Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 893
Filtrar
1.
PLoS One ; 15(8): e0238380, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32866185

RESUMO

Pancreatic adenocarcinoma is characterized by a complex tumor environment with a wide diversity of infiltrating stromal and immune cell types that impact the tumor response to conventional treatments. However, even in this poorly responsive tumor the extent of T cell infiltration as determined by quantitative immunohistology is a candidate prognostic factor for patient outcome. As such, even more comprehensive immunophenotyping of the tumor environment, such as immune cell type deconvolution via inference models based on gene expression profiling, holds significant promise. We hypothesized that RNA-Seq can provide a comprehensive alternative to quantitative immunohistology for immunophenotyping pancreatic cancer. We performed RNA-Seq on a prospective cohort of pancreatic tumor specimens and compared multiple approaches for gene expression-based immunophenotyping analysis compared to quantitative immunohistology. Our analyses demonstrated that while gene expression analyses provide additional information on the complexity of the tumor immune environment, they are limited in sensitivity by the low overall immune infiltrate in pancreatic cancer. As an alternative approach, we identified a set of genes that were enriched in highly T cell infiltrated pancreatic tumors, and demonstrate that these can identify patients with improved outcome in a reference population. These data demonstrate that the poor immune infiltrate in pancreatic cancer can present problems for analyses that use gene expression-based tools; however, there remains enormous potential in using these approaches to understand the relationships between diverse patterns of infiltrating cells and their impact on patient treatment outcomes.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Linfócitos T/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
2.
J Immunother Cancer ; 8(2)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32675312

RESUMO

BACKGROUND: Pandemic COVID-19 by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) infection is facilitated by the ACE2 receptor and protease TMPRSS2. Modestly sized case series have described clinical factors associated with COVID-19, while ACE2 and TMPRSS2 expression analyses have been described in some cell types. Patients with cancer may have worse outcomes to COVID-19. METHODS: We performed an integrated study of ACE2 and TMPRSS2 gene expression across and within organ systems, by normal versus tumor, across several existing databases (The Cancer Genome Atlas, Census of Immune Single Cell Expression Atlas, The Human Cell Landscape, and more). We correlated gene expression with clinical factors (including but not limited to age, gender, race, body mass index, and smoking history), HLA genotype, immune gene expression patterns, cell subsets, and single-cell sequencing as well as commensal microbiome. RESULTS: Matched normal tissues generally display higher ACE2 and TMPRSS2 expression compared with cancer, with normal and tumor from digestive organs expressing the highest levels. No clinical factors were consistently identified to be significantly associated with gene expression levels though outlier organ systems were observed for some factors. Similarly, no HLA genotypes were consistently associated with gene expression levels. Strong correlations were observed between ACE2 expression levels and multiple immune gene signatures including interferon-stimulated genes and the T cell-inflamed phenotype as well as inverse associations with angiogenesis and transforming growth factor-ß signatures. ACE2 positively correlated with macrophage subsets across tumor types. TMPRSS2 was less associated with immune gene expression but was strongly associated with epithelial cell abundance. Single-cell sequencing analysis across nine independent studies demonstrated little to no ACE2 or TMPRSS2 expression in lymphocytes or macrophages. ACE2 and TMPRSS2 gene expression associated with commensal microbiota in matched normal tissues particularly from colorectal cancers, with distinct bacterial populations showing strong associations. CONCLUSIONS: We performed a large-scale integration of ACE2 and TMPRSS2 gene expression across clinical, genetic, and microbiome domains. We identify novel associations with the microbiota and confirm host immunity associations with gene expression. We suggest caution in interpretation regarding genetic associations with ACE2 expression suggested from smaller case series.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Neoplasias/imunologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/imunologia , Serina Endopeptidases/metabolismo , Idoso , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Conjuntos de Dados como Assunto , Feminino , Microbioma Gastrointestinal/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Antígenos HLA/sangue , Antígenos HLA/imunologia , Humanos , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/microbiologia , Neoplasias/patologia , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , RNA-Seq
3.
Nat Commun ; 11(1): 2860, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32503978

RESUMO

The MYC oncogene drives T- and B- lymphoid malignancies, including Burkitt's lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). Here, we demonstrate a systemic reduction in natural killer (NK) cell numbers in SRα-tTA/Tet-O-MYCON mice bearing MYC-driven T-lymphomas. Residual mNK cells in spleens of MYCON T-lymphoma-bearing mice exhibit perturbations in the terminal NK effector differentiation pathway. Lymphoma-intrinsic MYC arrests NK maturation by transcriptionally repressing STAT1/2 and secretion of Type I Interferons (IFNs). Treating T-lymphoma-bearing mice with Type I IFN improves survival by rescuing NK cell maturation. Adoptive transfer of mature NK cells is sufficient to delay both T-lymphoma growth and recurrence post MYC inactivation. In MYC-driven BL patients, low expression of both STAT1 and STAT2 correlates significantly with the absence of activated NK cells and predicts unfavorable clinical outcomes. Our studies thus provide a rationale for developing NK cell-based therapies to effectively treat MYC-driven lymphomas in the future.


