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Antígenos B7/genética , Neoplasias Endometriales/genética , Neoplasias Ováricas/genética , Linfocitos T/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Neoplasias Endometriales/inmunología , Neoplasias Endometriales/patología , Femenino , Humanos , Inmunoterapia , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Ratones , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/patología , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
Snail is a major transcriptional factor that induces epithelial-mesenchymal transition (EMT). In this study, we explore the effect of Snail on tumor immunity. Snail knockdown in mouse ovarian cancer cells suppresses tumor growth in immunocompetent mice, associated with an increase of CD8+ tumor-infiltrating lymphocytes and a decrease of myeloid-derived suppressor cells (MDSCs). Snail knockdown reduces the expression of CXCR2 ligands (CXCL1 and CXCL2), chemokines that attract MDSCs to the tumor via CXCR2. Snail upregulates CXCR ligands through NF-kB pathway, and most likely, through direct binding to the promoters. A CXCR2 antagonist suppresses MDSC infiltration and delays tumor growth in Snail-expressing mouse tumors. Ovarian cancer patients show elevated serum CXCL1/2, which correlates with Snail expression, MDSC infiltration, and short overall survival. Thus, Snail induces cancer progression via upregulation of CXCR2 ligands and recruitment of MDSCs. Blocking CXCR2 represents an immunological therapeutic approach to inhibit progression of Snail-high tumors undergoing EMT.
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Células Supresoras de Origen Mieloide/inmunología , Neoplasias Ováricas/inmunología , Receptores de Interleucina-8B/inmunología , Factores de Transcripción de la Familia Snail/metabolismo , Animales , Quimiocina CXCL1/sangre , Quimiocina CXCL1/metabolismo , Quimiocina CXCL2/sangre , Quimiocina CXCL2/metabolismo , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal/genética , Transición Epitelial-Mesenquimal/inmunología , Femenino , Regulación Neoplásica de la Expresión Génica/inmunología , Técnicas de Silenciamiento del Gen , Humanos , Ratones , Ratones Endogámicos ICR , Ratones Desnudos , Persona de Mediana Edad , Neoplasias Ováricas/sangre , Neoplasias Ováricas/genética , Neoplasias Ováricas/mortalidad , Receptores de Interleucina-8B/antagonistas & inhibidores , Receptores de Interleucina-8B/metabolismo , Transducción de Señal , Factores de Transcripción de la Familia Snail/genética , Regulación hacia Arriba , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Previous studies have reported genome-wide mutation profile analyses in ovarian clear cell carcinomas (OCCCs). This study aims to identify specific novel molecular alterations by combined analyses of somatic mutation and copy number variation. We performed whole exome sequencing of 39 OCCC samples with 16 matching blood tissue samples. Four hundred twenty-six genes had recurrent somatic mutations. Among the 39 samples, ARID1A (62%) and PIK3CA (51%) were frequently mutated, as were genes such as KRAS (10%), PPP2R1A (10%), and PTEN (5%), that have been reported in previous OCCC studies. We also detected mutations in MLL3 (15%), ARID1B (10%), and PIK3R1 (8%), which are associations not previously reported. Gene interaction analysis and functional assessment revealed that mutated genes were clustered into groups pertaining to chromatin remodeling, cell proliferation, DNA repair and cell cycle checkpointing, and cytoskeletal organization. Copy number variation analysis identified frequent amplification in chr8q (64%), chr20q (54%), and chr17q (46%) loci as well as deletion in chr19p (41%), chr13q (28%), chr9q (21%), and chr18q (21%) loci. Integration of the analyses uncovered that frequently mutated or amplified/deleted genes were involved in the KRAS/phosphatidylinositol 3-kinase (82%) and MYC/retinoblastoma (75%) pathways as well as the critical chromatin remodeling complex switch/sucrose nonfermentable (85%). The individual and integrated analyses contribute details about the OCCC genomic landscape, which could lead to enhanced diagnostics and therapeutic options.
