Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.336
Filtrar
1.
PLoS One ; 16(12): e0261082, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34910746

RESUMO

INTRODUCTION: Multiple previous studies have shown the monoclonal antibody Das-1 (formerly called 7E12H12) is specifically reactive towards metaplastic and carcinomatous lesions in multiple organs of the gastrointestinal system (e.g. Barrett's esophagus, intestinal-type metaplasia of the stomach, gastric adenocarcinoma, high-grade pancreatic intraepithelial neoplasm, and pancreatic ductal adenocarcinoma) as well as in other organs (bladder and lung carcinomas). Beyond being a useful biomarker in tissue, mAb Das-1 has recently proven to be more accurate than current paradigms for identifying cysts harboring advanced neoplasia. Though this antibody has been used extensively for clinical, basic science, and translational applications for decades, its epitope has remained elusive. METHODS: In this study, we chemically deglycosylated a standard source of antigen, which resulted in near complete loss of the signal as measured by western blot analysis. The epitope recognized by mAb Das-1 was determined by affinity to a comprehensive glycan array and validated by inhibition of a direct ELISA. RESULTS: The epitope recognized by mAb Das-1 is 3'-Sulfo-Lewis A/C (3'-Sulfo-LeA/C). 3'-Sulfo-LeA/C is broadly reexpressed across numerous GI epithelia and elsewhere during metaplastic and carcinomatous transformation. DISCUSSION: 3'-Sulfo-LeA/C is a clinically important antigen that can be detected both intracellularly in tissue using immunohistochemistry and extracellularly in cyst fluid and serum by ELISA. The results open new avenues for tumorigenic risk stratification of various gastrointestinal lesions.


Assuntos
Anticorpos Monoclonais/imunologia , Transformação Celular Neoplásica/imunologia , Epitopos de Linfócito B/imunologia , Neoplasias Gastrointestinais/imunologia , Mucosa Intestinal/imunologia , Antígenos do Grupo Sanguíneo de Lewis/imunologia , Oligossacarídeos/imunologia , Especificidade de Anticorpos , Biomarcadores Tumorais/imunologia , Linhagem Celular Tumoral , Humanos , Imuno-Histoquímica
2.
Clin Immunol ; 232: 108872, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34648954

RESUMO

Ferroptosis is a novel form of cell death characterized by heavy iron accumulation and lipid peroxidation that plays a critical role in the tumor microenvironment. However, promising biomarkers associated with tumor immune cell infiltration and the immunotherapy response to ferroptosis regulators remain to be elucidated in lung adenocarcinoma (LUAD) patients. In this study, we defined ferroptosis regulators in LUAD through database analysis and experimental validation to determine the implementation of genes associated with clinical relevance, immunotherapy response and tumor microenvironment in LUAD patients. Multiomics data analysis was performed to explore the CNV features, molecular mechanisms and immunogenic characteristics of ferroptosis regulators in LUAD patients. Then, univariate and multivariate Cox regression analyses were used to identify three genes (DDIT4, RRM2, and SLC2A1) that were closely associated with the prognosis of LUAD patients. The prognostic model based on the determination of these three genes was an independent prognostic factor (p < 0.05, HR = 2.838), and patients with superior predictive performance and higher prognostic risk were more likely to have poor survival rates than those with lower prognostic risk in the training group (p < 0.001, HR = 3.19) and the test group (p < 0.001, HR = 2.94; p < 0.001, HR = 3.44). Activated immune cells, including T helper cells and activated CD8 T cells, were lower in the high-risk group, while type 2 T cells were higher (p < 0.05). Patients with higher prognostic risk were less likely to benefit from immunotherapy, partly due to low CTLA4 levels and an immunosuppressive microenvironment (p < 0.05). Combined with LUAD tissue samples and mouse trials, RRM2 was found to influence lung cancer progression and affect tumor immune cell infiltration. RRM2 inhibition effectively promoted M1 macrophage polarization and suppressed M2 macrophage polarization in vitro and in vivo. And ferroptosis inhibitor ferrostatin-1 treatment effectively re-blanced macrophage polarization mediated by RRM2 inhibition. Taken together, the results of the multiomics data analysis and experimental validation identified ferroptosis regulators as promising biomarkers and therapeutic targets associated with tumor immune infiltration in LUAD patients.


