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1.
Medicine (Baltimore) ; 100(40): e27473, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34622876

RESUMO

BACKGROUND: FOXP4-AS1 expression participates in multiple signal pathways and has been previously reported in colorectal cancer, cervical cancer, and other cancer cells. However, its role on prognosis and immune infiltrates in ovarian serous cystadenocarcinoma (OVs) remains unclear. The purpose of our study was to investigate the expression of FOXP4-AS1 in OVs and its association with immune infiltrates, and determined its prognostic roles in OVs. METHODS: Using The Cancer Genome Atlas (TCGA) database, we retrieved FOXP4-AS1 expression and clinical information for 376 patients with OVs. Wilcoxon rank sum test was used to compare the expression of FOXP4-AS1 in OVs and normal ovarian tissue. Logistic regression was used to analyze the relationship between clinicopathologic features and FOXP4-AS1. Gene Set Enrichment Analysis (GSEA), and single sample Gene Set Enrichment Analysis (ssGSEA) was conducted to investigate the enrich pathways and functions and quantify the extent of immune cells infiltration for FOXP4-AS1. Kaplan-Meier method was used to generate survival curves, and Cox regression was used to analyze the relationship between FOXP4-AS1 and survival rate. RESULTS: High FOXP4-AS1 expression was significantly correlated with tumor FIGO stage (P = .026). Multivariate survival analysis showed that FOXP4-AS1was an independent prognostic marker for overall survival (OS; hazard ratio [HR]: 0.638; 95% confidence interval [CI]:0.467-0.871; P = .001) and disease-specific survival (DSS; HR: 0.649; CI: 0.476-0.885; P = .006). GSEA showed that High FOXP4-AS1 expression may active programmed cell death 1 (PD-1) signaling, the cytotoxic T lymphocyte-associated antigen-4 (CTLA4) pathway, the B cell receptor signaling pathway, apoptosis, fibroblast growth factor receptor (FGFR) signaling, and the Janus-activated kinase signal transducers and activators of transcription (JAK-STAT) signaling pathway. FOXP4-AS1 expression was negatively correlated with markers of immune cells, including aDC, cytotoxic cells and neutrophils. CONCLUSION: High FOXP4-AS1 expression has the potential to be a prognostic molecular marker of favorable survival in OVs.


Assuntos
Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/imunologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , RNA Longo não Codificante/biossíntese , Biomarcadores Tumorais , Cistadenocarcinoma Seroso/mortalidade , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Prognóstico
2.
Nat Commun ; 12(1): 5321, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493732

RESUMO

CARM1 is often overexpressed in human cancers including in ovarian cancer. However, therapeutic approaches based on CARM1 expression remain to be an unmet need. Cancer cells exploit adaptive responses such as the endoplasmic reticulum (ER) stress response for their survival through activating pathways such as the IRE1α/XBP1s pathway. Here, we report that CARM1-expressing ovarian cancer cells are selectively sensitive to inhibition of the IRE1α/XBP1s pathway. CARM1 regulates XBP1s target gene expression and directly interacts with XBP1s during ER stress response. Inhibition of the IRE1α/XBP1s pathway was effective against ovarian cancer in a CARM1-dependent manner both in vitro and in vivo in orthotopic and patient-derived xenograft models. In addition, IRE1α inhibitor B-I09 synergizes with immune checkpoint blockade anti-PD1 antibody in an immunocompetent CARM1-expressing ovarian cancer model. Our data show that pharmacological inhibition of the IRE1α/XBP1s pathway alone or in combination with immune checkpoint blockade represents a therapeutic strategy for CARM1-expressing cancers.


Assuntos
Carcinoma Epitelial do Ovário/terapia , Endorribonucleases/genética , Neoplasias Ovarianas/terapia , Receptor de Morte Celular Programada 1/genética , Proteína-Arginina N-Metiltransferases/genética , Proteínas Serina-Treonina Quinases/genética , Proteína 1 de Ligação a X-Box/genética , Animais , Anticorpos Monoclonais/farmacologia , Sequência de Bases , Benzopiranos/farmacologia , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/imunologia , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Endorribonucleases/antagonistas & inibidores , Endorribonucleases/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Himecromona/análogos & derivados , Himecromona/farmacologia , Inibidores de Checkpoint Imunológico , Camundongos , Terapia de Alvo Molecular , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Ligação Proteica , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/imunologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/imunologia , Transdução de Sinais , Proteína 1 de Ligação a X-Box/antagonistas & inibidores , Proteína 1 de Ligação a X-Box/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Int J Mol Sci ; 22(18)2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34575893