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Cromosomas Humanos/genética , Exoma/genética , Redes Reguladoras de Genes , Mutación/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Análisis de Secuencia de ADN/métodos , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/patología , Variaciones en el Número de Copia de ADN/genética , Proteínas de Unión al ADN , Femenino , Heterocigoto , Homocigoto , Humanos , Proteínas Nucleares/genética , Fosfohidrolasa PTEN/genética , Polimorfismo de Nucleótido Simple/genética , Factores de Transcripción/genéticaRESUMEN
Emerging evidence has highlighted the host immune system in modulating the patient response to chemotherapy, but the mechanism of this modulation remains unclear. The aim of this study was to analyze the effect of chemotherapy on antitumor immunity in the tumor microenvironment of ovarian cancer. Treatment of ovarian cancer cell lines with various chemotherapeutic agents resulted in upregulated expression of MHC class I and programmed cell death 1 ligand 1 (PD-L1) in a NF-κB-dependent manner and suppression of antigen-specific T-cell function in vitro. In a mouse model of ovarian cancer, treatment with paclitaxel increased CD8(+) T-cell infiltration into the tumor site, upregulated PD-L1 expression, and activated NF-κB signaling. In particular, tumor-bearing mice treated with a combination of paclitaxel and a PD-L1/PD-1 signal blockade survived longer than mice treated with paclitaxel alone. In summary, we found that chemotherapy induces local immune suppression in ovarian cancer through NF-κB-mediated PD-L1 upregulation. Thus, a combination of chemotherapy and immunotherapy targeting the PD-L1/PD-1 signaling axis may improve the antitumor response and offers a promising new treatment modality against ovarian cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Antígeno B7-H1/biosíntesis , FN-kappa B/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Microambiente Tumoral/inmunología , Animales , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Antígeno B7-H1/inmunología , Capecitabina/administración & dosificación , Capecitabina/farmacología , Línea Celular Tumoral , Docetaxel , Femenino , Humanos , Ratones , FN-kappa B/inmunología , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/farmacología , Neoplasias Ováricas/genética , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Taxoides/administración & dosificación , Taxoides/farmacología , Transcriptoma/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: Programmed death-1 (PD-1), a coinhibitory immune signal receptor expressed in T cells, binds to PD-1 ligand and regulates antitumor immunity. Nivolumab is an anti-PD-1 antibody that blocks PD-1 signaling. We assessed the safety and antitumor activity of nivolumab in patients with platinum-resistant ovarian cancer. PATIENTS AND METHODS: Twenty patients with platinum-resistant ovarian cancer were treated with an intravenous infusion of nivolumab every 2 weeks at a dose of 1 or 3 mg/kg (constituting two 10-patient cohorts) from October 21, 2011. This phase II trial defined the primary end point as the best overall response. Patients received up to six cycles (four doses per cycle) of nivolumab treatment or received doses until disease progression occurred. Twenty nivolumab-treated patients were evaluated at the end of the trial on December 7, 2014. RESULTS: Grade 3 or 4 treatment-related adverse events occurred in eight (40%) of 20 patients. Two patients had severe adverse events. In the 20 patients in whom responses could be evaluated, the best overall response was 15%, which included two patients who had a durable complete response (in the 3-mg/kg cohort). The disease control rate in all 20 patients was 45%. The median progression-free survival time was 3.5 months (95% CI, 1.7 to 3.9 months), and the median overall survival time was 20.0 months (95% CI, 7.0 months to not reached) at study termination. CONCLUSION: This study, to our knowledge, is the first to explore the effects of nivolumab against ovarian cancer. The encouraging safety and clinical efficacy of nivolumab in patients with platinum-resistant ovarian cancer indicate the merit of additional large-scale investigations (UMIN Clinical Trials Registry UMIN000005714).
