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1.
Nat Commun ; 11(1): 4835, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973173

RESUMO

Immune checkpoint blockade therapies have shown clinical promise in a variety of cancers, but how tumor-infiltrating T cells are activated remains unclear. In this study, we explore the functions of PD-L1 on dendritic cells (DCs), which highly express PD-L1. We observe that PD-L1 on DC plays a critical role in limiting T cell responses. Type 1 conventional DCs are essential for PD-L1 blockade and they upregulate PD-L1 upon antigen uptake. Upregulation of PD-L1 on DC is mediated by type II interferon. While DCs are the major antigen presenting cells for cross-presenting tumor antigens to T cells, subsequent PD-L1 upregulation protects them from killing by cytotoxic T lymphocytes, yet dampens the antitumor responses. Blocking PD-L1 in established tumors promotes re-activation of tumor-infiltrating T cells for tumor control. Our study identifies a critical and dynamic role of PD-L1 on DC, which needs to be harnessed for better invigoration of antitumor immune responses.


Assuntos
Antígeno B7-H1/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Ativação Linfocitária , Animais , Antígenos de Neoplasias/metabolismo , Antígeno B7-H1/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Interferon gama/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T Citotóxicos/imunologia , Microambiente Tumoral/imunologia , Regulação para Cima
2.
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
3.
PLoS Med ; 17(9): e1003292, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32970670

RESUMO

BACKGROUND: Identifying stage II patients with colorectal cancer (CRC) at higher risk of progression is a clinical priority in order to optimize the advantages of adjuvant chemotherapy while avoiding unnecessary toxicity. Recently, the intensity and the quality of the host immune response in the tumor microenvironment have been reported to have an important role in tumorigenesis and an inverse association with tumor progression. This association is well established in microsatellite instable CRC. In this work, we aim to assess the usefulness of measures of T-cell infiltration as prognostic biomarkers in 640 stage II, CRC tumors, 582 of them confirmed microsatellite stable. METHODS AND FINDINGS: We measured both the quantity and clonality index of T cells by means of T-cell receptor (TCR) immunosequencing in a discovery dataset (95 patients with colon cancer diagnosed at stage II and microsatellite stable, median age 67, 30% women) and replicated the results in 3 additional series of stage II patients from 2 countries. Series 1 and 2 were recruited in Barcelona, Spain and included 112 fresh frozen (FF, median age 69, 44% women) and 163 formalin-fixed paraffin-embedded (FFPE, median age 67, 39% women) samples, respectively. Series 3 included 270 FFPE samples from patients recruited in Haifa, Northern Israel, as part of a large case-control study of CRC (median age 73, 46% women). Median follow-up time was 81.1 months. Cox regression models were fitted to evaluate the prognostic value of T-cell abundance and Simpson clonality of TCR variants adjusting by sex, age, tumor location, and stage (IIA and IIB). In the discovery dataset, higher TCR abundance was associated with better prognosis (hazard ratio [HR] for ≥Q1 = 0.25, 95% CI 0.10-0.63, P = 0.003). A functional analysis of gene expression on these tumors revealed enrichment in pathways related to immune response. Higher values of clonality index (lower diversity) were not associated with worse disease-free survival, though the HR for ≥Q3 was 2.32 (95% CI 0.90-5.97, P = 0.08). These results were replicated in an independent FF dataset (TCR abundance: HR = 0.30, 95% CI 0.12-0.72, P = 0.007; clonality: HR = 3.32, 95% CI 1.38-7.94, P = 0.007). Also, the association with prognosis was tested in 2 independent FFPE datasets. The same association was observed with TCR abundance (HR = 0.41, 95% CI 0.18-0.93, P = 0.03 and HR = 0.56, 95% CI 0.31-1, P = 0.042, respectively, for each FFPE dataset). However, the clonality index was associated with prognosis only in the FFPE dataset from Israel (HR = 2.45, 95% CI 1.39-4.32, P = 0.002). Finally, a combined analysis combining all microsatellite stable (MSS) samples demonstrated a clear prognosis value both for TCR abundance (HR = 0.39, 95% CI 0.26-0.57, P = 1.3e-06) and the clonality index (HR = 2.13, 95% CI 1.44-3.15, P = 0.0002). These associations were also observed when variables were considered continuous in the models (HR per log2 of TCR abundance = 0.85, 95% CI 0.78-0.93, P = 0.0002; HR per log2 or clonality index = 1.16, 95% CI 1.03-1.31, P = 0.016). LIMITATIONS: This is a retrospective study, and samples had been preserved with different methods. Validation series lack complete information about microsatellite instability (MSI) status and pathology assessment. The Molecular Epidemiology of Colorectal Cancer (MECC) study had information about overall survival instead of progression-free survival. CONCLUSION: Results from this study demonstrate that tumor lymphocytes, assessed by TCR repertoire quantification based on a sequencing method, are an independent prognostic factor in microsatellite stable stage II CRC.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Repetições de Microssatélites/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Estudos de Casos e Controles , Quimioterapia Adjuvante , Neoplasias Colorretais/metabolismo , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Instabilidade de Microssatélites , Repetições de Microssatélites/imunologia , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Espanha , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
4.
Nat Commun ; 11(1): 3912, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32764562