Assuntos
Linfoma de Burkitt/imunologia , Células Matadoras Naturais/imunologia , Linfoma de Células T/imunologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transferência Adotiva , Animais , Linfoma de Burkitt/mortalidade , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Vigilância Imunológica/genética , Interferon Tipo I/farmacologia , Interferon Tipo I/uso terapêutico , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/transplante , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/genética , Linfoma de Células T/patologia , Masculino , Camundongos , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-myc/genética , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia
4.
Cancer Immunol Immunother ; 69(9): 1881-1890, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32372138

RESUMO

BACKGROUND: Lung adenocarcinoma (LUAD) has become the most frequent histologic type of lung cancer in the past several decades. Recent successes with immune checkpoint blockade therapy have demonstrated that the manipulation of the immune system is a very potent treatment for LUAD. This study aims to explore the role of immune-related genes in the development of LUAD and establish a signature that can predict overall survival for LUAD patients. METHODS: To identify the differential expression genes (DEGs) between normal and tumor tissues, we developed an analysis strategy to combine an independent-sample design and a paired-sample design using RNA-seq transcriptomic profiling data of The Cancer Genome Atlas LUAD samples. Further, we selected prognostic markers from DEGs and evaluated their prognostic value in a prediction model. RESULTS: We identified and validated PD1, PDL1 and CTLA4 genes as prognostic markers, which are well-known immune checkpoints, and revealed two new potential prognostic immune checkpoints for LUAD, HHLA2 (logFC = 2.55, FDR = 1.89 × 10-6) and VTCN1 (logFC = -2.86, FDR = 1.72 × 10-11). Furthermore, we identified an 18-gene LUAD prognostic biomarker panel and observed that the classified high-risk group presented a significantly shorter overall survival time (HR = 3.57, p value = 4.07 × 10-10). The prediction model was validated in five independent high-throughput gene expression datasets. CONCLUSIONS: The identified DEG features may serve as potential biomarkers for prognosis prediction of LUAD patients and immunotherapy. Based on that assumption, we identified a gene expression-based immune signature for lung adenocarcinoma prognosis.


Assuntos
Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Transcriptoma/genética , Transcriptoma/imunologia , Idoso , Biomarcadores Tumorais/imunologia , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Masculino , Prognóstico
5.
Nat Genet ; 52(6): 594-603, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32451460

RESUMO

Immunotherapy for metastatic colorectal cancer is effective only for mismatch repair-deficient tumors with high microsatellite instability that demonstrate immune infiltration, suggesting that tumor cells can determine their immune microenvironment. To understand this cross-talk, we analyzed the transcriptome of 91,103 unsorted single cells from 23 Korean and 6 Belgian patients. Cancer cells displayed transcriptional features reminiscent of normal differentiation programs, and genetic alterations that apparently fostered immunosuppressive microenvironments directed by regulatory T cells, myofibroblasts and myeloid cells. Intercellular network reconstruction supported the association between cancer cell signatures and specific stromal or immune cell populations. Our collective view of the cellular landscape and intercellular interactions in colorectal cancer provide mechanistic information for the design of efficient immuno-oncology treatment strategies.


Assuntos
Linhagem da Célula , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Neoplasias Colorretais/patologia , Mucosa Gástrica/imunologia , Mucosa Gástrica/patologia , Humanos , Análise de Sequência de RNA , Análise de Célula Única , Células Estromais/patologia , Linfócitos T/imunologia , Linfócitos T/patologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
6.
Nat Commun ; 11(1): 1669, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32245950

RESUMO

Programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) interaction plays a crucial role in tumor-associated immune escape. Here, we verify that triple-negative breast cancer (TNBC) has higher PD-L1 expression than other subtypes. We then discover that nucleophosmin (NPM1) binds to PD-L1 promoter specifically in TNBC cells and activates PD-L1 transcription, thus inhibiting T cell activity in vitro and in vivo. Furthermore, we demonstrate that PARP1 suppresses PD-L1 transcription through its interaction with the nucleic acid binding domain of NPM1, which is required for the binding of NPM1 at PD-L1 promoter. Consistently, the PARP1 inhibitor olaparib elevates PD-L1 expression in TNBC and exerts a better effect with anti-PD-L1 therapy. Together, our research has revealed NPM1 as a transcription regulator of PD-L1 in TNBC, which could lead to potential therapeutic strategies to enhance the efficacy of cancer immunotherapy.


