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1.
Anticancer Res ; 39(8): 4517-4523, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366554

RESUMO

BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs) have dramatically changed the clinical outcomes of advanced tumours. However, biomarkers for monitoring immunological features during immunotherapy remain unclear, especially those in the peripheral blood, which are easily available. This study evaluated the usefulness of nCounter Analysis System in identifying immunological biomarkers in peripheral blood mononuclear cells (PBMCs) during ICI therapy. PATIENTS AND METHODS: PBMCs from two patients who responded well to ICI therapy were used, and the expression levels of immune-related mRNA and extracellular proteins were analyzed. RESULTS: Changes in the expression levels of 55 genes from pre-treatment to on-treatment were bioinformatically similar between the two cases. The expression levels of PD-1 were consistent with those by flow cytometry analysis, a reliable tool for monitoring various markers. CONCLUSION: The nCounter Analysis System may be a potent tool to simultaneously investigate genes and proteins on PBMCs as biomarkers during immunotherapy using a small amount of sample.


Assuntos
Biomarcadores Tumorais/sangue , Imunoterapia , Neoplasias Pulmonares/sangue , Proteínas de Neoplasias/genética , Idoso , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/sangue
2.
Cancer Immunol Immunother ; 68(7): 1157-1169, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31197461

RESUMO

Chordoma is difficult to eradicate due to high local recurrence rates. The immune microenvironment is closely associated with tumor prognosis; however, its role in skull base chordoma is unknown. The expression of Galectin-9 (Gal9) and tumor-infiltrating lymphocyte (TIL) markers was assessed by immunohistochemistry. Kaplan-Meier and multivariate Cox analyses were used to assessing local recurrence-free survival (LRFS) and overall survival (OS) of patients. MiR-455-5p was identified as a regulator of Gal9 expression. Immunopositivity for Gal9 was associated with tumor invasion (p = 0.019), Karnofsky performance status (KPS) score (p = 0.017), and total TIL count (p < 0.001); downregulation of miR-455-5p was correlated with tumor invasion (p = 0.017) and poor prognosis; and the T-cell immunoglobulin and mucin-domain 3 (TIM3)+ TIL count was associated with chordoma invasion (p = 0.010) and KPS score (p = 0.037). Furthermore, multivariate analysis indicated that only TIM3+ TIL density was an independent prognostic factor for LRFS (p = 0.010) and OS (p = 0.016). These results can be used to predict clinical outcome and provide a basis for immune therapy in skull base chordoma patients.


Assuntos
Cordoma/patologia , Galectinas/genética , Linfócitos do Interstício Tumoral/imunologia , MicroRNAs/metabolismo , Neoplasias da Base do Crânio/patologia , Adolescente , Adulto , Idoso , Criança , Cordoma/genética , Cordoma/imunologia , Cordoma/mortalidade , Intervalo Livre de Doença , Feminino , Seguimentos , Galectinas/imunologia , Galectinas/metabolismo , Regulação Neoplásica da Expressão Gênica/imunologia , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/imunologia , Prognóstico , Estudos Retrospectivos , Neoplasias da Base do Crânio/imunologia , Neoplasias da Base do Crânio/mortalidade , Análise de Sobrevida , Adulto Jovem
3.
J BUON ; 24(2): 779-790, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31128036

RESUMO

PURPOSE: Gastroenteropancreatic tumors (GEPNETs) is a heterogeneous disease with variable clinical course. While promising therapeutic options exist for other adult cancers, there are no new molecular-based treatments developed for GEPNETs. One of the main targets of cancer immunotherapy is the Programmed Cell Death Ligand-1 (PD-L1) pathway. Our purpose was to investigate the profile of PD-L1 expression in different organs of GEPNETs and compare the conventional immunohistochemistry (IHC) with the RNA expression analysis via real time polymerase chain reaction (RT-PCR) in order to determine which patients might be appropriate for immune check point-targeted therapy. METHODS: A total of 59 surgically or endoscopically resected GEPNET tissues were retrospectively collected. The expression of PD-L1 and mRNA was evaluated with IHC. RESULTS: The expression of PD-L1 was significantly associated with the high-grade classification (p=0.012). PD-L1 mRNA expression in tumor samples appeared to be higher compared to the corresponding normal tissues. In appendix, stomach and small intestine, the expression of PD-L1 mRNA was higher in the tumor tissues compared to the respective controls. In pancreas and colon, control tissues tend to have a higher PD-L1 mRNA expression compared to tumor tissues. PD-L1 mRNA expression was higher in GEP carcinomas (p=0.0031). CONCLUSION: RT-PCR was found to be more sensitive in detecting PD-L1 expression than conventional IHC. This study may provide an important starting point and useful background information for future research about immunotherapy for appendix, stomach and small intestine neuroendocrine carcinomas.