RESUMO

Immunotherapy has emerged as a promising approach to treat cancer, however, its efficacy in highly malignant brain-tumors, glioblastomas (GBM), is limited. Here, we generate distinct imageable syngeneic mouse GBM-tumor models and utilize RNA-sequencing, CyTOF and correlative immunohistochemistry to assess immune-profiles in these models. We identify immunologically-inert and -active syngeneic-tumor types and show that inert tumors have an immune-suppressive phenotype with numerous exhausted CD8 T cells and resident macrophages; fewer eosinophils and SiglecF+ macrophages. To mimic the clinical-settings of first line of GBM-treatment, we show that tumor-resection invigorates an anti-tumor response via increasing T cells, activated microglia and SiglecF+ macrophages and decreasing resident macrophages. A comparative CyTOF analysis of resected-tumor samples from GBM-patients and mouse GBM-tumors show stark similarities in one of the mouse GBM-tumors tested. These findings guide informed choices for use of GBM models for immunotherapeutic interventions and offer a potential to facilitate immune-therapies in GBM patients.


Assuntos
Neoplasias Encefálicas/imunologia , Glioblastoma/imunologia , Animais , Encéfalo/imunologia , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Tolerância Imunológica , Imunofenotipagem , Imunoterapia , Isoenxertos , Linfócitos do Interstício Tumoral/classificação , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Microambiente Tumoral/imunologia
5.
PLoS One ; 15(8): e0237465, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32785290

RESUMO

BACKGROUND: Tumor-infiltrating lymphocytes include tumor-reactive lymphocytes and regulatory T-cells. However, the prognostic value of tumor-infiltrating lymphocytes in oral squamous cell carcinoma (OSCC) remains unclear. METHODS: We used immunohistochemistry to evaluate the presence of tumor-infiltrating FoxP3⁺ T-cells and CTLA-4⁺ cells in four distinct histological compartments (tumor parenchyma and stroma at the tumor center, and parenchyma and stroma at the invasive front) and assessed the association between the prevalence of these cells and the histopathological status of 137 patients with OSCC. RESULTS: Five-year overall survival, disease-specific survival, and recurrence-free survival were favorable in patients with high numbers of FoxP3⁺ T-cells in the parenchyma of the invasive front. Recurrence-free survival and metastasis-free survival were decreased in patients with high numbers of CTLA-4⁺ cells in the parenchyma of the invasive front. CONCLUSIONS: The presence of FoxP3⁺ T-cells in the parenchyma of the invasive front may be a useful prognostic factor. Our results indicate that FoxP3⁺ T-cells may exert site-specific anti-tumor effects but may not play an immunosuppressive role in OSCC. In addition, our results suggest that CTLA-4+ cells suppress the function of FoxP3+ T-cells and promote anti-tumor immunity in OSCC.