RESUMO

Immunotherapy holds tremendous potential in cancer therapy, in particular, when treatment regimens are combined to achieve synergy between pathways along the cancer immunity cycle. In previous works, we demonstrated that in situ vaccination with the plant virus cowpea mosaic virus (CPMV) activates and recruits innate immune cells, therefore reprogramming the immunosuppressive tumor microenvironment toward an immune-activated state, leading to potent anti-tumor immunity in tumor mouse models and canine patients. CPMV therapy also increases the expression of checkpoint regulators on effector T cells in the tumor microenvironment, such as PD-1/PD-L1, and we demonstrated that combination with immune checkpoint therapy improves therapeutic outcomes further. In the present work, we tested the hypothesis that CPMV could be combined with anti-PD-1 peptides to replace expensive antibody therapies. Specifically, we set out to test whether a multivalent display of anti-PD-1 peptides (SNTSESF) would enhance efficacy over a combination of CPMV and soluble peptide. Efficacy of the approaches were tested using a syngeneic mouse model of intraperitoneal ovarian cancer. CPMV combination with anti-PD-1 peptides (SNTSESF) resulted in increased efficacy; however, increased potency against metastatic ovarian cancer was only observed when SNTSESF was conjugated to CPMV, and not added as a free peptide. This can be explained by the differences in the in vivo fates of the nanoparticle formulation vs. the free peptide; the larger nanoparticles are expected to exhibit prolonged tumor residence and favorable intratumoral distribution. Our study provides new design principles for plant virus-based in situ vaccination strategies.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Vacinas Anticâncer/imunologia , Imunoterapia , Nanopartículas , Neoplasias Ovarianas/terapia , Peptídeos/imunologia , Vírus de Plantas , Vacinas de Partículas Semelhantes a Vírus/imunologia , Sequência de Aminoácidos , Animais , Vacinas Anticâncer/administração & dosagem , Comovirus , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Peptídeos/química , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Cancer Res Clin Oncol ; 147(12): 3545-3555, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34476576

RESUMO

PURPOSE: An in-depth analysis of the tumor microenvironment of ovarian cancer is needed. The purpose of this study was to elucidate the architecture of the immune microenvironment of high-grade serous ovarian cancers (HGSCs) with or without BRCA1 and BRCA2 mutations. METHODS: A cohort of highly annotated HGSC patients with known germline BRCA1 and BRCA2 status was selected, and pretreatment tumor tissue specimens were analyzed with a multiplexed staining technique aimed at detecting lymphocytes, macrophages, and fibroblasts in the whole tumor area and in specific regions including epithelium, stroma, and perivascular areas. RESULTS: BRCA1- or BRCA2-mutated tumors showed a more immunogenic microenvironment, characterized by a higher abundance of CD8+ and PD-L1+ cells, than did tumors with wild-type BRCA1 and BRCA2. High numbers of PD-L1+ and PD-L1+CD8+ cells were prognostic for event-free survival (hazard ratio [HR]: 0.41, 95% CI 0.21-0.79, p = 0.008 and HR 0.49, 95% CI 0.26-0.91, p = 0.025, respectively), as were high numbers of epithelial PD-L1+ and FAP+PD-L1+ cells (HR 0.52, 95% CI 0.28-0.96, p = 0.037 and HR 0.27, 95% CI 0.08-0.87, p = 0.029) and CD8+ cells (HR 0.51, 95% CI 0.28-0.93, p = 0.027). CONCLUSIONS: This study reveals substantial differences between the immune microenvironment composition of germline BRCA-mutated and BRCA wild-type HGSC.


Assuntos
Cistadenocarcinoma Seroso/imunologia , Neoplasias Ovarianas/imunologia , Microambiente Tumoral/imunologia , Adulto , Idoso , Proteína BRCA1/genética , Proteína BRCA2/genética , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Feminino , Mutação em Linhagem Germinativa , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia
5.
Front Immunol ; 12: 645839, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34349753

RESUMO

Background: Ovarian cancer (OC) has the highest mortality rate among gynecologic malignancy. Hypoxia is a driver of the malignant progression in OC, which results in poor prognosis. We herein aimed to develop a validated model that was based on the hypoxia genes to systematically evaluate its prognosis in tumor immune microenvironment (TIM). Results: We identified 395 hypoxia-immune genes using weighted gene co-expression network analysis (WGCNA). We then established a nine hypoxia-related genes risk model using least absolute shrinkage and selection operator (LASSO) Cox regression, which efficiently distinguished high-risk patients from low-risk ones. We found that high-risk patients were significantly related to poor prognosis. The high-risk group showed unique immunosuppressive microenvironment, lower antigen presentation, and higher levels of inhibitory cytokines. There were also significant differences in somatic copy number alterations (SCNAs) and mutations between the high- and low-risk groups, indicating immune escape in the high-risk group. Tumor immune dysfunction and exclusion (TIDE) and SubMap algorithms showed that low-risk patients are significantly responsive to programmed cell death protein-1 (PD-1) inhibitors. Conclusions: In this study, we highlighted the clinical significance of hypoxia in OC and established a hypoxia-related model for predicting prognosis and providing potential immunotherapy strategies.