Assuntos
Antígeno B7-H1/genética , Carcinoma Neuroendócrino/genética , Imuno-Histoquímica , Neoplasias Intestinais/genética , Tumores Neuroendócrinos/genética , Neoplasias Pancreáticas/genética , Neoplasias Gástricas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/genética , Carcinoma Neuroendócrino/imunologia , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/terapia , Colo/metabolismo , Feminino , Mucosa Gástrica/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imunoterapia , Neoplasias Intestinais/imunologia , Neoplasias Intestinais/patologia , Neoplasias Intestinais/terapia , Intestino Delgado/metabolismo , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/imunologia , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/terapia , Pâncreas/metabolismo , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , RNA Mensageiro/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Adulto Jovem
4.
Nat Rev Cancer ; 19(6): 307-325, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31092904

RESUMO

Tertiary lymphoid structures (TLSs) are ectopic lymphoid organs that develop in non-lymphoid tissues at sites of chronic inflammation including tumours. Key common characteristics between secondary lymphoid organogenesis and TLS neogenesis have been identified. TLSs exist under different maturation states in tumours, culminating in germinal centre formation. The mechanisms that underlie the role of TLSs in the adaptive antitumour immune response are being deciphered. The description of the correlation between TLS presence and clinical benefit in patients with cancer, suggesting that TLSs could be a prognostic and predictive factor, has drawn strong interest into investigating the role of TLSs in tumours. A current major challenge is to exploit TLSs to promote lymphocyte infiltration, activation by tumour antigens and differentiation to increase the antitumour immune response. Several approaches are being developed using chemokines, cytokines, antibodies, antigen-presenting cells or synthetic scaffolds to induce TLS formation. Strategies aiming to induce TLS neogenesis in immune-low tumours and in immune-high tumours, in this case, in combination with therapeutic agents dampening the inflammatory environment and/or with immune checkpoint inhibitors, represent promising avenues for cancer treatment.


Assuntos
Neoplasias/imunologia , Neoplasias/terapia , Estruturas Linfoides Terciárias/patologia , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imunoterapia , Inflamação/imunologia , Inflamação/patologia , Neoplasias/patologia , Prognóstico , Estruturas Linfoides Terciárias/imunologia , Microambiente Tumoral/imunologia
5.
Oncol Rep ; 41(6): 3455-3463, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30942469

RESUMO

CD19 chimeric antigen receptor (CAR) T cell therapy has changed the outcomes of relapsed/refractory B­cell leukemia and lymphoma. However, its efficacy in patients with relapsed/refractory non­Hodgkin lymphoma (NHL) has been less impressive compared with that in patients with acute lymphoid leukemia. Furthermore, immune checkpoints have a critical role in the immune system. Several clinical trials have confirmed the dramatic effects of programmed death­1/programmed death­ligand 1 (PD­1/PD­L1) inhibitors in numerous malignancies, but the immune­associated adverse events of PD­1/PD­L1 inhibitors may occur in a number of systems. The aim of the present study was to investigate the combination of CD19 CAR­T cells with a reduced dose of PD­1 inhibitor. This method is expected to overcome the side-effects of PD­1 inhibitors, while maintaining therapeutic efficacy. The findings demonstrated that a reduced dose of PD­1 inhibitor did not affect the transfection rate, proliferation rate or cytokine secretion of CD19 CAR­T cells. An interesting finding of the present study was that the number of PD­1­positive cells CAR­T cells, measured by flow cytometry, declined when they were cultured in vitro, but returned to high levels with gradual prolongation of the co­culture time of CD19 CAR­T cells with lymphoma cells; however, there was no change in the mRNA expression of T cells and CAR­T cells during this process. This phenomenon may be one of the reasons why the curative effect of CAR­T cells on B­cell lymphoma is unsatisfactory compared with B­cell leukemia. The synergistic effect of a reduced­dose PD­1 inhibitor combined with CD19 CAR­T cells from T cells highly expressing PD­1 was confirmed in a mouse trial. Mice in the combined treatment group achieved the longest survival time. In this group, the proportion of CAR­T cells and the level of interleukin­6 were higher compared with those in the CAR­T cell group. In conclusion, a reduced dose of a PD­1 inhibitor combined with CD19 CAR­T cells appears to be a promising treatment option for relapsed/refractory B­NHL exhibiting high PD­1 expression by T cells. This method may achieve good clinical efficacy while reducing the side-effects of PD­1 inhibitors.