Assuntos
Antígeno B7-H1/genética , Linfócitos do Interstício Tumoral/imunologia , Proteínas Nucleares/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Linfócitos T/imunologia , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Mama/patologia , Linhagem Celular Tumoral , Proteínas de Ligação a DNA , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Técnicas de Silenciamento de Genes , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Ftalazinas/farmacologia , Ftalazinas/uso terapêutico , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Prognóstico , Regiões Promotoras Genéticas/genética , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Análise Serial de Tecidos , Ativação Transcricional/imunologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/mortalidade , Regulação para Cima/efeitos dos fármacos
8.
Cancer Immunol Immunother ; 69(5): 799-811, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32055918

RESUMO

The underlying basis for cancer immune evasion is important for effective immunotherapy and prognosis in breast cancers. Human leucocyte antigens (HLA)-I comprising three classical antigens (HLA-A, -B and -C) is mandatory for anti-tumor immunity. Its loss occurred frequently in many cancers resulting in effective immune evasion. Most studies examined HLA-I as a whole. Alterations in specific locus could have different clinical ramifications. Hence, we evaluated the expression of the three HLA-I loci in a large cohort of breast cancers. Low expression of HLA-A, -B and -C were found in 71.1%, 66.3%, and 60.2% of the cases. Low and high expression in all loci was found in 48.3% and 17.9% of the cases respectively. The remaining showed high expression in one or two loci. Cases with all HLA high expression (all HLA high) was frequent in the ER-HER2- (27.4%) and ER-HER2+ (23.1%) cases and was associated with characteristic pathologic features related to these tumor (higher grade, necrosis, high tumor infiltrating lymphocyte (TIL), pT stage, low hormonal receptor, high basal marker expression) (p ≤ 0.019). Interestingly, in HER2+ cancers, only cases with all HLA high and high TIL showed significantly better survival. In node positive cancers, concordant high HLA expression in primary tumors and nodal metastases was favorable prognostically (DFS: HR = 0.741, p < 0.001; BCSS: HR = 0.699, p = 0.003). The data suggested an important clinical value of a combined analysis on the co-expression HLA-I status in both primary and metastatic tumors. This could be a potential additional key component to be incorporated into TIL evaluation for improved prognostication.


Assuntos
Neoplasias da Mama/patologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Receptor ErbB-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Mama/imunologia , Mama/patologia , Mama/cirurgia , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Intervalo Livre de Doença , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica/imunologia , Genes MHC Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Estimativa de Kaplan-Meier , Mastectomia , Pessoa de Meia-Idade , Prognóstico , Análise Serial de Tecidos , Adulto Jovem
9.
Cancer Immunol Immunother ; 69(5): 813-824, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32055920

RESUMO

Despite significant therapeutic improvements chronic lymphocytic leukemia (CLL) remains an incurable disease and there is a persistent pursuit of new treatment alternatives. Lurbinectedin, a selective inhibitor of active transcription of protein-coding genes, is currently in phase II/III clinical trials for solid tumors such as small-cell lung cancer (SCLC). In this study, we aimed to evaluate the activity of Lurbinectedin on circulating mononuclear cells from CLL patients and to determine whether Lurbinectedin could affect the cross-talk between B-CLL cells and the tumor microenvironment. We found that Lurbinectedin induced a dose- and time-dependent death in all cell types evaluated, with B cells, monocytes and monocytic myeloid derived suppressor cells (Mo-MDSC) being the most susceptible populations. At sub-apoptotic doses, Lurbinectedin decreased the expression of CCR7 in B-CLL cells and impaired their migration towards CCL19 and CCL21. Furthermore, low concentrations of Lurbinectedin stimulated the synthesis of pro-IL1ß in monocytes and nurse-like cells, without inducing the inflammasome activation. Altogether, these results indicate that Lurbinectedin might have antitumor activity in CLL due to its direct action on leukemic cells in combination with its effects on the tumor microenvironment. Our findings encourage further investigation of Lurbinectedin as a potential therapy for CLL.