Assuntos
Antígeno CTLA-4/metabolismo , Carcinoma de Células Escamosas/patologia , Fatores de Transcrição Forkhead/metabolismo , Neoplasias Bucais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Feminino , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/metabolismo , Neoplasias Bucais/mortalidade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Taxa de Sobrevida , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo
6.
Life Sci ; 258: 118170, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32735883

RESUMO

AIMS: Coronavirus disease 2019 (COVID-19), which is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is a major health concern worldwide. Due to the lack of specific medication and vaccination, drug-repurposing attempts has emerged as a promising approach and identified several human proteins interacting with the virus. This study aims to provide a comprehensive molecular profiling of the immune cell-enriched SARS-CoV-2 interacting protein USP13. MATERIALS AND METHODS: The list of immune cell-enriched proteins interacting with SARS-CoV-2 was retrieved from The Human Protein Atlas. Genomic alterations were identified using cBioPortal. Survival analysis was performed via Kaplan-Meier Plotter. Analyses of protein expression and tumor infiltration levels were carried out by TIMER. KEY FINDINGS: 14 human proteins that interact with SARS-CoV-2 were enriched in immune cells. Among these proteins, USP13 had the highest frequency of genomic alterations. Higher USP13 levels were correlated with improved survival in breast and lung cancers, while resulting in poor prognosis in ovarian and gastric cancers. Furthermore, copy number variations of USP13 significantly affected the infiltration levels of distinct subtypes of immune cells in head & neck, lung, ovarian and stomach cancers. Although our results suggested a tumor suppressor role for USP13 in lung cancer, in other cancers, its role seemed to be context-dependent. SIGNIFICANCE: It is critical to identify and characterize human proteins that interact with SARS-CoV-2 in order to have a better understanding of the disease and to develop better therapies/vaccines. Here, we provided a comprehensive molecular profiling the immune cell-enriched SARS-CoV-2 interacting protein USP13, which will be useful for future studies.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Endopeptidases/imunologia , Leucócitos/imunologia , Neoplasias/imunologia , Pneumonia Viral/imunologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Variações do Número de Cópias de DNA , Bases de Dados de Proteínas , Endopeptidases/genética , Humanos , Leucócitos/virologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/virologia , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/virologia , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/genética , Pneumonia Viral/virologia , Prognóstico
7.
Life Sci ; 258: 118170, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: covidwho-680463

RESUMO

AIMS: Coronavirus disease 2019 (COVID-19), which is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is a major health concern worldwide. Due to the lack of specific medication and vaccination, drug-repurposing attempts has emerged as a promising approach and identified several human proteins interacting with the virus. This study aims to provide a comprehensive molecular profiling of the immune cell-enriched SARS-CoV-2 interacting protein USP13. MATERIALS AND METHODS: The list of immune cell-enriched proteins interacting with SARS-CoV-2 was retrieved from The Human Protein Atlas. Genomic alterations were identified using cBioPortal. Survival analysis was performed via Kaplan-Meier Plotter. Analyses of protein expression and tumor infiltration levels were carried out by TIMER. KEY FINDINGS: 14 human proteins that interact with SARS-CoV-2 were enriched in immune cells. Among these proteins, USP13 had the highest frequency of genomic alterations. Higher USP13 levels were correlated with improved survival in breast and lung cancers, while resulting in poor prognosis in ovarian and gastric cancers. Furthermore, copy number variations of USP13 significantly affected the infiltration levels of distinct subtypes of immune cells in head & neck, lung, ovarian and stomach cancers. Although our results suggested a tumor suppressor role for USP13 in lung cancer, in other cancers, its role seemed to be context-dependent. SIGNIFICANCE: It is critical to identify and characterize human proteins that interact with SARS-CoV-2 in order to have a better understanding of the disease and to develop better therapies/vaccines. Here, we provided a comprehensive molecular profiling the immune cell-enriched SARS-CoV-2 interacting protein USP13, which will be useful for future studies.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Endopeptidases/imunologia , Leucócitos/imunologia , Neoplasias/imunologia , Pneumonia Viral/imunologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Variações do Número de Cópias de DNA , Bases de Dados de Proteínas , Endopeptidases/genética , Humanos , Leucócitos/virologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/virologia , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/virologia , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/genética , Pneumonia Viral/virologia , Prognóstico
8.
Int J Nanomedicine ; 15: 4151-4169, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606670