Assuntos
Neoplasias Ovarianas/mortalidade , Hipóxia Tumoral/fisiologia , Variações do Número de Cópias de DNA , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Nomogramas , Neoplasias Ovarianas/etiologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Prognóstico , Microambiente Tumoral
6.
Cells ; 10(7)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34359872

RESUMO

Ovarian cancer is the most lethal gynecological malignancy, with serous histotype as the most prevalent epithelial ovarian cancer (EOC). Peritoneal ascites is a frequent comorbidity in advanced EOC. EOC-associated ascites provide a reliable sampling source for studying lymphocytes directly from tumor environment. Herein, we carried out flow cytometry-based analysis to readdress issues on NK and T lymphocyte subsets in women with advanced EOC, additionally evaluating phenotypic modulation of their intracellular pathways involved in interleukin (IL)-2 and IL-15 signaling. Results depicted ascites as an inflammatory and immunosuppressive environment, presenting significantly (p < 0.0001) higher amounts of IL-6 and IL-10 than in the patients' blood, as well as significantly (p < 0.05) increased expression of checkpoint inhibitory receptors (programmed death protein-1, PD-1) and ectonucleotidase (CD39) on T lymphocytes. However, NK lymphocytes from EOC-associated ascites showed higher (p < 0.05) pS6 phosphorylation compared with NK from blood. Additionally, in vitro treatment of lymphocytes with IL-2 or IL-15 elicited significantly (p < 0.001) phosphorylation of the STAT5 protein in NK, CD3 and CD8 lymphocytes, both from blood and ascites. EOC-associated ascites had a significantly (p < 0.0001) higher proportion of NK CD56bright lymphocytes than blood, which, in addition, were more responsive (p < 0.05) to stimulation by IL-2 than CD56dim NK. EOC-associated ascites allow studies on lymphocyte phenotype modulation in the tumor environment, where inflammatory profile contrasts with the presence of immunosuppressive elements and development of cellular self-regulating mechanisms.


Assuntos
Ascite/imunologia , Antígeno CD56/imunologia , Cistadenocarcinoma Seroso/imunologia , Células Matadoras Naturais/imunologia , Neoplasias Ovarianas/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Apirase/genética , Apirase/imunologia , Ascite/genética , Ascite/patologia , Antígeno CD56/genética , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imunofenotipagem , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-15/genética , Interleucina-15/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Células K562 , Células Matadoras Naturais/patologia , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/imunologia , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/patologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
7.
J Hematol Oncol ; 14(1): 118, 2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34325726

RESUMO

Although chimeric antigen receptor (CAR)-engineered T cells have shown great success in the treatment of B cell malignancies, this strategy has limited efficacy in patients with solid tumors. In mouse CAR-T cells, IL-7 and CCL19 expression have been demonstrated to improve T cell infiltration and CAR-T cell survival in mouse tumors. Therefore, in the current study, we engineered human CAR-T cells to secrete human IL-7 and CCL19 (7 × 19) and found that these 7 × 19 CAR-T cells showed enhanced capacities of expansion and migration in vitro. Furthermore, 7 × 19 CAR-T cells showed superior tumor suppression ability compared to conventional CAR-T cells in xenografts of hepatocellular carcinoma (HCC) cell lines, primary HCC tissue samples and pancreatic carcinoma (PC) cell lines. We then initiated a phase 1 clinical trial in advanced HCC/PC/ovarian carcinoma (OC) patients with glypican-3 (GPC3) or mesothelin (MSLN) expression. In a patient with advanced HCC, anti-GPC3-7 × 19 CAR-T treatment resulted in complete tumor disappearance 30 days post intratumor injection. In a patient with advanced PC, anti-MSLN-7 × 19 CAR-T treatment resulted in almost complete tumor disappearance 240 days post-intravenous infusion. Our results demonstrated that the incorporation of 7 × 19 into CAR-T cells significantly enhanced the antitumor activity against human solid tumor. Trial registration: NCT03198546. Registered 26 June 2017, https://clinicaltrials.gov/ct2/show/NCT03198546?term=NCT03198546&draw=2&rank=1.


Assuntos
Quimiocina CCL19/imunologia , Proteínas Ligadas por GPI/análise , Glipicanas/análise , Imunoterapia Adotiva/métodos , Interleucina-7/imunologia , Neoplasias/terapia , Animais , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/terapia , Feminino , Proteínas Ligadas por GPI/imunologia , Glipicanas/imunologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/terapia , Camundongos , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/terapia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/terapia , Linfócitos T/imunologia , Resultado do Tratamento
8.
Front Immunol ; 12: 690201, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220848

RESUMO

Ovarian carcinomas (OCs) are poorly immunogenic and immune checkpoint inhibitors (ICIs) have offered a modest benefit. In this study, high CD3+ T-cells and CD163+ tumor-associated macrophages (TAMs) densities identify a subgroup of immune infiltrated high-grade serous carcinomas (HGSCs) with better outcomes and superior response to platinum-based therapies. On the contrary, in most clear cell carcinomas (CCCs) showing poor prognosis and refractory to platinum, a high TAM density is associated with low T cell frequency. Immune infiltrated HGSC are characterized by the 30-genes signature (OC-IS30) covering immune activation and IFNγ polarization and predicting good prognosis (n = 312, TCGA). Immune infiltrated HGSC contain CXCL10 producing M1-type TAM (IRF1+pSTAT1Y701+) in close proximity to T-cells. A fraction of these M1-type TAM also co-expresses TREM2. M1-polarized TAM were barely detectable in T-cell poor CCC, but identifiable across various immunogenic human cancers. Single cell RNA sequencing data confirm the existence of a tumor-infiltrating CXCL10+IRF1+STAT1+ M1-type TAM overexpressing antigen processing and presentation gene programs. Overall, this study highlights the clinical relevance of the CXCL10+IRF1+STAT1+ macrophage subset as biomarker for intratumoral T-cell activation and therefore offers a new tool to select patients more likely to respond to T-cell or macrophage-targeted immunotherapies.