Assuntos
Carbolinas/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Quimiocina CCL19/imunologia , Quimiocina CCL19/metabolismo , Quimiocina CCL21/imunologia , Quimiocina CCL21/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Cultura Primária de Células , Receptores CCR7/imunologia , Receptores CCR7/metabolismo , Células Tumorais Cultivadas , Microambiente Tumoral/imunologia
10.
Cancer Immunol Immunother ; 69(5): 835-846, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32062693

RESUMO

Tumor-associated macrophages (TAMs) are important regulators of the complex interplay between immune system and breast cancer. TAMs fuel the cancer progression and metastasis by reprogramming their specific functional phenotype in cancer settings. Therefore, it is important to clarify the mechanisms of shaping specific functional phenotype of macrophages in tumor milieu. LncRNA profiles of TAMs were identified by LncRNA microarray. Flow cytometry was used to detect the surface markers of TAMs. The co-localization among lincRNA-p21, p53 and Mouse Double Minute 2 (MDM2) was identified by FISH probe and immunofluorescence. PyVT-MMTV and BALB/c mice were used for in vivo analysis. In the present work, we found that lincRNA-p21 significantly up-regulated in 4T1 educated macrophages. LincRNA-p21 knockdown facilitated macrophage polarization into pro-inflammatory M1 in tumor microenvironment, which might be caused by MDM2 eliciting proteasome-dependent degradation to p53 and activated NF-κB and STAT3 pathway. TAMs with lincRNA-p21 knockdown induced cancer cell apoptosis, inhibited tumor cell migration and invasion. In vivo, lincRNA-p21 knockdown macrophage adoptive transfer could alleviate breast cancer progression. Our results indicated that lincRNA-p21 was a key regulator of TAMs function in tumor milieu. Our data also shed a light on novel therapeutic targets of tumors characterized by monocytes/macrophages infiltration.


Assuntos
Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Macrófagos/imunologia , Proteínas Proto-Oncogênicas c-mdm2/genética , RNA Longo não Codificante/metabolismo , Animais , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Cultura Primária de Células , Proteólise , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , RNA Longo não Codificante/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima
11.
Oncol Rep ; 43(3): 795-806, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32020214

RESUMO

Establishing a prognostic genetic signature closely related to the tumor immune microenvironment (TIME) to predict clinical outcomes is necessary. Using the Gene Expression Omnibus (GEO) database of a non­small cell lung cancer (NSCLC) cohort and the immune score derived from the Estimation of Stromal and Immune cells in Malignant Tumours using Expression data (ESTIMATE) algorithm, we applied the least absolute shrinkage and selection operator (LASSO) Cox regression model to screen a 10­gene signature among the 448 differentially expressed genes and found that the risk prediction models constructed by 10 genes could be more sensitive to prognosis than TNM (Tumor, Lymph node and Metastasis) stage (P=0.006). The CIBERSORT method was applied to quantify the relative levels of different immune cell types. It was found that the ratio of eosinophils, mast cells (MCs) resting and CD4 T cells memory activated in the low­risk group was higher than that in the high­risk group, and the difference was statistically significant (P=0.003, P=0.014 and P=0.018, respectively). Inconsistently, the ratio of resting natural killer (NK) cells and activated plasma cells in the low­risk group was significantly lower than that in the high­risk group (P=0.05 and P=0.009, respectively). Kaplan­Meier survival results showed that patients of the high­risk group had significantly shorter overall survival (OS) than those of the low­risk group in the training set (P<0.001). Furthermore, Kaplan­Meier survival showed that patients of the high­risk group had significantly shorter OS than those of the low­risk group (P=0.0025 and P=0.0157, respectively) in the validation set [GSE31210 and TCGA (The Cancer Genome Atlas)]. The 10­gene signature was found to be an independent risk factor for prognosis in univariate and multivariate Cox proportional hazard regression analyses (P<0.001). In addition, it was found that the risk model constructed by the 10­gene signature was related to the clinical related factors in logistic regression analysis. The genetic signature closely related to the immune microenvironment was found to be able to predict differences in the proportion of immune cells (eosinophils, resting MCs, memory activated CD4 T cells, resting NK cells and plasma cells) in the risk model. Our findings suggest that the genetic signature closely related to TIME could predict the prognosis of NSCLC patients, and provide some reference for immunotherapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Prognóstico , Microambiente Tumoral/imunologia , Idoso , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Bases de Dados Genéticas , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/imunologia , Estadiamento de Neoplasias , RNA Longo não Codificante/genética , Fatores de Risco , Transcriptoma/imunologia
12.
Cancer Immunol Immunother ; 69(4): 569-580, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31980915