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Terapia Recuperativa , Adenocarcinoma de Células Claras/tratamiento farmacológico , Adenocarcinoma de Células Claras/mortalidad , Adenocarcinoma de Células Claras/secundario , Anciano , Estudios de Cohortes , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/mortalidad , Cistadenocarcinoma Seroso/secundario , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/mortalidad , Neoplasias Endometriales/secundario , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Nivolumab , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/mortalidad , Neoplasias Peritoneales/secundario , Platino (Metal)/farmacología , Pronóstico , Receptor de Muerte Celular Programada 1/inmunología , Tasa de SupervivenciaRESUMEN
Metastin/kisspeptin is encoded by KISS1 and functions as an endogenous ligand of GPR54. Interaction of metastin with GPR54 suppresses metastasis and also regulates release of gonadotropin-releasing hormone, which promotes secretion of estradiol (E2) and progesterone (P4). We have previously demonstrated epigenetic regulation of GPR54 in endometrial cancer and the potent role of metastin peptides in inhibiting metastasis in endometrial cancer. However, little is known about how the metastin-GPR54 axis is regulated in the endometrium, the precursor tissue of endometrial cancer. Endometrial stromal cells (ESCs) and endometrial glandular cells (EGCs) within the endometrium show morphological changes when exposed to E2 and P4. In this study, we show that metastin expression is induced in ESCs through decidualization, but is repressed in glandular components of atypical endometrial hyperplasia (AEH) and endometrial cancer relative to EGCs. The promoter of GPR54 is unmethylated in normal endometrium and in AEH. These results indicate metastin may function in decidualized endometrium to prepare for adequate placentation but this autocrine secretion of metastin is deregulated during oncogenesis to enable tumor cells to spread.
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Endometrio/metabolismo , Kisspeptinas/metabolismo , Ciclo Menstrual/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Adulto , Hiperplasia Endometrial/genética , Hiperplasia Endometrial/metabolismo , Neoplasias Endometriales/genética , Neoplasias Endometriales/metabolismo , Epigénesis Genética/genética , Estradiol/metabolismo , Femenino , Humanos , Kisspeptinas/genética , Ciclo Menstrual/genética , Persona de Mediana Edad , Progesterona/metabolismo , Regiones Promotoras Genéticas/genética , Receptores Acoplados a Proteínas G/genética , Receptores de Kisspeptina-1 , Células del Estroma/metabolismoRESUMEN
Recent studies of the interferon-induced transcription factor STAT1 have associated its dysregulation with poor prognosis in some cancers, but its mechanistic contributions are not well defined. In this study, we report that the STAT1 pathway is constitutively upregulated in type II endometrial cancers. STAT1 pathway alteration was especially prominent in serous papillary endometrial cancers (SPEC) that are refractive to therapy. Our results defined a "SPEC signature" as a molecular definition of its malignant features and poor prognosis. Specifically, we found that STAT1 regulated MYC as well as ICAM1, PD-L1, and SMAD7, as well as the capacity for proliferation, adhesion, migration, invasion, and in vivo tumorigenecity in cells with a high SPEC signature. Together, our results define STAT1 as a driver oncogene in SPEC that modulates disease progression. We propose that STAT1 functions as a prosurvival gene in SPEC, in a manner important to tumor progression, and that STAT1 may be a novel target for molecular therapy in this disease.
Asunto(s)
Cistadenocarcinoma Papilar/patología , Cistadenocarcinoma Seroso/patología , Neoplasias Endometriales/patología , Factor de Transcripción STAT1/fisiología , Animales , Línea Celular Tumoral , Progresión de la Enfermedad , Neoplasias Endometriales/etiología , Neoplasias Endometriales/mortalidad , Femenino , Perfilación de la Expresión Génica , Genes myc , Humanos , Interferón gamma/fisiología , Ratones , Pronóstico , Factor de Transcripción STAT1/análisisRESUMEN
The expression of A-type lamins, subdivided into lamin A and C, is developmentally regulated. Retinoic acid (RA)-induced differentiation of P19 embryonic carcinoma cells, in which A-type lamins are absent, increases the expression of lamin A/C. We previously showed, using P19 cells as a model system, that the lamin A/C promoter has a retinoic acid-responsive element (L-RARE), and that Sp1 and Sp3 bind the CACCC box of the L-RARE. In this study, we report that Sp1, Sp3, and c-Jun increase transactivation of the L-RARE during RA treatment. Sp1 and Sp3 regulate the lamin A/C promoter in Sp1-deficient SL2 cells and contribute to RA-dependent activation in GAL4-based transcriptional assays. Overexpression of c-Jun causes transactivation of a chimeric promoter consisting of four tandem L-RARE repeats fused with the luciferase gene in P19 cells. c-Jun also transactivates a reporter construct with five tandem GAL4-binding sites, only when co-expressed with either GAL4-Sp1 or Sp3 fusion proteins. Furthermore, we detect a physiological interaction between c-Jun with Sp1/Sp3 in RA-treated cells. Our data suggest that Sp1, Sp3, and c-Jun play an important role in gene expression through the L-RARE during RA treatment.