Assuntos
Carcinoma/metabolismo , Quimiocina CXCL10/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias Císticas, Mucinosas e Serosas/metabolismo , Neoplasias Ovarianas/metabolismo , Microambiente Tumoral , Macrófagos Associados a Tumor/metabolismo , Idoso , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Complexo CD3/metabolismo , Carcinoma/tratamento farmacológico , Carcinoma/genética , Carcinoma/imunologia , Células Cultivadas , Quimiocina CXCL10/genética , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Fator Regulador 1 de Interferon/genética , Fator Regulador 1 de Interferon/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Neoplasias Císticas, Mucinosas e Serosas/tratamento farmacológico , Neoplasias Císticas, Mucinosas e Serosas/genética , Neoplasias Císticas, Mucinosas e Serosas/imunologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Fenótipo , Prognóstico , Receptores de Superfície Celular/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Macrófagos Associados a Tumor/imunologia
9.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070369

RESUMO

Folate receptor beta (FRß) is a folate binding receptor expressed on myeloid lineage hematopoietic cells. FRß is commonly expressed at high levels on malignant blasts in patients with acute myeloid leukemia (AML), as well as on M2 polarized tumor-associated macrophages (TAMs) in the tumor microenvironment of many solid tumors. Therefore, FRß is a potential target for both direct and indirect cancer therapy. We demonstrate that FRß is expressed in both AML cell lines and patient-derived AML samples and that a high-affinity monoclonal antibody against FRß (m909) has the ability to cause dose- and expression-dependent ADCC against these cells in vitro. Importantly, we find that administration of m909 has a significant impact on tumor growth in a humanized mouse model of AML. Surprisingly, m909 functions in vivo with and without the infusion of human NK cells as mediators of ADCC, suggesting potential involvement of mouse macrophages as effector cells. We also found that TAMs from primary ovarian ascites samples expressed appreciable levels of FRß and that m909 has the ability to cause ADCC in these samples. These results indicate that the targeting of FRß using m909 has the potential to limit the outgrowth of AML in vitro and in vivo. Additionally, m909 causes cytotoxicity to TAMs in the tumor microenvironment of ovarian cancer warranting further investigation of m909 and its derivatives as therapeutic agents in patients with FRß-expressing cancers.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Receptor 2 de Folato , Imunoterapia , Leucemia Mieloide Aguda , Proteínas de Neoplasias , Neoplasias Ovarianas , Animais , Células CHO , Cricetulus , Feminino , Receptor 2 de Folato/antagonistas & inibidores , Receptor 2 de Folato/imunologia , Células HL-60 , Humanos , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/imunologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Células THP-1 , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Lancet Oncol ; 22(7): 1034-1046, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34143970