RESUMO

BACKGROUND: The chemokine MIP-3α (CCL20) binds to CCR6 on immature dendritic cells. DNA vaccines fusing MIP-3α to melanoma-associated antigens have shown improved efficacy and immunogenicity in the B16F10 mouse melanoma model. Here, we report that the combination of type-I interferon therapy (IFNα) with 5-Aza-2'-deoxycitidine (5Aza) profoundly enhanced the therapeutic efficacy of a MIP-3α-Gp100-Trp2 DNA vaccine. METHODS: Beginning on day 5 post-transplantation of B16F10 melanoma, vaccine was administered intramuscularly (i.m.) by electroporation. CpG adjuvant was given 2 days later. 5Aza was given intraperitoneally at 1 mg/kg and IFNα therapy either intratumorally or i.m. as noted. Tumor sizes, tumor growth, and mouse survival were assessed. Tumor lysate gene expression levels and tumor-infiltrating lymphocytes (TILs) were assessed by qRT-PCR and flow cytometry, respectively. RESULTS: Adding IFNα and 5Aza treatments to mice vaccinated with MIP-3α-Gp100-Trp2 leads to reduced tumor burden and increased median survival (39% over vaccine and 95% over controls). Tumor lysate expression of CCL19 and CCR7 were upregulated ten and fivefold over vaccine, respectively. Vaccine-specific and overall CD8+ TILs were increased over vaccine (sevenfold and fourfold, respectively), as well as the proportion of TILs that were CD8+ (twofold). CONCLUSIONS: Efficient targeting of antigen to immature dendritic cells with a chemokine-fusion vaccine offers an alternative to classic and dendritic cell vaccines. Combining this approach with IFNα and 5Aza treatment significantly improved vaccine efficacy. This improved efficacy correlated with changes in chemokine gene expression and CD8+ TIL infiltration and was dependent on the presence of all therapeutic components.


Assuntos
Vacinas Anticâncer/imunologia , Decitabina/imunologia , Células Dendríticas/imunologia , Interferon-alfa/imunologia , Melanoma Experimental/imunologia , Animais , Vacinas Anticâncer/administração & dosagem , Linhagem Celular Tumoral , Quimiocina CCL19/genética , Quimiocina CCL19/imunologia , Metilação de DNA/efeitos dos fármacos , Decitabina/administração & dosagem , Células Dendríticas/citologia , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imunoterapia/métodos , Interferon-alfa/administração & dosagem , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Melanoma Experimental/genética , Melanoma Experimental/terapia , Camundongos Endogâmicos C57BL , Receptores CCR7/genética , Receptores CCR7/imunologia
13.
Int J Radiat Oncol Biol Phys ; 106(5): 1039-1051, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31959545

RESUMO

PURPOSE: The outcome of locally advanced cervical cancer (LACC) is dismal. Biomarkers are needed to individualize treatments and to improve patient outcomes. Here, we investigated whether coexpression of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3) could be an outcome prognostic biomarker, and whether targeting both EGFR and HER3 with a dual antibody (MEHD7945A) enhanced ionizing radiation (IR) efficacy. METHODS AND MATERIALS: Expression of EGFR and HER3 was evaluated by immunohistochemistry in cancer biopsies (n = 72 patients with LACC). The antitumor effects of the MEHD7945A and IR combotherapy were assessed in 2 EGFR- and HER3-positive cervical cancer cell lines (A431 and CaSki) and in A431 cell xenografts. The mechanisms involved in tumor cell radiosensitization were also studied. The interaction of MEHD7945A, IR, and cisplatin was evaluated using dose-response matrix data. RESULTS: EGFR and HER3 were coexpressed in only in 7 of the 22 biopsies of FIGO IVB cervix cancer. The median overall survival was 14.6 months and 23.1 months in patients with FIGO IVB tumors that coexpressed or did not coexpress EGFR and HER3, respectively. In mice xenografted with A431 (squamous cell carcinoma) cells, MEHD7945A significantly increased IR response by reducing tumor growth and increasing cleaved caspase-3 expression. In A431 and CaSki cells, the combotherapy increased DNA damage and cell death, particularly immunogenic cell death, and decreased survival by inhibiting the MAPK and AKT pathways. An additive effect was observed when IR, MEHD7945A, and cisplatin were combined. CONCLUSIONS: Targeting EGFR and HER3 with a specific dual antibody enhanced IR efficacy. These preliminary results and the prognostic value of EGFR and HER3 coexpression should be confirmed in a larger sample.