RESUMO

Purpose: Focused ultrasound (FUS) is a noninvasive method to produce thermal and mechanical destruction along with an immune-stimulatory effect against cancer. However, FUS ablation alone appears insufficient to generate consistent antitumor immunity. In this study, a multifunctional nanoparticle was designed to boost FUS-induced immune effects and achieve systemic, long-lasting antitumor immunity, along with imaging and thermal enhancement. Materials and Methods: PEGylated PLGA nanoparticles encapsulating astragalus polysaccharides (APS) and gold nanorods (AuNRs) were constructed by a simple double emulsion method, characterized, and tested for cytotoxicity. The abilities of PA imaging and thermal-synergetic ablation efficiency were analyzed in vitro and in vivo. The immune-synergistic effect on dendritic cell (DC) differentiation in vitro and the immune response in vivo were also evaluated. Results: The obtained APS/AuNR/PLGA-PEG nanoparticles have an average diameter of 255.00±0.1717 nm and an APS-loading efficiency of 54.89±2.07%, demonstrating their PA imaging capability and high biocompatibility both in vitro and in vivo. In addition, the as-prepared nanoparticles achieved a higher necrosis cell rate and induced apoptosis rate in an in vitro cell suspension assay, greater necrosis area and decreased energy efficiency factor (EEF) in an in vivo rabbit liver assay, and remarkable thermal-synergic performance. In particular, the nanoparticles upregulated the expression of MHC-II, CD80 and CD86 on cocultured DCs in vitro, followed by declining phagocytic function and enhanced interleukin (IL)-12 and interferon (INF)-γ production. Furthermore, they boosted the production of tumor necrosis factor (TNF)-α, IFN-γ, IL-4, IL-10, and IgG1 (P< 0.001) but not IgG2a. Immune promotion peaked on day 3 after FUS in vivo. Conclusion: The multifunctional APS/AuNR/PLGA-PEG nanoparticles can serve as an excellent synergistic agent for FUS therapy, facilitating real-time imaging, promoting thermal ablation effects, and boosting FUS-induced immune effects, which have the potential to be used for further clinical FUS treatment.


Assuntos
Astrágalo (Planta)/química , Neoplasias da Mama/terapia , Ouro/química , Nanopartículas Multifuncionais/química , Nanotubos/química , Polissacarídeos/química , Terapia por Ultrassom , Animais , Antígenos CD/metabolismo , Apoptose , Morte Celular , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Citocinas/metabolismo , Células Dendríticas/citologia , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Imunoglobulina G/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Camundongos Endogâmicos BALB C , Fagocitose , Técnicas Fotoacústicas , Poliésteres/síntese química , Poliésteres/química , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Coelhos , Nanomedicina Teranóstica , Fator A de Crescimento do Endotélio Vascular/metabolismo
9.
Nat Commun ; 11(1): 3584, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32681091

RESUMO

Responses to immunotherapy are uncommon in estrogen receptor (ER)-positive breast cancer and to date, lack predictive markers. This randomized phase II study defines safety and response rate of epigenetic priming in ER-positive breast cancer patients treated with checkpoint inhibitors as primary endpoints. Secondary and exploratory endpoints included PD-L1 modulation and T-cell immune-signatures. 34 patients received vorinostat, tamoxifen and pembrolizumab with no excessive toxicity after progression on a median of five prior metastatic regimens. Objective response was 4% and clinical benefit rate (CR + PR + SD > 6 m) was 19%. T-cell exhaustion (CD8+ PD-1+/CTLA-4+) and treatment-induced depletion of regulatory T-cells (CD4+ Foxp3+/CTLA-4+) was seen in tumor or blood in 5/5 patients with clinical benefit, but only in one non-responder. Tumor lymphocyte infiltration was 0.17%. Only two non-responders had PD-L1 expression >1%. This data defines a novel immune signature in PD-L1-negative ER-positive breast cancer patients who are more likely to benefit from immune-checkpoint and histone deacetylase inhibition (NCT02395627).


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Imunoterapia , Linfócitos T/imunologia , Tamoxifeno/administração & dosagem , Vorinostat/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Linfócitos do Interstício Tumoral/imunologia , Pessoa de Meia-Idade , Receptores Estrogênicos/genética , Receptores Estrogênicos/imunologia , Linfócitos T/efeitos dos fármacos , Resultado do Tratamento
10.
Cancer Immunol Immunother ; 69(10): 2157-2162, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32638080