RESUMO

BACKGROUND: Most patients with ovarian cancer will relapse after receiving frontline platinum-based chemotherapy and eventually develop platinum-resistant or platinum-refractory disease. We report results of avelumab alone or avelumab plus pegylated liposomal doxorubicin (PLD) compared with PLD alone in patients with platinum-resistant or platinum-refractory ovarian cancer. METHODS: JAVELIN Ovarian 200 was an open-label, parallel-group, three-arm, randomised, phase 3 trial, done at 149 hospitals and cancer treatment centres in 24 countries. Eligible patients were aged 18 years or older with epithelial ovarian, fallopian tube, or peritoneal cancer (maximum of three previous lines for platinum-sensitive disease, none for platinum-resistant disease) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1:1) via interactive response technology to avelumab (10 mg/kg intravenously every 2 weeks), avelumab plus PLD (40 mg/m2 intravenously every 4 weeks), or PLD and stratified by disease platinum status, number of previous anticancer regimens, and bulky disease. Primary endpoints were progression-free survival by blinded independent central review and overall survival in all randomly assigned patients, with the objective to show whether avelumab alone or avelumab plus PLD is superior to PLD. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02580058. The trial is no longer enrolling patients and this is the final analysis of both primary endpoints. FINDINGS: Between Jan 5, 2016, and May 16, 2017, 566 patients were enrolled and randomly assigned (combination n=188; PLD n=190, avelumab n=188). At data cutoff (Sept 19, 2018), median duration of follow-up for overall survival was 18·4 months (IQR 15·6-21·9) for the combination group, 17·4 months (15·2-21·3) for the PLD group, and 18·2 months (15·8-21·2) for the avelumab group. Median progression-free survival by blinded independent central review was 3·7 months (95% CI 3·3-5·1) in the combination group, 3·5 months (2·1-4·0) in the PLD group, and 1·9 months (1·8-1·9) in the avelumab group (combination vs PLD: stratified HR 0·78 [repeated 93·1% CI 0·59-1·24], one-sided p=0·030; avelumab vs PLD: 1·68 [1·32-2·60], one-sided p>0·99). Median overall survival was 15·7 months (95% CI 12·7-18·7) in the combination group, 13·1 months (11·8-15·5) in the PLD group, and 11·8 months (8·9-14·1) in the avelumab group (combination vs PLD: stratified HR 0·89 [repeated 88·85% CI 0·74-1·24], one-sided p=0·21; avelumab vs PLD: 1·14 [0·95-1·58], one-sided p=0·83]). The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysesthesia syndrome (18 [10%] in the combination group vs nine [5%] in the PLD group vs none in the avelumab group), rash (11 [6%] vs three [2%] vs none), fatigue (ten [5%] vs three [2%] vs none), stomatitis (ten [5%] vs five [3%] vs none), anaemia (six [3%] vs nine [5%] vs three [2%]), neutropenia (nine [5%] vs nine [5%] vs none), and neutrophil count decreased (eight [5%] vs seven [4%] vs none). Serious treatment-related adverse events occurred in 32 (18%) patients in the combination group, 19 (11%) in the PLD group, and 14 (7%) in the avelumab group. Treatment-related adverse events resulted in death in one patient each in the PLD group (sepsis) and avelumab group (intestinal obstruction). INTERPRETATION: Neither avelumab plus PLD nor avelumab alone significantly improved progression-free survival or overall survival versus PLD. These results provide insights for patient selection in future studies of immune checkpoint inhibitors in platinum-resistant or platinum-refractory ovarian cancer. FUNDING: Pfizer and Merck KGaA, Darmstadt, Germany.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Compostos de Platina/uso terapêutico , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Progressão da Doença , Intervalo Livre de Doença , Doxorrubicina/análogos & derivados , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Pessoa de Meia-Idade , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/mortalidade , Compostos de Platina/efeitos adversos , Polietilenoglicóis/uso terapêutico , Fatores de Tempo
11.
Elife ; 102021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34114949

RESUMO

Transcoelomic spread of cancer cells across the peritoneal cavity occurs in most initially diagnosed ovarian cancer (OC) patients and accounts for most cancer-related death. However, how OC cells interact with peritoneal stromal cells to evade the immune surveillance remains largely unexplored. Here, through an in vivo genome-wide CRISPR/Cas9 screen, we identified IL20RA, which decreased dramatically in OC patients during peritoneal metastasis, as a key factor preventing the transcoelomic metastasis of OC. Reconstitution of IL20RA in highly metastatic OC cells greatly suppresses the transcoelomic metastasis. OC cells, when disseminate into the peritoneal cavity, greatly induce peritoneum mesothelial cells to express IL-20 and IL-24, which in turn activate the IL20RA downstream signaling in OC cells to produce mature IL-18, eventually resulting in the polarization of macrophages into the M1-like subtype to clear the cancer cells. Thus, we show an IL-20/IL20RA-mediated crosstalk between OC and mesothelial cells that supports a metastasis-repressing immune microenvironment.


Assuntos
Sistemas CRISPR-Cas , Interleucinas/genética , Metástase Neoplásica/genética , Neoplasias Ovarianas/genética , Receptores de Interleucina/genética , Animais , Linhagem Celular Tumoral , Epitélio/imunologia , Feminino , Técnicas de Silenciamento de Genes , Humanos , Interleucinas/metabolismo , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/metabolismo , Cavidade Peritoneal/patologia , Receptores de Interleucina/metabolismo , Transdução de Sinais , Microambiente Tumoral
12.
Sci Rep ; 11(1): 12574, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34131176

RESUMO

Human neutrophils constitutively express high amounts of arginase-1, which depletes arginine from the surrounding medium and downregulates T-cell activation. Here, we have found that neutrophil arginase-1, released from activated human neutrophils or dead cells, induced apoptosis in cancer cells through an endoplasmic reticulum (ER) stress pathway. Silencing of PERK in cancer cells prevented the induction of ER stress and apoptosis. Arginase inhibitor Nω-hydroxy-nor-arginine inhibited apoptosis and ER stress response induced by conditioned medium from activated neutrophils. A number of tumor cell lines, derived from different tissues, were sensitive to neutrophil arginase-1, with pancreatic, breast, ovarian and lung cancer cells showing the highest sensitivity. Neutrophil-released arginase-1 and arginine deprivation potentiated the antitumor action against pancreatic cancer cells of the ER-targeted antitumor alkylphospholipid analog edelfosine. Our study demonstrates the involvement of neutrophil arginase-1 in cancer cell killing and highlights the importance and complex role of neutrophils in tumor surveillance and biology.