Assuntos
Linfoma/terapia , Nivolumabe/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Antígenos CD19/genética , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Proliferação de Células/efeitos dos fármacos , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imunoterapia Adotiva/métodos , Linfoma/genética , Linfoma/imunologia , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Receptor de Morte Celular Programada 1/genética , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
World J Gastroenterol ; 25(14): 1684-1696, 2019 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-31011254

RESUMO

BACKGROUND: Recently, more and more studies have demonstrated the pivotal role of programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway in the immune evasion of tumors from the host immune system. However, the role of PD-1/PD-L1 pathway in gastric neuroendocrine carcinomas (G-NECs) remains unknown. AIM: To investigate the expression of PD-1/PD-L1 and role of PD-1/PD-L1 pathway in G-NECs, which occur rarely but are highly malignant and clinically defiant. METHODS: We investigated the expression of PD-L1 on tumor cells and PD-1+, CD8+, and FOXP3+ T cell infiltration by immunohistochemistry in 43 resected G-NEC tissue specimens. The copy number alterations of PD-L1 were assessed by qRT-PCR. RESULTS: Most of the G-NECs tumor cells exhibited a near-uniform expression pattern of PD-L1, while some showed a tumor-stromal interface enhanced pattern. Of the 43 G-NECs, 21 (48.8%) were classified as a high PD-L1 expression group, and the high expression of PD-L1 was associated with poor overall survival (OS). The high expression of PD-L1 was correlated with abundant PD-1+ tumor infiltrating lymphocytes (TILs) instead of CD8+ TILs and FOXP3+ regulatory T cells (Tregs). Our analysis also suggested that the infiltration of CD8+ TILs tended to be a favorable factor for OS, although the difference did not reach the statistical significance (P = 0.065). Meanwhile, PD-L1 was significantly overexpressed in cases with copy number gain as compared with those without. CONCLUSION: Our data demonstrated for the first time that high expression of PD-L1 in G-NECs is associated with a poor prognosis, while the high expression may be due to the copy number variation of PD-L1 gene or stimulation of TILs. These results provide a basis for the immunotherapy targeting PD-1/PD-L1 pathway in G-NECs.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma Neuroendócrino/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais/imunologia , Neoplasias Gástricas/imunologia , Idoso , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/patologia , Variações do Número de Cópias de DNA , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imunoterapia/métodos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais/efeitos dos fármacos , Estômago/patologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Evasão Tumoral/imunologia
7.
Biochim Biophys Acta Mol Cell Res ; 1866(8): 1322-1337, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30928610

RESUMO

The development of drug-resistance by neoplastic cells is recognized as a major cause of targeted therapy failure and disease progression. The mechanistic (previously mammalian) target of rapamycin (mTOR) is a highly conserved Ser/Thr kinase that acts as the catalytic subunit of two structurally and functionally distinct large multiprotein complexes, referred to as mTOR complex 1 (mTORC1) and mTORC2. Both mTORC1 and mTORC2 play key roles in a variety of healthy cell types/tissues by regulating physiological anabolic and catabolic processes in response to external cues. However, a body of evidence identified aberrant activation of mTOR signaling as a common event in many human tumors. Therefore, mTOR is an attractive target for therapeutic targeting in cancer and this fact has driven the development of numerous mTOR inhibitors, several of which have progressed to clinical trials. Nevertheless, mTOR inhibitors have met with a very limited success as anticancer therapeutics. Among other reasons, this failure was initially ascribed to the activation of several compensatory signaling pathways that dampen the efficacy of mTOR inhibitors. The discovery of these regulatory feedback mechanisms greatly contributed to a better understanding of cancer cell resistance to mTOR targeting agents. However, over the last few years, other mechanisms of resistance have emerged, including epigenetic alterations, compensatory metabolism rewiring and the occurrence of mTOR mutations. In this article, we provide the reader with an updated overview of the mechanisms that could explain resistance of cancer cells to the various classes of mTOR inhibitors.


Assuntos
Proteínas de Neoplasias/imunologia , Neoplasias/imunologia , Transdução de Sinais/imunologia , Serina-Treonina Quinases TOR/imunologia , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/imunologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/imunologia , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 2 de Rapamicina/genética , Alvo Mecanístico do Complexo 2 de Rapamicina/imunologia , Mutação , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética
8.
Cancer Immunol Immunother ; 68(6): 961-971, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30955067

RESUMO

Hepatocellular carcinoma (HCC) is the third most lethal cancer in the world. Natural killer (NK) cell-mediated immunity is crucial for tumor surveillance and therapy. Characterization of the regulatory mechanisms of NK cell function is important for developing novel immunotherapies against HCC. In this study, we used a chemical-induced mouse HCC model to identify the upregulation of Sirtuin2 (SIRT2) in liver NK cells. In particular, SIRT2 was predominantly expressed in liver CD94+ NK cells. The HCC liver microenvironment induced SIRT2 expression in NK cells. In addition, overexpression of exogenous SIRT2 significantly upregulated the production of cytokines and cytotoxic mediators in activated NK cells. Consistently, SIRT2-overexpressing NK cells showed a stronger tumoricidal effect on hepatoma cells. Moreover, SIRT2 remarkably promoted the phosphorylation of Extracellular-signal-regulated kinase 1/2 (Erk1/2) and p38 Mitogen-activated protein kinases (MAPK) in activated NK cells. SIRT2 knockdown in liver CD94+ NK cells impaired their cytotoxic effect on hepatoma cells. Our study indicates that SIRT2 enhances the tumoricidal activity of liver NK cells in HCC.