RESUMO

Epidemiological evidence suggests that females have an advantage over males in cases of melanoma incidence, progression, and survival. However, the biological mechanisms underlying these sex differences remain unclear. With the knowledge that females generally have a more robust immune system than males, we investigated sex differences in melanoma progression in a B16-F10/BL6 syngeneic mouse model. We observed significantly less tumor volume and growth rate over 14 days in female mice compared to male mice. Furthermore, higher populations of CD4+ and CD8+ T cells, which indicate adaptive immune responses, were found in the circulating blood and tumors of females and corresponded with less tumor growth, and vice versa in males. Our results highlight a mouse model that represents melanoma progression in the human population and displays a higher immune response to melanoma in females compared to males. These findings suggest that the immune system may be one of the mechanisms responsible for sex differences in melanoma.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Linfócitos do Interstício Tumoral/imunologia , Melanoma Experimental/imunologia , Neoplasias Cutâneas/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Feminino , Masculino , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Cutâneas/secundário , Linfócitos T Citotóxicos/patologia , Carga Tumoral , Células Tumorais Cultivadas
11.
Nat Commun ; 11(1): 2908, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32518267

RESUMO

Adoptive cell therapy (ACT) with tumor-specific T cells can mediate cancer regression. The main target of tumor-specific T cells are neoantigens arising from mutations in self-proteins. Although the majority of cancer neoantigens are unique to each patient, and therefore not broadly useful for ACT, some are shared. We studied oligoclonal T-cell receptors (TCRs) that recognize a shared neoepitope arising from a driver mutation in the p53 oncogene (p53R175H) presented by HLA-A2. Here we report structures of wild-type and mutant p53-HLA-A2 ligands, as well as structures of three tumor-specific TCRs bound to p53R175H-HLA-A2. These structures reveal how a driver mutation in p53 rendered a self-peptide visible to T cells. The TCRs employ structurally distinct strategies that are highly focused on the mutation to discriminate between mutant and wild-type p53. The TCR-p53R175H-HLA-A2 complexes provide a framework for designing TCRs to improve potency for ACT without sacrificing specificity.


Assuntos
Antígenos de Neoplasias/química , Antígeno HLA-A2/química , Mutação , Linfócitos T/imunologia , Proteína Supressora de Tumor p53/química , Sítios de Ligação , Biotinilação , Códon , Cristalografia por Raios X , Epitopos , Escherichia coli/metabolismo , Humanos , Imunoterapia Adotiva , Ligantes , Linfócitos do Interstício Tumoral/imunologia , Neoplasias/metabolismo , Peptídeos/química , Ligação Proteica , Conformação Proteica , Dobramento de Proteína , Receptores de Antígenos de Linfócitos T/metabolismo , Software , Ressonância de Plasmônio de Superfície
12.
PLoS One ; 15(6): e0233676, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32484812

RESUMO

In urothelial cell type non-muscle invasive urinary bladder carcinoma, TNM stage and WHO grade are widely used to classify patients into low and high­risk groups for prognostic and therapeutic decision-making. However, stage and grade reproducibility and prediction accuracy are wanting. This may lead to suboptimal treatment. We evaluated whether proliferation features, nuclear area of the epithelial cancer cells and the composition of stromal and tumor infiltrating lymphocytes have independent prognostic value. In 183 primary non-muscle invasive bladder cancer patients with long follow-up (median for stage progression cohort: 119 months, range 5-173; median for tumor recurrence cohort: 82, range 3-165) proliferation features Ki67, PPH3 and Mitotic Activity Index (MAI), Mean Nuclear Area (MNA), lymphocyte subsets (CD8+, CD4+, CD25+) and plasma cells (CD138+) were assessed on consecutive sections. Post-resection instillation treatments (none, mitomycin, BCG) were strictly standardized during the intake period. Risk of recurrence was associated with expression of Ki67 (≤ 39 vs. > 39) and Multifocality (p = 0.01). Patients with low Ki67 had a higher recurrence rate than those with high Ki67. Lymphocyte composition did not predict recurrence. Stage progression was strongly associated with high values for MAI (>15) and CD25+ (>0.2%). In a multivariate analysis the combination of MAI and CD25+ was the single most prognostic feature (p<0.001). Validation of these results in additional, independent studies is warranted.


Assuntos
Carcinoma de Células de Transição/patologia , Linfócitos do Interstício Tumoral/imunologia , Índice Mitótico , Recidiva Local de Neoplasia/diagnóstico , Neoplasias da Bexiga Urinária/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/imunologia , Progressão da Doença , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Estimativa de Kaplan-Meier , Antígeno Ki-67/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia , Estadiamento de Neoplasias , Prognóstico , Reprodutibilidade dos Testes , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/mortalidade
13.
Life Sci ; 256: 117906, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32504750

RESUMO

AIMS: Head and neck squamous cell carcinoma (HNSCC) is an highly aggressive tumor with heterogeneous prognosis. We here report that immune-related genes (IRGs) could effectively distinguish prognostically different HNSCC patients. MATERIALS AND METHODS: MRNA levels of 1333 IRGs that from ImmPort database in HNSCC samples were acquired from the Cancer Genome Atlas (TCGA). H2o, a machine learning-based R package, was used for screening the top most representative genes from the IRGs. Univariate Cox-regression analysis was performed to identify prognostically-related genes based on the randomly generated training samples from TCGA set. LASSO Cox-regression analysis was applied for the construction of prognostic model for HNSCC. A total of six IRGs were finally retained for their prognostic significance and used for LASSO Cox-regression analysis. KEY FINDINGS: Samples from exclusive training and testing set that randomly generated from TCGA, and another independent validation set from the Gene Expression Omnibus (GEO) were divided into high- and low-risk groups according to the prognostic model. HNSCC samples within high-risk groups have significantly inferior overall survival (OS) compared with those within low-risk groups. Differences in genomic mutation landscape and tumor infiltration immune cells also exist between the two sample groups. What's more, risk score was proved to be an independent prognostic factor for HNSCC by stratification analysis. SIGNIFICANCE: IRGs are pivotal HNSCC prognostic signatures and should be helpful for its clinical decision-making.


Assuntos
Regulação Neoplásica da Expressão Gênica , Imunidade/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise por Conglomerados , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Prognóstico , Fatores de Risco , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Adulto Jovem
14.
Nature ; 583(7817): 609-614, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32581358

RESUMO

Cytokines were the first modern immunotherapies to produce durable responses in patients with advanced cancer, but they have only modest efficacy and limited tolerability1,2. In an effort to identify alternative cytokine pathways for immunotherapy, we found that components of the interleukin-18 (IL-18) pathway are upregulated on tumour-infiltrating lymphocytes, suggesting that IL-18 therapy could enhance anti-tumour immunity. However, recombinant IL-18 previously did not demonstrate efficacy in clinical trials3. Here we show that IL-18BP, a high-affinity IL-18 decoy receptor, is frequently upregulated in diverse human and mouse tumours and limits the anti-tumour activity of IL-18 in mice. Using directed evolution, we engineered a 'decoy-resistant' IL-18 (DR-18) that maintains signalling potential but is impervious to inhibition by IL-18BP. Unlike wild-type IL-18, DR-18 exerted potent anti-tumour effects in mouse tumour models by promoting the development of poly-functional effector CD8+ T cells, decreasing the prevalence of exhausted CD8+ T cells that express the transcriptional regulator of exhaustion TOX, and expanding the pool of stem-like TCF1+ precursor CD8+ T cells. DR-18 also enhanced the activity and maturation of natural killer cells to effectively treat anti-PD-1 resistant tumours that have lost surface expression of major histocompatibility complex class I molecules. These results highlight the potential of the IL-18 pathway for immunotherapeutic intervention and implicate IL-18BP as a major therapeutic barrier.


Assuntos
Imunoterapia , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Interleucina-18/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Animais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Feminino , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Estimativa de Kaplan-Meier , Células Matadoras Naturais/citologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos , Receptores de Interleucina-18/metabolismo , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
15.
Oncology ; 98(10): 680-688, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32526753