Assuntos
Arginase/genética , Estresse do Retículo Endoplasmático/genética , Linfócitos T/imunologia , eIF-2 Quinase/genética , Apoptose/genética , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Retículo Endoplasmático/enzimologia , Feminino , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neutrófilos/enzimologia , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Linfócitos T/enzimologia
13.
J Obstet Gynaecol Res ; 47(9): 2978-2989, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34184357

RESUMO

AIMS: Tissue factor pathway inhibitor (TFPI)-2 has recently emerged as a serodiagnostic marker for patients with epithelial ovarian cancer (EOC), especially clear cell carcinoma (CCC). This review discusses the biological properties of TFPI-2 and why serum levels are elevated in CCC patients. METHODS: A comprehensive literature search was conducted in PubMed up until March, 2021. RESULTS: TFPI-2 is a Kunitz-type protease inhibitor and negatively regulates the enzymatic activities, such as plasmin. TFPI-2 has been characterized as a tumor suppressor gene and was frequently downregulated through promoter hypermethylation in various human cancers. In contrast, TFPI-2 was overexpressed only in CCC. TFPI-2 may be involved in the pathophysiology of CCC, possibly through regulation of coagulation system, stabilization of extracellular matrix (ECM), and induction of intracellular signal transduction. TFPI-2 suppresses tissue factor-induced hypercoagulation in a hypoxic environment. TFPI-2, secreted by CCC cells, platelets, and adjacent vascular endothelial cells, may suppress tumor growth and invasion through ECM remodeling. Nuclear TFPI-2 may suppress matrix metalloproteinase production via transcription factors and modulate caspase-mediated cell apoptosis. CCC cells may upregulate the TFPI-2 expression to adapt to survival in the demanding environment. TFPI-2 is secreted by CCC cells and enters the systemic circulation, resulting in elevated blood levels. DISCUSSION: Serum TFPI-2 reflects the overexpression of TFPI-2 in CCC tissues and is a potential serodiagnostic marker. Further research is needed to explore the expression, clinical significance, biological function, and potential mechanism of TFPI-2 in CCC.


Assuntos
Carcinoma , Células Endoteliais , Glicoproteínas , Neoplasias Ovarianas , Carcinoma/diagnóstico , Carcinoma/imunologia , Feminino , Glicoproteínas/genética , Glicoproteínas/imunologia , Humanos , Lipoproteínas , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/imunologia , Ovário , Testes Sorológicos
14.
Biochem Biophys Res Commun ; 563: 40-46, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34058473

RESUMO

Standard chemotherapy for ovarian cancers is often abrogated by drug resistance. Specifically, resistance to cisplatin is a major clinical obstacle to successful treatment of ovarian cancers. The aim of this study was to develop a therapeutic strategy using natural killer (NK) cells to treat cisplatin-resistant ovarian cancers. First, we compared the responses of ovarian cancer cell line A2780 and its cisplatin-resistant counterpart, A2780cis, to treatment with cisplatin plus NK92MI cells. Although combined treatment induces apoptosis of ovarian cancer cells via ROS-dependent and -independent mechanisms, A2780cis were resistant to NK92MI cell-mediated cytotoxicity. We found that A2780cis cells showed markedly higher expression of immune checkpoint protein, PD-L1, than the parental cells. Although pretreatment of A2780cis cells with cisplatin stimulated further expression of PD-L1, it also increased expression of ULBP ligands, which are activating receptors on NK92MI cells, both in vitro and in vivo. These findings suggest that combined use of cisplatin plus NK cell-mediated immunotherapy could overcome immunoresistance of chemoresistant ovarian cancers.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células Matadoras Naturais/citologia , Neoplasias Ovarianas/terapia , Antineoplásicos/química , Cisplatino/química , Feminino , Humanos , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Células Tumorais Cultivadas
15.
Biomed Res Int ; 2021: 6680036, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33997040

RESUMO

Backgrounds: The dysregulated long noncoding RNAs (lncRNAs) have been described to be crucial regulators in the progression of ovarian carcinoma. The infiltration status of immune cells is also related to the clinical outcomes in ovarian carcinoma. The present research is aimed at constructing an immune-associated lncRNA signature with potential prognostic value for ovarian carcinoma patients. Methods: We obtained 379 ovarian carcinoma cases with available clinical data and transcriptome data from The Cancer Genome Atlas database to evaluate the infiltration status of immune cells, thereby generating high and low immune cell infiltration groups. According to the expression of the immune-associated lncRNA signature, the risk score of each case was calculated. The high- and low-risk groups were classified using the median risk score as threshold. Results: A total of 169 immune-associated lncRNAs that differentially expressed in ovarian carcinoma were included. According to the Lasso regression analysis and Cox univariate and multivariate analyses, 5 immune-associated lncRNAs, including AC134312.1, AL133467.1, CHRM3-AS2, LINC01722, and LINC02207, were identified as a predictive signature with significant prognostic value in ovarian carcinoma. The following Kaplan-Meier analysis, ROC analysis, and Cox univariate and multivariate analyses further suggested that the predicted signature may be an independent prognosticator for patients with ovarian carcinoma. The following gene set enrichment analysis showed that this 5 immune-associated lncRNAs signature was significantly related to the hedgehog pathway, basal cell carcinoma, Wnt signaling pathway, cytokine receptor interaction, antigen processing and presentation, and T cell receptor pathway. Conclusion: : This study suggested a predictive model with 5 immune-associated lncRNAs that has an independent prognostic value for ovarian carcinoma patients.