Assuntos
Receptores ErbB/imunologia , Imunoglobulina G/imunologia , Receptor ErbB-3/imunologia , Neoplasias do Colo do Útero/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/imunologia , Sobrevivência Celular/efeitos da radiação , Transformação Celular Neoplásica , Terapia Combinada , Dano ao DNA , Receptores ErbB/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Imunoglobulina G/uso terapêutico , Camundongos , Pessoa de Meia-Idade , Receptor ErbB-3/metabolismo , Estudos Retrospectivos , Transdução de Sinais/imunologia , Transdução de Sinais/efeitos da radiação , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/radioterapia
14.
Clin Exp Immunol ; 200(1): 12-21, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31901178

RESUMO

CD28H and B7-H5 have been identified as receptor-ligand pairs in the B7/CD28 family, and have co-stimulatory activity in immune cells. Here, we have systematically reviewed the research reports concerning the CD28H/B7-H5 pathway. It was found that CD28H is mainly expressed in T cells and natural killer (NK) cells with naive and poorly differentiated properties, and repeated antigen stimulation leads to permanent loss of CD28H. In tumors, CD28H is mainly expressed in tissue-resident memory (TRM ) lymphocyte T cells, which is associated with improved tumor prognosis. B7-H5 is a ligand for CD28H and is widely expressed in tumor cells. B7-H5 expression is closely related to the prognosis of the tumor. Studies have shown that high expression of B7-H5 in tumor is related to a worse prognosis for lung cancer, osteosarcoma, oral squamous cell carcinoma (OSCC), breast carcinoma, human clear cell renal cell carcinoma (ccRCC), intrahepatic cholangiocarcinoma (ICC), bladder urothelial carcinoma (BUC) and colorectal cancer (CRC), but is associated with a better prognosis for pancreatic ductal adenocarcinoma (PDAC) and glioma. Controversial views exist in studies on gastric cancer prognosis.


Assuntos
Antígenos B7/imunologia , Antígenos CD28/imunologia , Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Linfócitos T/imunologia , Células Th1/imunologia , Antígenos B7/genética , Antígenos B7/metabolismo , Antígenos CD28/genética , Antígenos CD28/metabolismo , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Células Matadoras Naturais/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Prognóstico , Linfócitos T/metabolismo , Células Th1/metabolismo
15.
World J Gastroenterol ; 26(2): 134-153, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31969776

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is a common cancer with a poor prognosis. Previous studies revealed that the tumor microenvironment (TME) plays an important role in HCC progression, recurrence, and metastasis, leading to poor prognosis. However, the effects of genes involved in TME on the prognosis of HCC patients remain unclear. Here, we investigated the HCC microenvironment to identify prognostic genes for HCC. AIM: To identify a robust gene signature associated with the HCC microenvironment to improve prognosis prediction of HCC. METHODS: We computed the immune/stromal scores of HCC patients obtained from The Cancer Genome Atlas based on the ESTIMATE algorithm. Additionally, a risk score model was established based on Differentially Expressed Genes (DEGs) between high- and low-immune/stromal score patients. RESULTS: The risk score model consisting of eight genes was constructed and validated in the HCC patients. The patients were divided into high- or low-risk groups. The genes (Disabled homolog 2, Musculin, C-X-C motif chemokine ligand 8, Galectin 3, B-cell-activating transcription factor, Killer cell lectin like receptor B1, Endoglin and adenomatosis polyposis coli tumor suppressor) involved in our risk score model were considered to be potential immunotherapy targets, and they may provide better performance in combination. Functional enrichment analysis showed that the immune response and T cell receptor signaling pathway represented the major function and pathway, respectively, related to the immune-related genes in the DEGs between high- and low-risk groups. The receiver operating characteristic (ROC) curve analysis confirmed the good potency of the risk score prognostic model. Moreover, we validated the risk score model using the International Cancer Genome Consortium and the Gene Expression Omnibus database. A nomogram was established to predict the overall survival of HCC patients. CONCLUSION: The risk score model and the nomogram will benefit HCC patients through personalized immunotherapy.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/mortalidade , Neoplasias Hepáticas/mortalidade , Modelos Genéticos , Microambiente Tumoral/genética , Idoso , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Bases de Dados Genéticas/estatística & dados numéricos , Conjuntos de Dados como Assunto , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Estimativa de Kaplan-Meier , Fígado/imunologia , Fígado/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nomogramas , Medicina de Precisão/métodos , Curva ROC , Medição de Risco/métodos , Resultado do Tratamento , Microambiente Tumoral/imunologia
16.
Cancer Lett ; 473: 33-49, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-31904478