Assuntos
Adenocarcinoma de Pulmão/imunologia , Biomarcadores Tumorais/metabolismo , Ferroptose/fisiologia , Neoplasias Pulmonares/imunologia , Ribonucleosídeo Difosfato Redutase/metabolismo , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Animais , Biomarcadores Tumorais/imunologia , Xenoenxertos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologia
3.
Int J Mol Sci ; 22(19)2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34638613

RESUMO

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortalities worldwide. Patients with early-stage HCC are eligible for curative treatments, such as surgical resection, liver transplantation (LT) and percutaneous ablation. Although curative treatments provide excellent long-term survival, almost 70-80% of patients experience HCC recurrence after curative treatments. Tumor-related factors, including tumor size, number and differentiation, and underlying liver disease, are well-known risk factors for recurrence following curative therapies. Moreover, the tumor microenvironment (TME) also plays a key role in the recurrence of HCC. Many immunosuppressive mechanisms, such as an increase in regulatory T cells and myeloid-derived suppressor cells with a decrease in cytotoxic T cells, are implicated in HCC recurrence. These suppressive TMEs are also modulated by several factors and pathways, including mammalian target of rapamycin signaling, vascular endothelial growth factor, programmed cell death protein 1 and its ligand 1. Based on these mechanisms and the promising results of immune checkpoint blockers (ICBs) in advanced HCC, there have been several ongoing adjuvant studies using a single or combination of ICB following curative treatments in HCC. In this review, we strive to provide biologic and immunological markers, prognostic factors, and challenges associated with clinical outcomes after curative treatments, including resection, LT and ablation.


Assuntos
Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/terapia , Técnicas de Ablação , Biomarcadores Tumorais/imunologia , Hepatectomia , Humanos , Transplante de Fígado , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/prevenção & controle , Prognóstico , Fatores de Risco , Microambiente Tumoral/imunologia
4.
Molecules ; 26(20)2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34684792

RESUMO

Importance: The protein p53 is an unequivocal tumor suppressor that is altered in half of all cancers. The immune system produces systemic p53 autoantibodies (p53 Abs) in many cancer patients. Objective: This systemic review and meta-analysis focuses on the prognostic value of p53 Abs expressed in the serum of patients with solid tumors. Data Sources: All the clinical investigations were searched on PubMed from the first study dated 1993 until May 2021 (date of submission of the manuscript). Study Selection: Studies were included that met the following criteria: (1) participants with cancer; (2) outcome results expressed in relation to the presence of a p53 antibody; (3) a primary outcome (disease-free survival, overall survival or progression-free survival) expressed as hazard ratio (HR). The following exclusion criteria were used: (1) insufficient data available to evaluate outcomes; (2) animal studies; (3) studies with less than 10 participants. As a result, 12 studies were included in the analysis. Data Extraction and Synthesis: PRISMA guidelines were used for abstracting and assessing data quality and validity by three independent observers. The summary estimates were generated using a fixed-effect model (Mantel-Haenszel method) or a random-effect model (DerSimonian-Laird method), depending on the absence or presence of heterogeneity (I2). Main Outcome(s) and Measure(s): The primary study outcome was to determine the prognostic value of p53 Abs from a large population of patients with solid tumors, as determined before data collection. Results: In total, 12 clinical studies involving 2094 patients were included in the meta-analysis, and it was determined that p53 Abs expression in the serum significantly correlated with poorer survival outcomes of cancer patients (95% CI 1.48 [1.24, 1.77]; p < 0.00001). Conclusions and Relevance: This is the first meta-analysis proving the diagnostic utility of p53-Abs for cancer patients in predicting poorer outcomes. The serum-p53 value (s-p53-value) may be useful for future theranostics.


Assuntos
Autoanticorpos/sangue , Neoplasias/diagnóstico , Neoplasias/imunologia , Proteína Supressora de Tumor p53/imunologia , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Feminino , Humanos , Masculino , Mutação , Neoplasias/genética , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Proteína Supressora de Tumor p53/genética
5.
Int J Mol Sci ; 22(18)2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34575971

RESUMO

BACKGROUND: The tumor immune microenvironment exerts a pivotal influence in tumor initiation and progression. The aim of this study was to analyze the immune context of sporadic and familial adenomatous polyposis (FAP) lesions along the colorectal adenoma-carcinoma sequence (ACS). METHODS: We analyzed immune cell counts (CD3+, CD4+, CD8+, Foxp3+, and CD57+), tumor mutation burden (TMB), MHC-I expression and PD-L1 expression of 59 FAP and 74 sporadic colorectal lesions, encompassing adenomas with low-grade dysplasia (LGD) (30 FAP; 30 sporadic), adenomas with high-grade dysplasia (22 FAP; 30 sporadic), and invasive adenocarcinomas (7 FAP; 14 sporadic). RESULTS: The sporadic colorectal ACS was characterized by (1) a stepwise decrease in immune cell counts, (2) an increase in TMB and MHC-I expression, and (3) a lower PD-L1 expression. In FAP lesions, we observed the same patterns, except for an increase in TMB along the ACS. FAP LGD lesions harbored lower Foxp3+ T cell counts than sporadic LGD lesions. A decrease in PD-L1 expression occurred earlier in FAP lesions compared to sporadic ones. CONCLUSIONS: The colorectal ACS is characterized by a progressive loss of adaptive immune infiltrate and by the establishment of a progressively immune cold microenvironment. These changes do not appear to be related with the loss of immunogenicity of tumor cells, or to the onset of an immunosuppressive tumor microenvironment.


Assuntos
Adenocarcinoma/imunologia , Polipose Adenomatosa do Colo/imunologia , Antígeno B7-H1/genética , Neoplasias Colorretais/imunologia , Microambiente Tumoral/imunologia , Imunidade Adaptativa/imunologia , Adenocarcinoma/complicações , Adenocarcinoma/genética , Adenocarcinoma/patologia , Polipose Adenomatosa do Colo/complicações , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/imunologia , Complexo CD3/imunologia , Linfócitos T CD4-Positivos/imunologia , Antígenos CD57/imunologia , Linfócitos T CD8-Positivos/imunologia , Contagem de Células , Linhagem da Célula/imunologia , Neoplasias Colorretais/complicações , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Fatores de Transcrição Forkhead/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Masculino , Pessoa de Meia-Idade
6.
Nat Commun ; 12(1): 5606, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34556668

RESUMO

Immune checkpoint therapy (ICT) provides substantial clinical benefits to cancer patients, but a large proportion of cancers do not respond to ICT. To date, the genomic underpinnings of primary resistance to ICT remain elusive. Here, we performed immunogenomic analysis of data from TCGA and clinical trials of anti-PD-1/PD-L1 therapy, with a particular focus on homozygous deletion of 9p21.3 (9p21 loss), one of the most frequent genomic defects occurring in ~13% of all cancers. We demonstrate that 9p21 loss confers "cold" tumor-immune phenotypes, characterized by reduced abundance of tumor-infiltrating leukocytes (TILs), particularly, T/B/NK cells, altered spatial TILs patterns, diminished immune cell trafficking/activation, decreased rate of PD-L1 positivity, along with activation of immunosuppressive signaling. Notably, patients with 9p21 loss exhibited significantly lower response rates to ICT and worse outcomes, which were corroborated in eight ICT trials of >1,000 patients. Further, 9p21 loss synergizes with PD-L1/TMB for patient stratification. A "response score" was derived by incorporating 9p21 loss, PD-L1 expression and TMB levels in pre-treatment tumors, which outperforms PD-L1, TMB, and their combination in identifying patients with high likelihood of achieving sustained response from otherwise non-responders. Moreover, we describe potential druggable targets in 9p21-loss tumors, which could be exploited to design rational therapeutic interventions.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 9/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Microambiente Tumoral/imunologia , Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Resistencia a Medicamentos Antineoplásicos/genética , Homozigoto , Humanos , Tolerância Imunológica , Imunoterapia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/mortalidade , Prognóstico , Transdução de Sinais/imunologia
7.
Cells ; 10(9)2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34571850

RESUMO

Oral cavity squamous cell carcinoma (OSCC) is a common head and neck cancer characterized by a poor prognosis associated with locoregional or distant failure. Among the predictors of prognosis, a dense infiltration of adaptive immune cells is protective and associated with improved clinical outcomes. However, few tools are available to integrate immune contexture variables into clinical settings. By using digital microscopy analysis of a large retrospective OSCC cohort (n = 182), we explored the clinical significance of tumor-infiltrating CD8+ T-cells. To this end, CD8+ T-cells counts were combined with well-established clinical variables and peripheral blood immune cell parameters. Through variable clustering, five metavariables (MV) were obtained and included descriptors of nodal (NODALMV) and primary tumor (TUMORMV) involvement, the frequency of myeloid (MYELOIDMV) or lymphoid (LYMPHOIDMV) peripheral blood immune cell populations, and the density of tumor-infiltrating CD8+ T-cells (TI-CD8MV). The clinical relevance of the MV was evaluated in the multivariable survival models. The NODALMV was significantly associated with all tested outcomes (p < 0.001), the LYMPHOIDMV showed a significant association with the overall, disease-specific and distant recurrence-free survival (p < 0.05) and the MYELOIDMV with the locoregional control only (p < 0.001). Finally, TI-CD8MV was associated with distant recurrence-free survival (p = 0.029). Notably, the performance in terms of survival prediction of the combined effect of NODALMV and immune metavariables (LYMPHOIDMV, MYELOIDMV and TI-CD8MV) was superior to the TNM stage for most of the outcomes analyzed. These findings indicate that the analysis of the baseline host immune features are promising tools to complement clinical features, in stratifying the risk of recurrences.


Assuntos
Biomarcadores Tumorais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Imunidade Adaptativa/imunologia , Imunidade Adaptativa/fisiologia , Idoso , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/patologia , Estudos de Coortes , Feminino , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Itália/epidemiologia , Linfócitos do Interstício Tumoral/fisiologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/fisiopatologia , Resultado do Tratamento
8.
Clin Immunol ; 232: 108847, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34506945

RESUMO

BACKGROUND: Cancer development is among other factors driven by tumor immune escape and tumor-mediated changes in the immune response. Investigating systemic immune changes may provide important knowledge for the improvement of patient prognosis and treatment opportunities. METHODS: The systemic immune profile of patients with ER-positive breast cancer (n = 22) and healthy controls (n = 30) was investigated based on complete blood counts, flow cytometric analysis of T cell subsets including regulatory T cells (Tregs), and immune assays investigating soluble (s)HLA-G and the cytokine profile in plasma. We further examined the correlation between the immune markers and clinical parameters including tumor size, tumor grade and lymph node involvement. RESULTS: Results indicated that breast cancer patients possessed a higher amount of neutrophils and monocytes and fewer lymphocytes and eosinophils compared with healthy controls. Breast cancer patients had significantly more CD25+CD127low Tregs than controls, and both lymphocyte and Treg numbers were negatively correlated with tumor size. Furthermore, Treg numbers were elevated in grade I tumors compared with grade II tumors and with healthy controls. No difference in sHLA-G levels was observed between patients and controls. Higher levels of IL-6 and TNF-α were observed in breast cancer patients. Cytokine and sHLA-G levels were not associated with clinical parameters. CONCLUSION: The results of this exploratory study contribute to the elucidation of the systemic immune response in breast cancer indicating a potential use of peripheral immune cell counts and Tregs to distinguish patients from healthy controls and as potential diagnostic and prognostic biomarkers to be investigated in future studies.


Assuntos
Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/sangue , Neoplasias da Mama/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade
9.
Int J Mol Sci ; 22(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34502043

RESUMO

The efficiency of immunotherapy using monoclonal antibodies that inhibit immune checkpoints has been proven in many clinical studies and well documented by numerous registration approaches. To date, PD-L1 expression on tumor and immune cells, tumor mutation burden (TMB), and microsatellite instability (MSI) are the only validated predictive factors used for the qualification of cancer patients for immunotherapy. However, they are not the ideal predictive factors. No response to immunotherapy could be observed in patients with high PD-L1 expression, TMB, or MSI. On the other hand, the effectiveness of this treatment method also may occur in patients without PD-L1 expression or with low TMB and with microsatellite stability. When considering the best predictive factor, we should remember that the effectiveness of immunotherapy relies on an overly complex process depending on many factors. To specifically stimulate lymphocytes, not only should their activity in the tumor microenvironment be unlocked, but above all, they should recognize tumor antigens. The proper functioning of the anticancer immune system requires the proper interaction of many elements of the specific and non-specific responses. For these reasons, a multi-parameter analysis of the immune system at its different activity levels is considered a very future-oriented predictive marker. Such complex immunological analysis is performed using modern molecular biology techniques. Based on the gene expression studies, we can determine the content of individual immune cells within the tumor, its stroma, and beyond. This includes all cell types from active memory cytotoxic T cells, M1 macrophages, to exhausted T cells, regulatory T cells, and M2 macrophages. In this article, we summarize the possibilities of using an immune system analysis to predict immunotherapy efficacy in cancer patients. Moreover, we present the advantages and disadvantages of immunoprofiling as well as a proposed future direction for this new method of immune system analysis in cancer patients who receive immunotherapy.


Assuntos
Biomarcadores Tumorais/imunologia , Imunofenotipagem/métodos , Imunoterapia/métodos , Neoplasias Pulmonares/imunologia , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia
10.
Front Immunol ; 12: 644350, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34489925

RESUMO

Tumor-infiltrating immune cells shape the tumor microenvironment and are closely related to clinical outcomes. Several transcription factors (TFs) have also been reported to regulate the antitumor activity and immune cell infiltration. This study aimed to quantify the populations of different immune cells infiltrated in tumor samples based on the bulk RNA sequencing data obtained from 50 cancer patients using the CIBERSORT and the EPIC algorithm. Weighted gene coexpression network analysis (WGCNA) identified eigengene modules strongly associated with tumorigenesis and the activation of CD4+ memory T cells, dendritic cells, and macrophages. TF genes FOXM1, MYBL2, TAL1, and ERG are central in the subnetworks of the eigengene modules associated with immune-related genes. The analysis of The Cancer Genome Atlas (TCGA) cancer data confirmed these findings and further showed that the expression of these potential TF genes regulating immune infiltration, and the immune-related genes that they regulated, was associated with the survival of patients within multiple cancers. Exome-seq was performed on 24 paired samples that also had RNA-seq data. The expression quantitative trait loci (eQTL) analysis showed that mutations were significantly more frequent in the regions flanking the TF genes compared with those of non-TF genes, suggesting a driver role of these TF genes regulating immune infiltration. Taken together, this study presented a practical method for identifying genes that regulate immune infiltration. These genes could be potential biomarkers for cancer prognosis and possible therapeutic targets.


Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica/genética , Sistema Imunitário/metabolismo , Neoplasias/genética , Análise de Sequência de RNA/métodos , Fatores de Transcrição/genética , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/imunologia , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/imunologia , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Mutação , Neoplasias/imunologia , Neoplasias/metabolismo , Prognóstico , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
11.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360795

RESUMO

Specific anti-tumor immune responses have proven to be pivotal in shaping tumorigenesis and tumor progression in solid cancers. These responses can also be of an autoimmune nature, and autoantibodies can sometimes be present even before the onset of clinically overt disease. Autoantibodies can be generated due to mutated gene products, aberrant expression and post-transcriptional modification of proteins, a pro-immunogenic milieu, anti-cancer treatments, cross-reactivity of tumor-specific lymphocytes, epitope spreading, and microbiota-related and genetic factors. Understanding these responses has implications for both basic and clinical immunology. Autoantibodies in solid cancers can be used for early detection of cancer as well as for biomarkers of prognosis and treatment response. High-throughput techniques such as protein microarrays make parallel detection of multiple autoantibodies for increased specificity and sensitivity feasible, affordable, and quick. Cancer immunotherapy has revolutionized cancer treatments and has made a considerable impact on reducing cancer-associated morbidity and mortality. However, immunotherapeutic interventions such as immune checkpoint inhibition can induce immune-related toxicities, which can even be life-threatening. Uncovering the reasons for treatment-induced autoimmunity can lead to fine-tuning of cancer immunotherapy approaches to evade toxic events while inducing an effective anti-tumor immune response.


Assuntos
Autoanticorpos/imunologia , Autoimunidade/efeitos dos fármacos , Biomarcadores Tumorais/imunologia , Inibidores de Checkpoint Imunológico , Imunoterapia/efeitos adversos , Neoplasias , Animais , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/imunologia , Neoplasias/terapia
12.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361047

RESUMO

Chemoresistance of germ cell tumors (GCTs) represents an intensively studied property of GCTs that is the result of a complicated multifactorial process. One of the driving factors in this process is the tumor microenvironment (TME). Intensive crosstalk between the DNA damage/DNA repair pathways and the TME has already been reported. This study aimed at evaluating the interplay between the immune TME and endogenous DNA damage levels in GCT patients. A cocultivation system consisting of peripheral blood mononuclear cells (PBMCs) from healthy donors and GCT cell lines was used in an in vitro study. The patient cohort included 74 chemotherapy-naïve GCT patients. Endogenous DNA damage levels were measured by comet assay. Immunophenotyping of leukocyte subpopulations was performed using flow cytometry. Statistical analysis included data assessing immunophenotypes, DNA damage levels and clinicopathological characteristics of enrolled patients. The DNA damage level in PBMCs cocultivated with cisplatin (CDDP)-resistant GCT cell lines was significantly higher than in PBMCs cocultivated with their sensitive counterparts. In GCT patients, endogenous DNA damage levels above the cutoff value were independently associated with increased percentages of natural killer cells, CD16-positive dendritic cells and regulatory T cells. The crosstalk between the endogenous DNA damage level and specific changes in the immune TME reflected in the blood of GCT patients was revealed. The obtained data contribute to a deeper understanding of ongoing interactions in the TME of GCTs.


Assuntos
Dano ao DNA , Leucócitos Mononucleares/imunologia , Neoplasias Testiculares/imunologia , Microambiente Tumoral/imunologia , Adulto , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/imunologia , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucócitos Mononucleares/classificação , Masculino , Pessoa de Meia-Idade , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/genética , Neoplasias Testiculares/patologia
13.
Front Immunol ; 12: 665002, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34367132

RESUMO

Immune checkpoint inhibitors (ICIs) have made breakthrough progress in the treatment of various malignant tumors. However, only some patients receiving ICIs obtain long-lasting clinical effects, and some patients still do not achieve remission. Improving the treatment benefits of this part of the population has become a concern of clinicians. IL-1 signaling plays an important role in the tumor microenvironment (TME). However, the relationship between the IL-1 signaling mutation status and the prognosis of colon adenocarcinoma (COAD) patients receiving ICIs has not been reported. We downloaded the data of a COAD cohort receiving ICIs, including prognostic data and mutation data. Additionally, we downloaded the data of a COAD cohort from The Cancer Genome Atlas (TCGA) database, including clinical data, expression data and mutation data. Gene set enrichment analysis (GSEA) was used to assess differences in the activity of some key physiological pathways between the IL-1 signaling mutated-type (IL-1-MT) and IL-1 signaling wild-type (IL-1-WT) groups. The CIBERSORT algorithm was used to evaluate the contents of immune cells in the TME of COAD patients. The multivariate Cox regression model results suggested that IL-1-MT can be used as an independent predictor of a better prognosis in COAD patients receiving ICIs (P = 0.03, HR = 0.269, 95% CI: 0.082-0.883). Additionally, IL-1-MT COAD patients had significantly longer overall survival (OS) (log-rank P = 0.015). CIBERSORT analysis showed that the IL-1-MT group had high infiltration levels of activated dendritic cells (DCs), M1 macrophages, neutrophils, activated natural killer (NK) cells, activated CD4+ memory T cells and CD8+ T cells. Similarly, the IL-1-MT group had significantly upregulated immunogenicity, including in terms of the tumor mutation burden (TMB), neoantigen load (NAL) and number of mutations in DNA damage repair (DDR) signaling. GSEA showed that the IL-1-MT group was highly enriched in the immune response and proinflammatory mediators. Additionally, the expression levels of immune-related genes, immune checkpoint molecules and immune-related signatures were significantly higher in the IL-1-MT group than in the IL-1-WT group. IL-1-MT may be an independent predictor of a good prognosis in COAD patients receiving ICIs, with significantly longer OS in IL-1-MT COAD patients. Additionally, IL-1-MT was associated with significantly increased immunogenicity, activated immune cell and inflammatory mediator levels and immune response-related scores.


Assuntos
Adenocarcinoma/imunologia , Biomarcadores Tumorais/genética , Neoplasias do Colo/imunologia , Interleucina-1/genética , Microambiente Tumoral/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Biomarcadores Tumorais/imunologia , Estudos de Coortes , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias do Colo/mortalidade , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoterapia , Interleucina-1/imunologia , Mutação , Prognóstico , Análise de Sobrevida , Microambiente Tumoral/imunologia
14.
Comput Math Methods Med ; 2021: 5549298, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34394706

RESUMO

Pancreatic cancer (PC) is a malignant tumor with poor prognosis. The poor effect of surgery and chemotherapy makes the research of immunotherapy target molecules significant. Therefore, identifying the new molecular targets of PC is important for patients. In our study, we systematically analyzed molecular correlates of pancreatic cancer by bioinformatic analysis. We characterized differentially expressed analysis based on the TCGA pancreatic cancer dataset. Then, univariate Cox regression was employed to screen out overall survival- (OS-) related DEGs. Based on these genes, we established a risk signature by the multivariate Cox regression model. The ICGC cohort and GSE62452 cohort were used to validate the reliability of the risk signature. The impact of T lymphocyte-related genes from risk signature was confirmed in PC. Here, we observed the correlation between the T lymphocyte-related genes and the expression level of targeted therapy. We established a five-mRNA (LY6D, ANLN, ZNF488, MYEOV, and SCN11A) prognostic risk signature. Next, we identified ANLN and MYEOV that were associated with T lymphocyte infiltrations (P < 0.05). High ANLN and MYEOV expression levels had a poorer prognosis in decreased T lymphocyte subgroup in PC. Correlation analysis between ANLN and MYEOV and immunomodulators showed that ANLN and MYEOV may have potential value in pancreatic cancer immunotherapy.


Assuntos
Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Idoso , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/imunologia , Estudos de Coortes , Biologia Computacional , Bases de Dados Genéticas , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoterapia , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Masculino , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/imunologia , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Canal de Sódio Disparado por Voltagem NAV1.9/genética , Canal de Sódio Disparado por Voltagem NAV1.9/imunologia , Neoplasias Pancreáticas/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/imunologia , RNA Mensageiro/genética , Linfócitos T/imunologia
15.
Sci Rep ; 11(1): 17155, 2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433835

RESUMO

For the sensitive diagnosis of colorectal cancer lesions, advanced molecular imaging techniques using cancer-specific targets have emerged. However, issues regarding the clearance of unbound probes and immunogenicity remain unresolved. To overcome these limitations, we developed a small-sized scFv antibody fragment conjugated with FITC for the real-time detection of colorectal cancer by in vivo molecular endoscopy imaging. A small-sized scFv fragment can target colon cancer secreted protein-2 (CCSP-2), highly expressed in colorectal adenocarcinoma tissues; moreover, its full-length IgG probe has been used for molecular imaging previously. To assess the efficacy of anti-CCSP-2 scFv-FITC, surgical specimens were obtained from 21 patients with colorectal cancer for ex vivo molecular fluorescence analysis, histology, and immunohistochemistry. Orthotopic mice were administered with anti-CCSP-2 scFv-FITC topically and intravenously, and distinct tumor lesions were observed by real-time fluorescence colonoscopy. The fluorescence imaging of human colon cancer specimens allowed the differentiation of malignant tissues from non-malignant tissues (p < 0.05), and the CCSP-2 expression level was found to be correlated with the fluorescence intensity. Here, we demonstrated the feasibility and safety of anti-CCSP-2 scFv-FITC for molecular imaging as well as its potential in real-time fluorescence colonoscopy for the differential diagnosis of tumor lesions.


Assuntos
Adenocarcinoma/diagnóstico por imagem , Colonoscopia/métodos , Neoplasias Colorretais/diagnóstico por imagem , Imagem Óptica/métodos , Anticorpos de Cadeia Única/imunologia , Adenocarcinoma/patologia , Animais , Biomarcadores Tumorais/imunologia , Proteínas de Ligação ao Cálcio/imunologia , Neoplasias Colorretais/patologia , Feminino , Fluoresceína-5-Isotiocianato , Imunofluorescência/métodos , Células HCT116 , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade
16.
Genes (Basel) ; 12(6)2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200642

RESUMO

FENDRR (Fetal-lethal non-coding developmental regulatory RNA, LncRNA FOXF1-AS1) is a recently identified tumor suppressor long non-coding (LncRNA) RNA, and its expression has been linked with epigenetic modulation of the target genes involved in tumor immunity. In this study, we aimed to understand the role of FENDRR in predicting immune-responsiveness and the inflammatory tumor environment. Briefly, FENDRR expression and its relationship to immune activation signals were assessed in murine cell lines. Data suggested that tumor cells (e.g., C26 colon, 4T1 breast) that typically upregulate immune activation genes and the MHC class I molecule exhibited high FENDRR expression levels. Conversely, tumor cells with a generalized downregulation of immune-related gene expression (e.g., B16F10 melanoma) demonstrated low to undetectable FENDRR levels. Mechanistically, the modulation of FENDRR expression enhanced the inflammatory and WNT signaling pathways in tumors. Our early data suggest that FENDRR can play an important role in the development of immune-relevant phenotypes in tumors, and thereby improve cancer immunotherapy.


Assuntos
Neoplasias do Colo/genética , Melanoma/genética , RNA Longo não Codificante/genética , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Melanoma/imunologia , Camundongos , Camundongos Endogâmicos C57BL , RNA Longo não Codificante/metabolismo , Via de Sinalização Wnt
17.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299016

RESUMO

Metaplastic breast carcinoma (MBC) is a heterogeneous group of infrequent triple negative (TN) invasive carcinomas with poor prognosis. MBCs have a different clinical behavior from other types of triple negative breast cancer (TNBC), being more resistant to standard chemotherapy. MBCs are an example of tumors with activation of epithelial-mesenchymal transition (EMT). The mechanisms involved in EMT could be responsible for the increase in the infiltrative and metastatic capacity of MBCs and resistance to treatments. In addition, a relationship between EMT and the immune response has been seen in these tumors. In this sense, MBC differ from other TN tumors showing a lower number of tumor-infiltrating lymphocytes (TILS) and a higher percentage of tumor cells expressing programmed death-ligand 1 (PD-L1). A better understanding of the relationship between the immune system and EMT could provide new therapeutic approaches in MBC.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Carcinoma/imunologia , Carcinoma/metabolismo , Transição Epitelial-Mesenquimal/imunologia , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Caderinas/metabolismo , Carcinoma/tratamento farmacológico , Carcinoma/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
18.
Int J Mol Sci ; 22(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34299136

RESUMO

Soft tissue sarcomas (STSs) are a family of rare malignant tumors encompassing more than 80 histologies. Current therapies for metastatic STS, a condition that affects roughly half of patients, have limited efficacy, making innovative therapeutic strategies urgently needed. From a molecular point of view, STSs can be classified as translocation-related and those with a heavily rearranged genotype. Although only the latter display an increased mutational burden, molecular profiles suggestive of an "immune hot" tumor microenvironment are observed across STS histologies, and response to immunotherapy has been reported in both translocation-related and genetic complex STSs. These data reinforce the notion that immunity in STSs is multifaceted and influenced by both genetic and epigenetic determinants. Cumulative evidence indicates that a fine characterization of STSs at different levels is required to identify biomarkers predictive of immunotherapy response and to discover targetable pathways to switch on the immune sensitivity of "immune cold" tumors. In this review, we will summarize recent findings on the interplay between genetic landscape, molecular profiling and immunity in STSs. Immunological and molecular features will be discussed for their prognostic value in selected STS histologies. Finally, the local and systemic immunomodulatory effects of the targeted drugs imatinib and sunitinib will be discussed.


Assuntos
Biomarcadores Tumorais/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Imunoterapia/métodos , Terapia de Alvo Molecular , Sarcoma/imunologia , Microambiente Tumoral/imunologia , Animais , Biomarcadores Tumorais/imunologia , Humanos , Sarcoma/tratamento farmacológico , Sarcoma/patologia
19.
Am J Surg Pathol ; 45(9): 1213-1220, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34310369

RESUMO

Immune checkpoint inhibitor therapy is effective only for a subset of patients with gastric cancer. Impaired neoantigen presentation caused by deficiency of human leukocyte antigen class I (HLA-I) has been reported as a common mechanism of immune evasion which is associated with resistance to immune checkpoint blockade. To elucidate the significance of HLA-I deficiency in gastric cancer with special focus on microsatellite instable (MSI) and Epstein-Barr virus (EBV)-positive tumors, we examined HLA-I expression on tumor cells and correlated the results with clinicopathologic features, programmed death-ligand 1 (PD-L1) expression, and degree of tumor-infiltrating immune cells. This study included 58 MSI, 44 EBV-positive, and 107 non-EBV non-MSI tumors for comparison. The frequency of HLA-I deficiency (≥1% tumor cells) was significantly higher in MSI tumors (52%) compared with EBV-positive tumors (23%) and the other tumors (28%). In contrast, PD-L1 expression levels were highest in EBV-positive tumors, followed by MSI tumors, with the lowest prevalence in the other tumors in both Tumor Proportion Score and Combined Positive Score. HLA-I deficiency was significantly more frequent in advanced tumors (pT2-4) than in early tumors (pT1) in MSI and non-EBV non-MSI subtypes. In addition, the degree of CD8-positive cells infiltration was significantly reduced in HLA-I deficient tumor areas compared with HLA-I preserved tumor area within a tumor. Based on our observations, HLA-I, as well as PD-L1, should be considered as a common mechanism of immune escape especially in the MSI subtype, and therefore could be a biomarker predicting response to immune checkpoint inhibitor therapy in gastric cancer.


Assuntos
Biomarcadores Tumorais/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Neoplasias Gástricas/imunologia , Evasão Tumoral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/metabolismo , Infecções por Vírus Epstein-Barr/complicações , Feminino , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade
20.
Front Immunol ; 12: 685992, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34262565

RESUMO

Background: Gastric cancer (GC) is a highly heterogeneous tumor with different responses to immunotherapy. Identifying immune subtypes and landscape of GC could improve immunotherapeutic strategies. Methods: Based on the abundance of tumor-infiltrating immune cells in GC patients from The Cancer Genome Atlas, we used unsupervised consensus clustering algorithm to identify robust clusters of patients, and assessed their reproducibility in an independent cohort from Gene Expression Omnibus. We further confirmed the feasibility of our immune subtypes in five independent pan-cancer cohorts. Finally, functional enrichment analyses were provided, and a deep learning model studying the pathological images was constructed to identify the immune subtypes. Results: We identified and validated three reproducible immune subtypes presented with diverse components of tumor-infiltrating immune cells, molecular features, and clinical characteristics. An immune-inflamed subtype 3, with better prognosis and the highest immune score, had the highest abundance of CD8+ T cells, CD4+ T-activated cells, follicular helper T cells, M1 macrophages, and NK cells among three subtypes. By contrast, an immune-excluded subtype 1, with the worst prognosis and the highest stromal score, demonstrated the highest infiltration of CD4+ T resting cells, regulatory T cells, B cells, and dendritic cells, while an immune-desert subtype 2, with an intermediate prognosis and the lowest immune score, demonstrated the highest infiltration of M2 macrophages and mast cells, and the lowest infiltration of M1 macrophages. Besides, higher proportion of EVB and MSI of TCGA molecular subtyping, over expression of CTLA4, PD1, PDL1, and TP53, and low expression of JAK1 were observed in immune subtype 3, which consisted with the results from Gene Set Enrichment Analysis. These subtypes may suggest different immunotherapy strategies. Finally, deep learning can predict the immune subtypes well. Conclusion: This study offers a conceptual frame to better understand the tumor immune microenvironment of GC. Future work is required to estimate its reference value for the design of immune-related studies and immunotherapy selection.


Assuntos
Aprendizado Profundo , Neoplasias Gástricas/classificação , Neoplasias Gástricas/imunologia , Linfócitos T/imunologia , Idoso , Biomarcadores Tumorais/imunologia , Feminino , Humanos , Imunoterapia , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Reprodutibilidade dos Testes , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Transcriptoma , Microambiente Tumoral/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...