Assuntos
Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/mortalidade , RNA Longo não Codificante/imunologia , Transdução de Sinais/imunologia , Transcriptoma/imunologia , Biologia Computacional , Feminino , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Prognóstico , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Transdução de Sinais/genética , Transcriptoma/genética
16.
J Immunol Res ; 2021: 8875450, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33855091

RESUMO

RIPK4 has been implicated in multiple cancer types, but its role in ovarian cancer (OC) has not been clearly elucidated. Our data from Gene Expression Profiling Interactive Analysis, RT-PCR, and immunohistochemical analysis showed that RIPK4 was expressed at higher levels in OC tissues and cells than in normal ovarian tissues and cells. Increased RIPK4 expression in OC markedly correlated with a worse overall survival than lower RIPK4 expression levels (hazard rate (HR) 1.5 (1.45-1.87); P = 0.001). In functional experiments, RIPK4 downregulation significantly inhibited metastatic behaviours in OC cells. Subsequently, based on data from 593 OC patients in the TCGA database, gene set enrichment analysis revealed that RIPK4 was involved in epithelial-mesenchymal transition (EMT) in OC. At the molecular level, silencing RIPK4 significantly downregulated vimentin, N-cadherin, and Twist expression but induced an increase in the protein level of E-cadherin and inhibited the IL-6 and STAT3 levels. Moreover, IL-6 levels were significantly decreased in RIPK4-silenced OC cells (P < 0.05). The addition of IL-6 to OC cells rescued the suppressive effect of RIPK4 knockdown on EMT. Thus, our data illustrate that downregulation of RIPK4 expression can restrain EMT in OC by inhibiting IL-6. This finding may provide a novel diagnostic and therapeutic target for improving the poor prognoses of OC patients.


Assuntos
Carcinoma Epitelial do Ovário/imunologia , Transição Epitelial-Mesenquimal/imunologia , Interleucina-6/metabolismo , Neoplasias Ovarianas/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Biologia Computacional , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Técnicas de Silenciamento de Genes , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Proteínas Serina-Treonina Quinases/genética , Regulação para Cima/imunologia , Adulto Jovem
17.
Cells ; 10(5)2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33922052

RESUMO

Immunotherapy with tumor-infiltrating lymphocytes (TIL) or oncolytic adenoviruses, have shown promising results in cancer treatment, when used as separate therapies. When used in combination, the antitumor effect is synergistically potentiated due oncolytic adenovirus infection and its immune stimulating effects on T cells. Indeed, studies in hamsters have shown a 100% complete response rate when animals were treated with oncolytic adenovirus coding for TNFa and IL-2 (Ad5/3-E2F-D24-hTNFa-IRES-hIL2; TILT-123) and TIL therapy. In humans, one caveat with oncolytic virus therapy is that intratumoral injection has been traditionally preferred over systemic administration, for achieving sufficient virus concentrations in tumors, especially when neutralizing antibodies emerge. We have previously shown that 5/3 chimeric oncolytic adenovirus can bind to human lymphocytes for avoidance of neutralization. In this study, we hypothesized that incubation of oncolytic adenovirus (TILT-123) with TILs prior to systemic injection would allow delivery of virus to tumors. This approach would deliver both components in one self-amplifying product. TILs would help deliver TILT-123, whose replication will recruit more TILs and increase their cytotoxicity. In vitro, TILT-123 was seen binding efficiently to lymphocytes, supporting the idea of dual administration. We show in vivo in different models that virus could be delivered to tumors with TILs as carriers.


Assuntos
Adenoviridae/genética , Linfócitos do Interstício Tumoral/imunologia , Linfócitos/imunologia , Terapia Viral Oncolítica/métodos , Neoplasias Ovarianas/terapia , Neoplasias Pancreáticas/terapia , Microambiente Tumoral/imunologia , Animais , Cricetinae , Feminino , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Int J Mol Sci ; 22(8)2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33920983

RESUMO

Ovarian cancer is an aggressive gynaecological cancer with extremely poor prognosis, due to late diagnosis as well as the development of chemoresistance after first-line therapy. Research advances have found stem-like cells present in ovarian tumours, which exist in a dynamic niche and persist through therapy. The stem cell niche interacts extensively with the immune and non-immune components of the tumour microenvironment. Significant pathways associated with the cancer stem cell niche have been identified which interfere with the immune component of the tumour microenvironment, leading to immune surveillance evasion, dysfunction and suppression. This review aims to summarise current evidence-based knowledge on the cancer stem cell niche within the ovarian cancer tumour microenvironment and its effect on immune surveillance. Furthermore, the review seeks to understand the clinical consequences of this dynamic interaction by highlighting current therapies which target these processes.


Assuntos
Vigilância Imunológica , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Nicho de Células-Tronco/imunologia , Animais , Feminino , Humanos , Inflamação/patologia , Neoplasias Ovarianas/terapia , Transdução de Sinais
19.
Int J Mol Sci ; 22(8)2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33921111

RESUMO

The pathogenesis and molecular mechanisms of ovarian low malignant potential (LMP) tumors or borderline ovarian tumors (BOTs) have not been fully elucidated to date. Surgery remains the cornerstone of treatment for this disease, and diagnosis is mainly made by histopathology to date. However, there is no integrated analysis investigating the tumorigenesis of BOTs with open experimental data. Therefore, we first utilized a functionome-based speculative model from the aggregated obtainable datasets to explore the expression profiling data among all BOTs and two major subtypes of BOTs, serous BOTs (SBOTs) and mucinous BOTs (MBOTs), by analyzing the functional regularity patterns and clustering the separate gene sets. We next prospected and assembled the association between these targeted biomolecular functions and their related genes. Our research found that BOTs can be accurately recognized by gene expression profiles by means of integrative polygenic analytics among all BOTs, SBOTs, and MBOTs; the results exhibited the top 41 common dysregulated biomolecular functions, which were sorted into four major categories: immune and inflammatory response-related functions, cell membrane- and transporter-related functions, cell cycle- and signaling-related functions, and cell metabolism-related functions, which were the key elements involved in its pathogenesis. In contrast to previous research, we identified 19 representative genes from the above classified categories (IL6, CCR2 for immune and inflammatory response-related functions; IFNG, ATP1B1, GAS6, and PSEN1 for cell membrane- and transporter-related functions; CTNNB1, GATA3, and IL1B for cell cycle- and signaling-related functions; and AKT1, SIRT1, IL4, PDGFB, MAPK3, SRC, TWIST1, TGFB1, ADIPOQ, and PPARGC1A for cell metabolism-related functions) that were relevant in the cause and development of BOTs. We also noticed that a dysfunctional pathway of galactose catabolism had taken place among all BOTs, SBOTs, and MBOTs from the analyzed gene set databases of canonical pathways. With the help of immunostaining, we verified significantly higher performance of interleukin 6 (IL6) and galactose-1-phosphate uridylyltransferase (GALT) among BOTs than the controls. In conclusion, a bioinformatic platform of gene-set integrative molecular functionomes and biophysiological pathways was constructed in this study to interpret the complicated pathogenic pathways of BOTs, and these important findings demonstrated the dysregulated immunological functionome and dysfunctional metabolic pathway as potential roles during the tumorigenesis of BOTs and may be helpful for the diagnosis and therapy of BOTs in the future.


Assuntos
Redes e Vias Metabólicas , Herança Multifatorial/genética , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Humanos , Inflamação/patologia , Interleucina-6/metabolismo , Aprendizado de Máquina , Neoplasias Ovarianas/genética , Reprodutibilidade dos Testes , Transdução de Sinais/genética , Transcriptoma , UTP-Hexose-1-Fosfato Uridililtransferase/metabolismo
20.
Int J Mol Sci ; 22(7)2021 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-33800608

RESUMO

Our increased understanding of tumour biology gained over the last few years has led to the development of targeted molecular therapies, e.g., vascular endothelial growth factor A (VEGF-A) antagonists, poly[ADP-ribose] polymerase 1 (PARP1) inhibitors in hereditary breast and ovarian cancer syndrome (BRCA1 and BRCA2 mutants), increasing survival and improving the quality of life. However, the majority of ovarian cancer (OC) patients still do not have access to targeted molecular therapies that would be capable of controlling their disease, especially resistant or relapsed. Chimeric antigen receptors (CARs) are recombinant receptor constructs located on T lymphocytes or other immune cells that change its specificity and functions. Therefore, in a search for a successful solid tumour therapy using CARs the specific cell surface antigens identification is crucial. Numerous in vitro and in vivo studies, as well as studies on humans, prove that targeting overexpressed molecules, such as mucin 16 (MUC16), annexin 2 (ANXA2), receptor tyrosine-protein kinase erbB-2 (HER2/neu) causes high tumour cells toxicity and decreased tumour burden. CARs are well tolerated, side effects are minimal and they inhibit disease progression. However, as OC is heterogenic in its nature with high mutation diversity and overexpression of different receptors, there is a need to consider an individual approach to treat this type of cancer. In this publication, we would like to present the history and status of therapies involving the CAR T cells in treatment of OC tumours, suggest potential T cell-intrinsic determinants of response and resistance as well as present extrinsic factors impacting the success of this approach.


Assuntos
Imunoterapia Adotiva/métodos , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/terapia , Receptores de Antígenos Quiméricos/imunologia , Animais , Antígenos de Neoplasias/metabolismo , Carcinoma Epitelial do Ovário/imunologia , Carcinoma Epitelial do Ovário/terapia , Membrana Celular/metabolismo , Ensaios Clínicos como Assunto , Feminino , Técnicas de Transferência de Genes , Humanos , Concentração de Íons de Hidrogênio , Imunoterapia Adotiva/tendências , Camundongos , Recidiva Local de Neoplasia , Células-Tronco Neoplásicas/citologia , Domínios Proteicos , Engenharia de Proteínas , Isoformas de Proteínas , Fator A de Crescimento do Endotélio Vascular/metabolismo
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