RESUMO

Long non-coding RNAs (lncRNAs) regulates the initiation and progression of osteosarcoma (OS), specifically lncRNA RP11-361F15.2 has been shown to play prominent roles in tumorigenesis. Previously, M2-Like polarization of tumor-associated macrophages (TAMs) has been identified to play a key role in cancer migration/invasion. Hence, it is essential to understand the role of RP11-361F15.2 in tumorigenesis and its association with M2-Like polarization of TAMs. The results indicate that RP11-361F15.2 is significantly increased in OS tissues, and its expression is positively correlated with cytoplasmic polyadenylation element binding protein 4 (CPEB4) expression and negatively associated with miR-30c-5p expression. Further, overexpression of RP11-361F15.2 increased OS cell migration/invasion and M2-Like polarization of TAMs in vitro, as well as promoted xenograft tumor growth in vivo. Mechanistically, luciferase reporter assays indicated that RP11-361F15.2 upregulated CPEB4 expression by competitively binding to miR-30c-5p. Further, we have identified that RP11-361F15.2 promotes CPEB4-mediated tumorigenesis and M2-Like polarization of TAMs through miR-30c-5p in OS. We also identified that RP11-361F15.2 acts as competitive endogenous RNA (ceRNA) against miR-30c-5p thereby binding and activating CPEB4. This RP11-361F15.2/miR-30c-5p/CPEB4 loop could be used as a potential therapeutic strategy for the treatment of OS.


Assuntos
Neoplasias Ósseas/genética , Carcinogênese/genética , Macrófagos/imunologia , MicroRNAs/metabolismo , Osteossarcoma/genética , RNA Longo não Codificante/metabolismo , Proteínas de Ligação a RNA/genética , Adolescente , Animais , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/imunologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Técnicas de Silenciamento de Genes , Humanos , Estimativa de Kaplan-Meier , Macrófagos/metabolismo , Masculino , Camundongos , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , Invasividade Neoplásica/genética , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/prevenção & controle , Osteossarcoma/imunologia , Osteossarcoma/mortalidade , Osteossarcoma/patologia , Células RAW 264.7 , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
17.
Cancer Lett ; 473: 148-155, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-31911080

RESUMO

The AT-rich interaction domain 1A (ARID1A, also known as BAF250a) is a chromatin remodeling gene, which frequently mutates across a broad spectrum of cancers with loss expression of the ARID1A protein. Recently, the association between ARID1A deficiency and immune checkpoint blockade (ICB) therapy has been reported. ARID1A deficiency contributes to the high microsatellite instability phenotype, increases tumor mutation burden, elevates expression of programmed cell death ligand 1 (PD-L1), and modulates the immune microenvironment, supporting the view that ARID1A loss might serve as a predictive biomarker for ICB. Furthermore, the therapeutic targeting strategies, which show "synthetic lethality" with ARID1A deficiency, exhibit potential synergy with ICB. We collectively reviewed the mechanisms underlying the correlation between ARID1A deficiency and ICB, the predictive function of ARID1A deficiency for ICB, and potential combined strategies of targeting agents, vulnerable for ARID1A deficiency, with ICB in cancer treatment.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/deficiência , Proteínas de Ligação a DNA/deficiência , Neoplasias/tratamento farmacológico , Fatores de Transcrição/deficiência , Animais , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/genética , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Camundongos , Instabilidade de Microssatélites , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Mutações Sintéticas Letais/efeitos dos fármacos , Fatores de Transcrição/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
18.
Cancer Res ; 80(6): 1330-1341, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31911555

RESUMO

Paracrine activation of cells contained in the tumor microenvironment promotes tumor progression and metastasis. In breast cancer, malignant cells recruit and educate macrophages into a M2 tumor-promoting phenotype that supports the metastatic spread of cancer cells. Here, we show that miR-149 functions as a metastasis-suppressing microRNA in breast cancer cells by limiting colony-stimulating factor-1 (CSF1)-dependent recruitment and M2 polarization of macrophages. In lymph node-positive, triple-negative breast cancer (TNBC) tissues, low miR-149 expression correlated with macrophage infiltration and reduced patient survival. By directly targeting CSF1, miR-149 expression in TNBC cell lines (MDA-MB-231 and BT-549) inhibited the recruitment of human monocytic THP-1 cells and primary human macrophages. Furthermore, in macrophages cocultured with MDA-MB-231 cells expressing miR-149, epidermal growth factor (EGF) and amphiregulin expression levels were strongly reduced, resulting in reduced EGF receptor activation in the cancer cells. In vivo, lung metastases developing from orthotopic MDA-MB-231 tumors were reduced by 75% by miR-149 expression, and this was associated with impaired M2 macrophage infiltration of the primary tumors. These data suggest that miR-149 downregulation functionally contributes to breast tumor progression by recruiting macrophages to the tumor and facilitating CSF1 and EGF receptor cross-talk between cancer cells and macrophages. SIGNIFICANCE: These findings contribute to the understanding of tumor-stroma interactions by showing that miR-149 downregulation in TNBC enhances reciprocal growth factor signaling between macrophages and cancer cells, which promotes tumor progression and metastasis. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/6/1330/F1.large.jpg.