Assuntos
Carcinoma Hepatocelular/imunologia , Citotoxicidade Imunológica/imunologia , Células Matadoras Naturais/imunologia , Neoplasias Hepáticas Experimentais/imunologia , Fígado/imunologia , Sirtuína 2/imunologia , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Citocinas/imunologia , Citocinas/metabolismo , Citotoxicidade Imunológica/genética , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imunoterapia Adotiva , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/transplante , Fígado/metabolismo , Neoplasias Hepáticas Experimentais/genética , Neoplasias Hepáticas Experimentais/terapia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Interferência de RNA , Sirtuína 2/genética , Sirtuína 2/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
9.
Nat Commun ; 10(1): 1856, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015447

RESUMO

Bronchial premalignant lesions (PMLs) are precursors of lung squamous cell carcinoma, but have variable outcome, and we lack tools to identify and treat PMLs at risk for progression to cancer. Here we report the identification of four molecular subtypes of PMLs with distinct differences in epithelial and immune processes based on RNA-Seq profiling of endobronchial biopsies from high-risk smokers. The Proliferative subtype is enriched with bronchial dysplasia and exhibits up-regulation of metabolic and cell cycle pathways. A Proliferative subtype-associated gene signature identifies subjects with Proliferative PMLs from normal-appearing uninvolved large airway brushings with high specificity. In progressive/persistent Proliferative lesions expression of interferon signaling and antigen processing/presentation pathways decrease and immunofluorescence indicates a depletion of innate and adaptive immune cells compared with regressive lesions. Molecular biomarkers measured in PMLs or the uninvolved airway can enhance histopathological grading and suggest immunoprevention strategies for intercepting the progression of PMLs to lung cancer.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Broncogênico/patologia , Regulação Neoplásica da Expressão Gênica/imunologia , Neoplasias Pulmonares/patologia , Lesões Pré-Cancerosas/patologia , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/imunologia , Biópsia , Brônquios/diagnóstico por imagem , Brônquios/imunologia , Brônquios/patologia , Broncoscopia , Carcinoma Broncogênico/genética , Carcinoma Broncogênico/imunologia , Carcinoma Broncogênico/prevenção & controle , Estudos de Coortes , Conjuntos de Dados como Assunto , Progressão da Doença , Detecção Precoce de Câncer/métodos , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/imunologia , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/prevenção & controle , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/diagnóstico por imagem , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/imunologia , RNA Mensageiro/genética , Mucosa Respiratória/citologia , Mucosa Respiratória/diagnóstico por imagem , Mucosa Respiratória/imunologia , Mucosa Respiratória/patologia , Análise de Sequência de RNA , Linfócitos T/imunologia , Tomografia Computadorizada por Raios X , Regulação para Cima
10.
World J Gastroenterol ; 25(11): 1341-1354, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30918427

RESUMO

BACKGROUND: Genomic profiling of tumors has contributed to the understanding of colorectal cancer (CRC), facilitating diagnosis, prognosis and selection of treatments, including targeted regimens. A report suggested that a 19-gene-based risk classifier (TCA19) was a prognostic tool for patients with stage III CRC. The survival outcomes in patients with stage IV CRC are still poor and appropriate selection of targeted therapies and immunotherapies is challenging. AIM: To assess clinical implication of TCA19 in patients with stage IV CRC, and to identify TCA19 with involvement in immune-oncology. METHODS: A retrospective review of the medical records of 60 patients with stage IV CRC was conducted, assessing clinicopathological variables and progression-free survival (PFS). TCA19 gene expression was determined by quantitative polymerase chain reaction (qPCR) in matched normal and tumor tissues taken from the study cohort. Expression of potential immune-oncology regulatory proteins and targets was examined by immunohistochemistry (IHC), western blot, immunofluorescence staining in tissues from a validation cohort of 10 patients, and in CRC cell lines co-cultured with monocyte in vitro. RESULTS: In the patients with TCA19 score higher than the median, the PFS rates of eight patients who received the targeted regimens were significantly higher than the PFS rates of four patients who received 5-fluorouracil-based regimen (P = 0.041). In multivariate analysis, expression of signaling lymphocytic activation molecule family, member 7 (SLAMF7) and triggering receptor expressed on myeloid cells 1 (TREM1) was associated with PFS in the 60-patient cohort. After checking another 10 validate set, the expression of the IHC, the level of real-time qPCR, and the level of western blot were lower for SLAMF7 and higher for TREM7 in primary and metastatic tumors than in normal tissues. In CRC cells expressing SLAMF7 that were co-cultured with a monocytic cell line, levels of CD 68 and CD 73 were significantly lower at day 5 of co-culture than at day 0. CONCLUSION: The TCA19 score might be prognostic for target-regimen-specific PFS in stage IV CRC. Down-regulation of SLAMF7 and up-regulation of TREM1 occur in primary and metastatic tumor tissues.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/mortalidade , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Estadiamento de Neoplasias , Seleção de Pacientes , Prognóstico , Intervalo Livre de Progressão , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Medição de Risco/métodos , Fatores de Risco , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/imunologia , Receptor Gatilho 1 Expresso em Células Mieloides/genética , Receptor Gatilho 1 Expresso em Células Mieloides/imunologia , Regulação para Cima
11.
Nat Commun ; 10(1): 1280, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894532

RESUMO

Understanding the intrinsic mediators that render CD8+ T cells dysfunctional in the tumor microenvironment is a requirement to develop more effective cancer immunotherapies. Here, we report that C/EBP homologous protein (Chop), a downstream sensor of severe endoplasmic reticulum (ER) stress, is a major negative regulator of the effector function of tumor-reactive CD8+ T cells. Chop expression is increased in tumor-infiltrating CD8+ T cells, which correlates with poor clinical outcome in ovarian cancer patients. Deletion of Chop in T cells improves spontaneous antitumor CD8+ T cell immunity and boosts the efficacy of T cell-based immunotherapy. Mechanistically, Chop in CD8+ T cells is elevated primarily through the ER stress-associated kinase Perk and a subsequent induction of Atf4; and directly represses the expression of T-bet, a master regulator of effector T cell function. These findings demonstrate the primary role of Chop in tumor-induced CD8+ T cell dysfunction and the therapeutic potential of blocking Chop or ER stress to unleash T cell-mediated antitumor immunity.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma Epitelial do Ovário/genética , Estresse do Retículo Endoplasmático/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Neoplasias Ovarianas/genética , Proteínas com Domínio T/genética , Fator de Transcrição CHOP/genética , Fator 4 Ativador da Transcrição/antagonistas & inibidores , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/imunologia , Transferência Adotiva , Animais , Linfócitos T CD8-Positivos/patologia , Carcinoma Epitelial do Ovário/imunologia , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/terapia , Linhagem Celular Tumoral , Feminino , Humanos , Imunidade Celular , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Camundongos , Camundongos Knockout , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/terapia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Análise de Sobrevida , Proteínas com Domínio T/imunologia , Fator de Transcrição CHOP/antagonistas & inibidores , Fator de Transcrição CHOP/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto , eIF-2 Quinase/antagonistas & inibidores , eIF-2 Quinase/genética , eIF-2 Quinase/imunologia
12.
Breast Cancer Res Treat ; 175(2): 459-472, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30778902

RESUMO

PURPOSE: Breast cancer is a heterogeneous disease, and although advances in molecular subtyping have been achieved in recent years, most subtyping strategies target individual genes independent of one another and primarily concentrate on proliferative markers. The contributions of biological processes and immune patterns have been neglected in breast cancer subtype stratification. METHODS: We performed a gene set variation analysis to simplify the information on biological processes using hallmark terms and to decompose immune cell data using the immune cell gene terms on 985 breast invasive ductal/lobular carcinoma RNAseq samples in the TCGA database. RESULTS: The samples were gathered into three clusters following implementation of the t-SNE and DBSCAN algorithms and were categorized as 'hallmark-tsne' subtypes. Here, we identified a high-risk luminal A dominant breast cancer subtype (C3) that displayed increased motility, cancer stem cell-like features, a higher expression of hormone/luminal-related genes, a lower expression of proliferation-related genes and immune dysfunction. With regard to immune dysfunction, we observed that the motility-increased C3 subtype exhibited high granulocyte colony stimulating factor (G-CSF) expression accompanied by neutrophil aggregation. Cancer cells that produce high levels of G-CSF can stimulate neutrophils to form neutrophil extracellular traps, which promote cancer cell migration. This finding sheds light on one potential explanation for why the C3 subtype correlates with poor prognosis. CONCLUSIONS: The hallmark-tsne subtypes confirmed again that even the luminal A subtype is heterogeneous and can be further subdivided. The biological processes and immune heterogeneity of breast cancer must be understood to facilitate the improvement of clinical treatments.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Fator Estimulador de Colônias de Granulócitos/genética , Proteínas de Neoplasias/genética , Algoritmos , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/classificação , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/classificação , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/classificação , Carcinoma Lobular/genética , Carcinoma Lobular/imunologia , Carcinoma Lobular/patologia , Movimento Celular/genética , Ensaio de Imunoadsorção Enzimática , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/imunologia , Fator Estimulador de Colônias de Granulócitos/imunologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Células MCF-7 , Proteínas de Neoplasias/imunologia , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/patologia , Neutrófilos/imunologia , Neutrófilos/patologia , Prognóstico , Receptores de Progesterona
13.
J Cancer Res Clin Oncol ; 145(2): 281-291, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30656409

RESUMO

PURPOSE: Esophageal cancer is a common disease in China with low survival rate due to no obvious early symptoms and lack of effective screening strategies. Traditional treatments usually do not produce desirable results in patients with advanced esophageal cancer, so immunotherapy which relies on tumor-related antigens is needed to combat low survival rates effectively. Cancer-testis antigens (CTA), a large family of tumor-related antigens, have a strong in vivo immunogenicity and tumor-restricted expressing patterns in normal adult tissues. These two characteristics are ideal features of anticancer immunotherapy targets and, therefore, promoted the development of some studies of CTA-based therapy. To provide ideas for the role of the cancer-testis antigens MAGE-A, NY-ESO-1, LAGE-1, and TTK in esophageal cancer, we summarized their expression, prognostic value, and development in immunotherapy. METHODS: The relevant literature from PubMed is reviewed in this study. RESULTS: In esophageal cancer, although the relationship between expression of MAGE-A, NY-ESO-1, LAGE-1, and TTK and prognosis value is still in a controversial situation, MAGE-A, NY-ESO-1, LAGE-1, and TTK are highly expressed and can induce specific CTL cells to produce particular killing effect on tumor cells, and some clinical trials have demonstrated that immunotherapy for esophageal cancer patients is effective and safe, which provides a new therapeutic strategy for the treatment of esophageal cancer in the future. CONCLUSION: In this review, we summarize expression and prognostic value of MAGE-A, NY-ESO-1, LAGE-1, and TTK in esophageal cancer and point out recent advances in immunotherapy about them.


Assuntos
Antígenos de Neoplasias/imunologia , Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/terapia , Imunoterapia/métodos , Testículo/imunologia , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Antígenos de Superfície/genética , Antígenos de Superfície/imunologia , Antígenos de Superfície/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/imunologia , Proteínas de Ciclo Celular/metabolismo , Progressão da Doença , Neoplasias Esofágicas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Prognóstico , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/imunologia , Proteínas Tirosina Quinases/metabolismo
14.
Proc Natl Acad Sci U S A ; 116(2): 599-608, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30587590

RESUMO

Previous studies have provided evidence that IL-15 expression within human tumors is crucial for optimal antitumor responses; however, the regulation of IL-15 within the tumor microenvironment (TME) is unclear. We report herein, in analyses of mice implanted with various tumor cell lines, soluble IL-15/IL-15Rα complexes (sIL-15 complexes) are abundant in the interstitial fluid of tumors with expression preceding the infiltration of tumor-infiltrating lymphocytes. Moreover, IL-15 as well as type I IFN, which regulates IL-15, was required for establishing normal numbers of CD8 T cells and natural killer cells in tumors. Depending on tumor type, both the tumor and the stroma are sources of sIL-15 complexes. In analyses of IL-15 reporter mice, most myeloid cells in the TME express IL-15 with CD11b+Ly6Chi cells being the most abundant, indicating there is a large source of IL-15 protein in tumors that lies sequestered within the tumor stroma. Despite the abundance of IL-15-expressing cells, the relative levels of sIL-15 complexes are low in advanced tumors but can be up-regulated by local stimulator of IFN genes (STING) activation. Furthermore, while treatment of tumors with STING agonists leads to tumor regression, optimal STING-mediated immunity and regression of distant secondary tumors required IL-15 expression. Overall, our study reveals the dynamic regulation of IL-15 in the TME and its importance in antitumor immunity. These findings provide insight into an unappreciated attribute of the tumor landscape that contributes to antitumor immunity, which can be manipulated therapeutically to enhance antitumor responses.


Assuntos
Regulação Neoplásica da Expressão Gênica/imunologia , Interleucina-15/imunologia , Melanoma/imunologia , Proteínas de Neoplasias/imunologia , Microambiente Tumoral/imunologia , Animais , Linhagem Celular Tumoral , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interleucina-15/genética , Melanoma/genética , Melanoma/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Receptores de Interleucina-15/genética , Receptores de Interleucina-15/imunologia , Microambiente Tumoral/genética
15.
Front Immunol ; 9: 2772, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30555465

RESUMO

Chemerin [RARRES2 [retinoic acid receptor responder 2], TIG2 [tazarotene induced gene 2 (TIG2)]] is a multifunctional cytokine initially described in skin cultures upon exposure to the synthetic retinoid tazarotene. Its secreted pro-form, prochemerin, is widely expressed, found systemically, and is readily converted into active chemerin by various proteases. Subsequent studies elucidated major roles of chemerin as both a leukocyte chemoattractant as well as an adipokine. Chemerin's main chemotactic receptor, the G-protein coupled receptor CMKLR1, is expressed on macrophages, dendritic, and NK cells. With respect to its role in immunology, chemerin mediates trafficking of these cells to sites of inflammation along its concentration gradient, and likely helps coordinate early responses, as it has been shown to have antimicrobial and angiogenic properties, as well. Recently, there has been mounting evidence that chemerin is an important factor in various cancers. As with its role in immune responses-where it can act as both a pro- and anti-inflammatory mediator-the potential functions or correlations chemerin has in or with cancer appears to be context dependent. Most studies, however, suggest a downregulation or loss of chemerin/RARRES2 in malignancies compared to the normal tissue counterparts. Here, we perform a comprehensive review of the literature to date and summarize relevant findings in order to better define the roles of chemerin in the setting of the tumor microenvironment and tumor immune responses, with an ultimate focus on the potential for therapeutic intervention.


Assuntos
Quimiocinas/imunologia , Regulação para Baixo/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias/imunologia , Animais , Células Dendríticas/imunologia , Células Dendríticas/patologia , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Macrófagos/imunologia , Macrófagos/patologia , Neoplasias/patologia , Receptores de Quimiocinas/imunologia
16.
Oncol Rep ; 40(6): 3427-3437, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30542694

RESUMO

A growing body of evidence confirms that long non­coding RNAs (lncRNAs) have an important role in biological processes by regulating gene expression at multiple levels. Dysregulated lncRNAs may be potential prognostic biomarkers or targets for the development of cancer treatments. However, the prognostic role of an lncRNA signature in pancreatic cancer has not been investigated. Pancreatic cancer lncRNA expression profiles from The Cancer Genome Atlas (TCGA) were analyzed in the current study. The prognostic value of differentially expressed lncRNAs (DElncRNAs) was evaluated via the Kaplan­Meier method. A risk score model was established based on the potential prognostic lncRNAs. The biological functions of lncRNAs were predicted by functional enrichment analysis. Then, an lncRNA­mRNA co­expression network was established and predicted the function of the lncRNAs. Seven DElncRNAs that were significantly associated with the prognosis of pancreatic cancer were identified. Patients were classified into high­risk and low­risk groups using a risk score based on a three­lncRNA signature. There was a significant difference in overall survival (OS) between the groups (median OS 1.33 vs. 3.65 years; log­rank test, P=0.0000). Cox regression analysis and ROC curves demonstrated that the three­lncRNA signature may be an effective independent prognostic biomarker in patients with pancreatic. The functional enrichment analysis showed that lncRNA AL137789.1, one component of the three­lncRNA signature, may be associated with tumor immune responses. In the present study, a novel three­lncRNA signature that was established that may be useful in predicting survival among patients with pancreatic cancer. These lncRNAs may be involved in tumor immunity and thus affect the prognosis of patients.


Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica/imunologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , RNA Longo não Codificante/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Conjuntos de Dados como Assunto , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/imunologia , Prognóstico , RNA Longo não Codificante/genética , RNA Longo não Codificante/imunologia , Curva ROC
17.
Int J Med Sci ; 15(14): 1702-1712, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30588194

RESUMO

Cancer-testis antigen MAGEA3, being restrictedly expressed in testis and various kinds of tumors, has long been considered as an ideal target for immunotherapy. In this study, we report that MAGEA3 interacts with STAT1 and regulates the expression of tyrosine phosphorylated STAT1 (pY-STAT1) in tumor cells. We show that pY-STAT1 is significantly up-regulated when MAGEA3 is silenced by MAGEA3-specific siRNA. RNA sequencing analysis identified 274 STAT1-related genes to be significantly altered in expression level in MAGEA3 knockdown cells. Further analysis of these differentially expressed genes with GO enrichment and KEGG pathway revealed that they are mainly enriched in plasma membrane, extracellular region and MHC class I protein complex, and involved in the interferon signaling pathways, immune response, antigen presentation and cell chemotaxis. The differentially expressed genes associated with chemokines, antigen presentation and vasculogenic mimicry formation were validated by biological experiments. Matrigel matrix-based tube formation assay showed that silencing MAGEA3 in tumor cells impairs tumor vasculogenic mimicry formation. These data indicate that MAGEA3 expression in tumor cells is associated with immune cells infiltration into tumor microenvironment and anti-tumor immune responses, implying that it may play an important role in tumor immune escape. Our findings reveal the potential impact of MAGEA3 on the immunosuppressive tumor microenvironment and will provide promising strategies for improving the efficacy of MAGEA3-targeted immunotherapy.


Assuntos
Antígenos de Neoplasias/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/imunologia , Fator de Transcrição STAT1/metabolismo , Evasão Tumoral , Microambiente Tumoral/imunologia , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/imunologia , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Neoplasias/patologia , Fosforilação , RNA Interferente Pequeno/metabolismo , Fator de Transcrição STAT1/imunologia , Transdução de Sinais/imunologia , Tirosina/metabolismo , Regulação para Cima
18.
Front Immunol ; 9: 2728, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30534127

RESUMO

Checkpoint inhibitors target the inhibitory receptors expressed by tumor-infiltrating T cells in order to reinvigorate an anti-tumor immune response. Therefore, understanding T cell composition and phenotype in human tumors is crucial. We analyzed by flow cytometry tumor-infiltrating lymphocytes (TILs) from two independent cohorts of patients with different cancer types, including RCC, lung, and colon cancer. In healthy donors, peripheral T cells are usually either CD4+ or CD8+ with a small percentage of CD4+ CD8+ DP cells (<5%). Compared to several other cancer types, including lung, and colorectal cancers, TILs from about a third of RCC patients showed an increased proportion of DP CD4+CD8+ T cells (>5%, reaching 30-50% of T cells in some patients). These DP T cells have an effector memory phenotype and express CD38, 4-1BB, and HLA-DR, suggesting antigen-driven expansion. In fact, TCR sequencing analysis revealed a high degree of clonality in DP T cells. Additionally, there were high levels of PD-1 and TIM-3 expression on DP T cells, which correlated with higher expression of PD-1 and TIM-3 in conventional single positive CD8 T cells from the same patients. These results suggest that DP T cells could be dysfunctional tumor-specific T cells with the potential to be reactivated by checkpoint inhibitors.


Assuntos
Antígenos de Diferenciação/imunologia , Antígenos CD4/imunologia , Antígenos CD8/imunologia , Carcinoma de Células Renais/imunologia , Neoplasias Renais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Proteínas de Neoplasias/imunologia , Linfócitos T/imunologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Neoplasias Renais/patologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Linfócitos T/patologia
19.
Breast Cancer Res ; 20(1): 154, 2018 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-30558648

RESUMO

BACKGROUND: The role of tumor-associated macrophages (TAMs) in the cancer immune landscape and their potential as treatment targets or modulators of response to treatment are gaining increasing interest. TAMs display high molecular and functional complexity. Therefore their objective assessment as breast cancer biomarkers is critical. The aims of this study were to objectively determine the in situ expression and significance of TAM biomarkers (CD68, CD163, and MMP-9) in breast cancer and to identify subclasses of patients who could benefit from TAM-targeting therapies. METHODS: We measured CD68, CD163, and MMP-9 protein expression in formalin-fixed paraffin-embedded tissues of breast carcinomas represented in tissue microarray format using multiplexed quantitative immunofluorescence (QIF) in two independent Yale cohorts: cohort A-n = 398, estrogen receptor-positive (ER+) and ER- cases-and the triple-negative breast cancer (TNBC)-only cohort B (n = 160). Associations between macrophage markers, ER status, and survival were assessed. Protein expression measured by QIF was compared with mRNA expression data from the METABRIC study. RESULTS: All three macrophage markers were co-expressed, displaying higher expression in ER- cancers. High pan-macrophage marker CD68 correlated with poorer overall survival (OS) only in ER- cases of cohort A (P = 0.02). High expression of CD163 protein in TAMs was associated with improved OS in ER- cases (cohort A, P = 0.03 and TNBC cohort B, P = 0.04, respectively) but not in ER+ cancers. MMP-9 protein was not individually associated with OS. High expression of MMP-9 in the CD68+/CD163+ TAMs was associated with worse OS in ER+ tumors (P <0.001) but not in ER- cancers. In the METABRIC dataset, mRNA levels followed the co-expression pattern observed in QIF but did not always show the same trend regarding OS. CONCLUSIONS: Macrophage activity markers correlate with survival differently in ER+ and ER- cancers. The association between high co-expression and co-localization of MMP-9/CD163/CD68 and poor survival in ER+ cancers suggests that these cancers may be candidates for macrophage-targeted therapies.


Assuntos
Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Biomarcadores Tumorais/análise , Neoplasias da Mama/patologia , Metaloproteinase 9 da Matriz/análise , Receptores de Superfície Celular/análise , Antígenos CD/imunologia , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/imunologia , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Metaloproteinase 9 da Matriz/imunologia , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Seleção de Pacientes , Prognóstico , Receptores de Superfície Celular/imunologia , Receptores de Superfície Celular/metabolismo , Receptores Estrogênicos/metabolismo , Estudos Retrospectivos , Análise de Sobrevida , Análise Serial de Tecidos , Microambiente Tumoral/imunologia
20.
Cancer Cell ; 34(6): 1012-1026.e3, 2018 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-30537506

RESUMO

Treatment of metastatic colorectal cancer is based upon the assumption that metastases are homogeneous within a patient. We quantified immune cell types of 603 whole-slide metastases and primary colorectal tumors from 222 patients. Primary lesions, and synchronous and metachronous metastases, had a heterogeneous immune infiltrate and mutational diversity. Small metastases had frequently a low Immunoscore and T and B cell score, while a high Immunoscore was associated with a lower number of metastases. Anti-epidermal growth factor receptor treatment modified immune gene expression and significantly increased T cell densities in the metastasis core. The predictive accuracy of the Immunoscore from a single biopsy was superior to the one of programmed cell death ligand 1 (PD-L1). The immune phenotype of the least-infiltrated metastasis had a stronger association with patient outcome than other metastases.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Estudos de Coortes , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Receptores ErbB/imunologia , Receptores ErbB/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
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