RESUMO

BACKGROUND: In patients with colorectal cancer, the rate of recurrence increases as the histologic stage progresses. However, the prediction of recurrence in individual patients is difficult. Many studies have reported on the relation between outcomes and tissue-infiltrating lymphocytes (TILs). The aim of our study was to clarify the relation between TILs and oncologic outcomes in patients with colon cancer using propensity score matching analysis. METHODS: The study group comprised 513 patients with colon cancer who received curative resection. By using propensity score matching for sex, age, tumor location, T stage, N stage, histologic type, and adjuvant therapy as conventional prognostic factors, 61 patients with recurrence and 61 patients with no recurrence were selected. Hematoxylin-eosin staining and immunohistochemical staining using CD3, CD8, CD4, and FoxP3 were performed for lymphocytes in the primary tissue. The results were evaluated separately in the whole tumor, the central part, and the invasive margin. RESULTS: The median follow-up period was 53 months. Among the 513 patients, 70 had recurrence and 443 had no recurrence. In the comparison of outcomes between the 61 patients with recurrence and the 61 patients with no recurrence, univariate analysis showed that the disease-free survival rate was significantly higher among the patients with positive TILs in the whole tumor and in the invasive margin (p = 0.016 and p = 0.012, respectively) and with CD8+ cells in the central part (p = 0.039) than among those with negative results. A multivariate analysis showed that TILs in the invasive margin (hazard ratio 1.81; 95% confidence interval, 1.03-3.05; p = 0.037) and CD8+ cell density in the central part (hazard ratio 1.76; 95% confidence interval, 1.07-2.93; p = 0.023) were prognostic factors that were independent from conventional prognostic factors. CONCLUSIONS: In patients with curatively resected colon cancer, TILs in the invasive margin and CD8+ cell density in the central part may be prognostic factors suggesting host antitumor immune response.


Assuntos
Neoplasias do Colo/imunologia , Neoplasias do Colo/cirurgia , Linfócitos do Interstício Tumoral/imunologia , Recidiva Local de Neoplasia/imunologia , Idoso , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Neoplasias do Colo/patologia , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/patologia , Masculino , Análise Multivariada , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Pontuação de Propensão
16.
Cancer Sci ; 111(9): 3132-3141, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32579769

RESUMO

Esophageal squamous cell carcinoma (ESCC) is the main prevalent histological type of esophageal cancer, predominantly constituting 90% of cases worldwide. Despite the development of multidisciplinary therapeutic approaches, its prognosis remains unfavorable. Recently, the development of monoclonal antibodies inhibiting programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1) has led to marked therapeutic responses among multiple malignancies including ESCC. However, only a few patients achieved clinical benefits due to resistance. Therefore, precise and accurate predictive biomarkers should be identified for personalized immunotherapy in clinical settings. Because the tumor immune microenvironment can potentially influence the patient's response to immune checkpoint inhibitors, tumor immunity, such as PD-L1 expression on tumors, tumor-infiltrating lymphocytes, tumor-associated macrophages, and myeloid-derived suppressor cells, in ESCC should be further investigated. In this review, accumulated evidence regarding the tumor immune microenvironment and immune checkpoint inhibitors in ESCC are summarized.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Neoplasias Esofágicas/etiologia , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/etiologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/patologia , Humanos , Imunomodulação/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Mutação , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Células Supressoras Mieloides/patologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo
17.
Nat Genet ; 52(6): 582-593, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32483290

RESUMO

In metastatic cancer, the degree of heterogeneity of the tumor microenvironment (TME) and its molecular underpinnings remain largely unstudied. To characterize the tumor-immune interface at baseline and during neoadjuvant chemotherapy (NACT) in high-grade serous ovarian cancer (HGSOC), we performed immunogenomic analysis of treatment-naive and paired samples from before and after treatment with chemotherapy. In treatment-naive HGSOC, we found that immune-cell-excluded and inflammatory microenvironments coexist within the same individuals and within the same tumor sites, indicating ubiquitous variability in immune cell infiltration. Analysis of TME cell composition, DNA copy number, mutations and gene expression showed that immune cell exclusion was associated with amplification of Myc target genes and increased expression of canonical Wnt signaling in treatment-naive HGSOC. Following NACT, increased natural killer (NK) cell infiltration and oligoclonal expansion of T cells were detected. We demonstrate that the tumor-immune microenvironment of advanced HGSOC is intrinsically heterogeneous and that chemotherapy induces local immune activation, suggesting that chemotherapy can potentiate the immunogenicity of immune-excluded HGSOC tumors.


Assuntos
Cistadenocarcinoma Seroso/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Neoplasias Ovarianas/tratamento farmacológico , Microambiente Tumoral/imunologia , Animais , Cisplatino/imunologia , Cisplatino/farmacologia , Estudos de Coortes , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/imunologia , Variações do Número de Cópias de DNA , Feminino , Perfilação da Expressão Gênica/estatística & dados numéricos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes myc , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Camundongos , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Análise de Componente Principal , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Via de Sinalização Wnt
18.
J Cancer Res Ther ; 16(2): 320-326, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32474519

RESUMO

Context: Increasing evidence has indicated an association between immune cell infiltration in lung adenocarcinoma (LUAD) and clinical outcomes. Aims: This study aimed to investigate the effect of 22 tumor-infiltrating immune cells (TIICs) on the prognosis of patients with LUAD. Settings and Design: This was a case-control study. Materials and Methods: The CIBERSORT algorithm calculated the proportion of cases from the Cancer Genome Atlas (TCGA) cohort. Cox regression analysis evaluated the effect of TIICs on the prognosis of LUAD. The immune risk score model was constructed based on a statistical correlation. Multivariate cox regression analysis investigated independent factors. P < 0.05 was considered to be statistically significant. Results: Certain immune cells had differential infiltration between normal tissues and LUAD. Univariate Cox regression analysis revealed that four immune cell types were statistically correlated with LUAD-related survival risk, and an immune risk scoring model was constructed. The results indicated that patients in the high-risk group were associated with poor outcomes. In addition, the multivariate cox analysis revealed that the immune risk scoring model was an independent factor for LUAD prognosis prediction. Ultimately, a nomogram was established to comprehensively predict the survival of LUAD patients. Conclusions: TIICs played an essential role in the prognosis of LUAD. Furthermore, the immune risk score was a poor predictive factor of LUAD, and the established model was reliable in predicting the prognosis of LUAD.


Assuntos
Adenocarcinoma de Pulmão/imunologia , Biomarcadores Tumorais/genética , Biologia Computacional/métodos , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Evasão Tumoral/imunologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Idoso , Algoritmos , Biomarcadores Tumorais/imunologia , Estudos de Casos e Controles , Estudos de Coortes , Bases de Dados Genéticas , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Evasão Tumoral/genética
19.
Anticancer Res ; 40(5): 2871-2880, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366437

RESUMO

BACKGROUND/AIM: This study aimed to improve the prognostic significance of neutrophil-to-lymphocyte ratio (NLR) and tumour-infiltrating lymphocytes (TILs). PATIENTS AND METHODS: In this retrospective study, NLR and TIL data from 677 operated breast cancer patients were analysed. The cut-off value of NLR was set at 2.72, and TIL levels were classified as low (<10%), intermediate (≥10 to <50%), and high (≥50%). RESULTS: Recurrence-free survival (RFS) was significantly longer in patients with low NLR (n=459) than in those with high NLR (n=218) (p=0.0383). In ER-positive/HER2-negative and TIL-low breast cancers, there were significant associations between NLR levels and RFS (p=0.0129) or overall survival (OS) (p=0.0046). On multivariate analysis, NLR was a significant and independent factor for OS (hazard ratio=3.78; 95% confidence interval=1.21-14.17; p=0.022). CONCLUSION: These data may be useful for predicting patient prognosis and understanding the clinical significance of immune status in breast cancers.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Linfócitos/imunologia , Neutrófilos/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Feminino , Humanos , Prognóstico , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/patologia
20.
Anticancer Res ; 40(5): 2881-2887, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366438

RESUMO

BACKGROUND/AIM: This study evaluated the prognostic significance of preoperative neutrophil-to-lymphocyte ratio (NLR) and CD8+ tumor-infiltrating lymphocytes (TILs), and whether preoperative NLR was associated with CD8+ TILs in biliary tract cancers (BTCs). PATIENTS AND METHODS: A total of 154 patients with BTCs who underwent surgery were enrolled in this study. We obtained neutrophil and lymphocyte counts, and calculated NLR from preoperative peripheral blood samples. CD8+ TILs were identified by immunohistochemical staining. RESULTS: The overall survival (OS) and recurrence-free survival (RFS) of patients with high NLR were shorter than those with low NLR. The OS and RFS of patients with high CD8+ TILs were longer than those with low CD8+ TILs. Preoperative NLR and CD8+ TILs were negatively correlated. CONCLUSION: NLR and CD8+ TILs were associated with OS and RFS in BTCs. NLR can predict CD8+ TILs infiltrating the cancer microenvironment.


Assuntos
Neoplasias do Sistema Biliar/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos/imunologia , Neutrófilos/imunologia , Idoso , Feminino , Humanos , Masculino
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