Assuntos
Regulação Neoplásica da Expressão Gênica/imunologia , Fator Estimulador de Colônias de Macrófagos/genética , Macrófagos/imunologia , MicroRNAs/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação para Baixo , Feminino , Células HEK293 , Humanos , Estimativa de Kaplan-Meier , Macrófagos/metabolismo , Comunicação Parácrina/genética , Comunicação Parácrina/imunologia , Cultura Primária de Células , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Cancer Res ; 80(5): 1011-1023, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31911554

RESUMO

PD-L1 is expressed in tumor cells and its interaction with PD-1 plays an important role in evading immune surveillance; this can be overcome using PD-L1 or PD-1 immunotherapy antibodies. This study reports a novel approach for targeting PD-L1. In human breast cancer cell lines and 4T1 mouse mammary tumor cells, PD-L1 expression was regulated by the nuclear receptor NR4A1/Sp1 complex bound to the proximal germinal center (GC)-rich region of the PD-L1 gene promoter. Treatment of breast cancer cells with bis-indole-derived NR4A1 antagonists including 1,1-bis(3'-indolyl)-1-(3-chloro-4-hydroxy-5-methoxyphenyl)methane (Cl-OCH3) decreased expression of PD-L1 mRNA, promoter-dependent luciferase activity, and protein. In in vivo studies using a syngeneic mouse model bearing orthotopically injected 4T1 cells, Cl-OCH3 decreased tumor growth and weight and inhibited lung metastasis. Cl-OCH3 also decreased expression of CD3+/CD4+/CD25+/FoxP3+ regulatory T cells and increased the Teff/Treg ratio. Therefore, the potent anticancer activities of NR4A1 antagonists are also accompanied by enhanced antitumor immunity in PD-L1-expressing triple-negative breast cancer and thus represent a novel class of drugs that mimic immunotherapy. SIGNIFICANCE: These findings show that the orphan nuclear receptor NR4A1 controls PD-L1 expression and identify a chemical probe capable of disrupting this regulatory axis.


Assuntos
Antineoplásicos/farmacologia , Antígeno B7-H1/metabolismo , Neoplasias Pulmonares/prevenção & controle , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Antígeno B7-H1/imunologia , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imunoterapia/métodos , Indóis/farmacologia , Indóis/uso terapêutico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Camundongos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Proteólise/efeitos dos fármacos , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
20.
Biomed Res Int ; 2020: 2147397, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31998783

RESUMO

Purpose: Establishing prognostic gene signature to predict clinical outcomes and guide individualized adjuvant therapy is necessary. Here, we aim to establish the prognostic efficacy of a gene signature that is closely related to tumor immune microenvironment (TIME). Methods and Results: There are 13,035 gene expression profiles from 130 tumor samples of the non-small cell lung cancer (NSCLC) in the data set GSE103584. A 5-gene signature was identified by using univariate survival analysis and Least Absolute Shrinkage and Selection Operator (LASSO) to build risk models. Then, we used the CIBERSORT method to quantify the relative levels of different immune cell types in complex gene expression mixtures. It was found that the ratio of dendritic cells (DCs) activated and mast cells (MCs) resting in the low-risk group was higher than that in the high-risk group, and the difference was statistically significant (P < 0.001 and P < 0.001 and P < 0.001 and P < 0.001 and P < 0.001 and P < 0.001 and P < 0.001 and P < 0.001 and P < 0.001 and P < 0.001 and P < 0.001 and P < 0.001 and. Conclusion: The 5-gene signature is a powerful and independent predictor that could predict the prognosis of NSCLC patients. In addition, our gene signature is correlated with TIME parameters, such as DCs activated and MCs resting. Our findings suggest that the 5-gene signature closely related to TIME could predict the prognosis of NSCLC patients and provide some reference for immunotherapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/imunologia , Neoplasias Pulmonares , Microambiente Tumoral , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA