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[PMID]:28922790
[Au] Autor:Marisa L; Svrcek M; Collura A; Becht E; Cervera P; Wanherdrick K; Buhard O; Goloudina A; Jonchère V; Selves J; Milano G; Guenot D; Cohen R; Colas C; Laurent-Puig P; Olschwang S; Lefèvre JH; Parc Y; Boige V; Lepage C; André T; Fléjou JF; Dérangère V; Ghiringhelli F; de Reynies A; Duval A
[Ad] Endereço:Programme "Cartes d'Identité des Tumeurs," Ligue Nationale Contre le Cancer, Paris, France; INSERM, UMRS 938 - Centre de Recherche Saint-Antoine, Equipe "Instabilité des Microsatellites et Cancers," Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, France; Sorbonne Université, UPMC U
[Ti] Título:The Balance Between Cytotoxic T-cell Lymphocytes and Immune Checkpoint Expression in the Prognosis of Colon Tumors.
[So] Source:J Natl Cancer Inst;110(1), 2018 Jan 01.
[Is] ISSN:1460-2105
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Background: Immune checkpoint (ICK) expression might represent a surrogate measure of tumor-infiltrating T cell (CTL) exhaustion and therefore be a more accurate prognostic biomarker for colorectal cancer (CRC) patients than CTL enumeration as measured by the Immunoscore. Methods: The expression of ICKs, Th1, CTLs, cytotoxicity-related genes, and metagenes, including Immunoscore-like metagenes, were evaluated in three independent cohorts of CRC samples (260 microsatellite instable [MSI], 971 non-MSI). Their associations with patient survival were analyzed by Cox models, taking into account the microsatellite instability (MSI) status and affiliation with various Consensus Molecular Subgroups (CMS). PD-L1 and CD8 expression were examined on a subset of tumors with immunohistochemistry. All statistical tests were two-sided. Results: The expression of Immunoscore-like metagenes was statistically significantly associated with improved outcome in non-MSI tumors displaying low levels of both CTLs and immune checkpoints (ICKs; CMS2 and CMS3; hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.43 to 0.92, P = .02; and HR = 0.55, 95% CI = 0.34 to 0.90, P = .02, respectively), but clearly had no prognostic relevance in CRCs displaying higher levels of CTLs and ICKs (CMS1 and CMS4; HR = 0.46, 95% CI = 0.10 to 2.10, P = .32; and HR = 1.13, 95% CI = 0.79 to 1.63, P = .50, respectively), including MSI tumors. ICK metagene expression was statistically significantly associated with worse prognosis independent of tumor staging in MSI tumors (HR = 3.46, 95% CI = 1.41 to 8.49, P = .007). ICK expression had a negative impact on the proliferation of infiltrating CD8 T cells in MSI neoplasms (median = 0.56 in ICK low vs median = 0.34 in ICK high, P = .004). Conclusions: ICK expression cancels the prognostic relevance of CTLs in highly immunogenic colon tumors and predicts a poor outcome in MSI CRC patients.
[Mh] Termos MeSH primário: Biomarcadores Tumorais/genética
Biomarcadores Tumorais/imunologia
Neoplasias Colorretais/genética
Neoplasias Colorretais/imunologia
Linfócitos do Interstício Tumoral
Linfócitos T Citotóxicos
[Mh] Termos MeSH secundário: Antígenos CD/genética
Antígeno B7-H1/análise
Antígeno B7-H1/genética
Antígenos CD8/análise
Antígeno CTLA-4/genética
Colo/química
Neoplasias Colorretais/química
Neoplasias Colorretais/patologia
Feminino
Expressão Gênica
Receptor Celular 2 do Vírus da Hepatite A/genética
Seres Humanos
Proteína Coestimuladora de Linfócitos T Induzíveis/genética
Masculino
Instabilidade de Microssatélites
Meia-Idade
Estadiamento de Neoplasias
Prognóstico
Proteína 2 Ligante de Morte Celular Programada 1/genética
Receptor de Morte Celular Programada 1/genética
Estudos Retrospectivos
Taxa de Sobrevida
Células Th1
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
0 (Antigens, CD); 0 (B7-H1 Antigen); 0 (Biomarkers, Tumor); 0 (CD223 antigen); 0 (CD274 protein, human); 0 (CD8 Antigens); 0 (CTLA-4 Antigen); 0 (HAVCR2 protein, human); 0 (Hepatitis A Virus Cellular Receptor 2); 0 (ICOS protein, human); 0 (Inducible T-Cell Co-Stimulator Protein); 0 (PDCD1 protein, human); 0 (PDCD1LG2 protein, human); 0 (Programmed Cell Death 1 Ligand 2 Protein); 0 (Programmed Cell Death 1 Receptor)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170920
[St] Status:MEDLINE
[do] DOI:10.1093/jnci/djx136


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[PMID]:28922789
[Au] Autor:Mlecnik B; Van den Eynde M; Bindea G; Church SE; Vasaturo A; Fredriksen T; Lafontaine L; Haicheur N; Marliot F; Debetancourt D; Pairet G; Jouret-Mourin A; Gigot JF; Hubert C; Danse E; Dragean C; Carrasco J; Humblet Y; Valge-Archer V; Berger A; Pagès F; Machiels JP; Galon J
[Ad] Endereço:Laboratory of Integrative Cancer Immunology, INSERM, UMRS1138, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMRS1138, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMRS1138, Centre de Recherche des Cordeliers, Paris, France; Inovarion, Paris, France; Department of Medic
[Ti] Título:Comprehensive Intrametastatic Immune Quantification and Major Impact of Immunoscore on Survival.
[So] Source:J Natl Cancer Inst;110(1), 2018 Jan 01.
[Is] ISSN:1460-2105
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Background: This study assesses how the metastatic immune landscape is impacting the response to treatment and the outcome of colorectal cancer (CRC) patients. Methods: Complete curative resection of metastases (n = 441) was performed for two patient cohorts (n = 153). Immune densities were quantified in the center and invasive margin of all metastases. Immunoscore and T and B cell (TB) score were analyzed in relation to radiological and pathological responses and patient's disease-free (DFS) and overall survival (OS) using multivariable Cox proportional hazards models. All statistical tests were two-sided. Results: The spatial distribution of immune cells within metastases was nonuniform. Patients, as well as metastases of the same patient, had variable immune infiltrates and response to therapy. A beneficial response was statistically significantly associated with increased immune densities. Among all metastases, Immunoscore (I) and TB score evaluated in the least immune-infiltrated metastases were the strongest predictors for DFS and OS (five-year follow-up, Immunoscore: I 3-4: DFS rate = 27.9%, 95% CI = 15.2 to 51.3; vs I 0-1-2: DFS rate = 12.3%, 95% CI = 4.9 to 30.6; HR = 0.45, 95% CI = 0.28 to 0.70, P = .02; I 3-4: OS rate = 64.6%, 95% CI = 46.6 to 89.6; vs I 0-1-2: OS rate = 32.5%, 95% CI = 17.2 to 61.4; HR = 0.32, 95% CI = 0.15 to 0.66, P = .001, C-index = 65.9%; five-year follow-up, TB score: TB 3-4: DFS rate = 25.7%, 95% CI = 14.2 to 46.6; vs TB 0-1-2: DFS rate = 5.0%, 95% CI = 0.8 to 32.4; HR = 0.36, 95% CI = 0.22 to 0.57, P < .001; TB 3-4: OS rate = 63.7%, 95% CI = 46.4 to 87.5; vs TB 0-1-2: OS rate: 21.4%, 95% CI = 9.2 to 49.8; HR = 0.25, 95% CI = 0.12 to 0.51, P < .001, C-index = 67.8%). High TB score and Immunoscore patients had a median survival of 70.5 months, while low patients survived only 25.1 to 38.3 months. Nonresponding patients with high-immune infiltrates had prolonged DFS (HR = 0.28, 95% CI = 0.15 to 0.52, P = .001) and OS (HR = 0.25, 95% CI = 0.1 to 0.62, P = .001). The immune parameters remained the only statistically significant prognostic factor associated with DFS and OS in multivariable analysis (P < .001), while response to treatment was not. Conclusions: Response to treatment and prolonged survival of metastatic CRC patients were statistically significantly associated with high-immune densities quantified into the least immune-infiltrated metastasis.
[Mh] Termos MeSH primário: Linfócitos B
Neoplasias Colorretais/imunologia
Neoplasias Hepáticas/imunologia
Neoplasias Pulmonares/imunologia
Linfócitos do Interstício Tumoral
Linfócitos T
[Mh] Termos MeSH secundário: Idoso
Antígenos CD20/análise
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Linfócitos B/química
Complexo CD3/análise
Linfócitos T CD8-Positivos
Quimioterapia Adjuvante
Neoplasias Colorretais/patologia
Neoplasias Colorretais/terapia
Intervalo Livre de Doença
Seguimentos
Fatores de Transcrição Forkhead/análise
Hepatectomia
Seres Humanos
Antígenos Comuns de Leucócito/análise
Neoplasias Hepáticas/secundário
Neoplasias Hepáticas/terapia
Neoplasias Pulmonares/secundário
Neoplasias Pulmonares/terapia
Contagem de Linfócitos
Metastasectomia
Meia-Idade
Metástase Neoplásica
Pneumonectomia
Período Pré-Operatório
Critérios de Avaliação de Resposta em Tumores Sólidos
Taxa de Sobrevida
Linfócitos T/química
Microambiente Tumoral/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD20); 0 (CD3 Complex); 0 (FOXP3 protein, human); 0 (Forkhead Transcription Factors); EC 3.1.3.48 (Leukocyte Common Antigens)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170920
[St] Status:MEDLINE
[do] DOI:10.1093/jnci/djx123


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[PMID]:28859291
[Au] Autor:Heindl A; Sestak I; Naidoo K; Cuzick J; Dowsett M; Yuan Y
[Ad] Endereço:Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK; Centre for Molecular Pathology, Royal Marsden Hospital, London, UK; Division of Molecular Pathology, The Institute of Cancer Research, London, UK; Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Qu
[Ti] Título:Relevance of Spatial Heterogeneity of Immune Infiltration for Predicting Risk of Recurrence After Endocrine Therapy of ER+ Breast Cancer.
[So] Source:J Natl Cancer Inst;110(2), 2018 Feb 01.
[Is] ISSN:1460-2105
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Background: Despite increasing evidence supporting the clinical utility of immune infiltration in the estrogen receptor-negative (ER-) subtype, the prognostic value of immune infiltration for ER+ disease is not well defined. Methods: Quantitative immune scores of cell abundance and spatial heterogeneity were computed using a fully automated hematoxylin and eosin-stained image analysis algorithm and spatial statistics for 1178 postmenopausal patients with ER+ breast cancer treated with five years' tamoxifen or anastrozole. The prognostic significance of immune scores was compared with Oncotype DX 21-gene recurrence score (RS), PAM50 risk of recurrence (ROR) score, IHC4, and clinical treatment score, available for 963 patients. Statistical tests were two-sided. Results: Scores of immune cell abundance were not associated with recurrence-free survival. In contrast, high immune spatial scores indicating increased cell spatial clustering were associated with poor 10-year, early (0-5 years), and late (5-10 years) recurrence-free survival (Immune Hotspot: LR-χ2 = 14.06, P < .001, for 0-10 years; LR-χ2 = 6.24, P = .01, for 0-5 years; LR-χ2 = 7.89, P = .005, for 5-10 years). The prognostic value of spatial scores for late recurrence was similar to that of IHC4 and RS in both populations, but was not as strong as other tests in comparison for recurrence across 10 years. Conclusions: These results provide a missing link between tumor immunity and disease outcome in ER+ disease by examining tumor spatial architecture. The association between spatial scores and late recurrence suggests a lasting memory of protumor immunity that may impact disease progression and evolution of endocrine treatment resistance, which may be exploited for therapeutic advances.
[Mh] Termos MeSH primário: Neoplasias da Mama/imunologia
Neoplasias da Mama/patologia
Linfócitos do Interstício Tumoral/imunologia
Recidiva Local de Neoplasia/imunologia
Receptores Estrogênicos/análise
[Mh] Termos MeSH secundário: Idoso
Antineoplásicos/uso terapêutico
Biomarcadores Tumorais/imunologia
Neoplasias da Mama/química
Neoplasias da Mama/tratamento farmacológico
Intervalo Livre de Doença
Feminino
Seres Humanos
Contagem de Linfócitos
Meia-Idade
Nitrilos/uso terapêutico
Fatores de Risco
Tamoxifeno/uso terapêutico
Triazóis/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Biomarkers, Tumor); 0 (Nitriles); 0 (Receptors, Estrogen); 0 (Triazoles); 094ZI81Y45 (Tamoxifen); 2Z07MYW1AZ (anastrozole)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170902
[St] Status:MEDLINE
[do] DOI:10.1093/jnci/djx137


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[PMID]:28460468
[Au] Autor:Jiang L; Su X; Zhang T; Yin X; Zhang M; Fu H; Han H; Sun Y; Dong L; Qian J; Xu Y; Fu X; Gavine PR; Zhou Y; Tian K; Huang J; Shen D; Jiang H; Yao Y; Han B; Gu Y
[Ad] Endereço:Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
[Ti] Título:PD-L1 expression and its relationship with oncogenic drivers in non-small cell lung cancer (NSCLC).
[So] Source:Oncotarget;8(16):26845-26857, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In order to explore the potential patient population who could benefit from anti PD-1/PD-L1 mono or combination therapies, this study aimed to profile a panel of immunotherapy related biomarkers (PD-1, PD-L1, CTLA-4 and CD8) and targeted therapy biomarkers (EGFR, KRAS, ALK, ROS1 and MET) in NSCLC.Tumor samples from 297 NSCLC patients, including 156 adenocarcinomas (AD) and 129 squamous cell carcinomas (SCC), were analyzed using immunohistochemistry, immunofluorescence, sequencing and fluorescence in situ hybridization.43.1% of NSCLC patients had PD-L1 positive staining on ≥ 5% tumor cells (TC). Furthermore, dual color immunofluorescence revealed that the majority of PD-L1/CD8 dual positive tumor infiltrating lymphocytes (TIL) had infiltrated into the tumor core. Finally, combined analysis of all eight biomarkers showed that tumor PD-L1 positivity overlapped with known alterations in NSCLC oncogenic tumor drivers in 26% of SCC and 76% of AD samples.Our illustration of the eight biomarkers' overlap provides an intuitive overview of NSCLC for personalized therapeutic strategies using anti-PD-1/PD-L1 immune therapies, either as single agents, or in combination with targeted therapies. For the first time, we also report that PD-L1 and CD8 dual positive TILs are predominantly located within the tumor core.
[Mh] Termos MeSH primário: Antígeno B7-H1/genética
Biomarcadores Tumorais
Carcinoma Pulmonar de Células não Pequenas/genética
Carcinoma Pulmonar de Células não Pequenas/patologia
Expressão Gênica
Neoplasias Pulmonares/genética
Neoplasias Pulmonares/patologia
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Antígeno B7-H1/metabolismo
Antígeno CTLA-4/genética
Antígeno CTLA-4/metabolismo
Carcinoma Pulmonar de Células não Pequenas/metabolismo
Carcinoma Pulmonar de Células não Pequenas/cirurgia
Transformação Celular Neoplásica/genética
Feminino
Amplificação de Genes
Seres Humanos
Imuno-Histoquímica
Hibridização in Situ Fluorescente
Neoplasias Pulmonares/metabolismo
Neoplasias Pulmonares/cirurgia
Linfócitos do Interstício Tumoral/imunologia
Linfócitos do Interstício Tumoral/metabolismo
Masculino
Meia-Idade
Mutação
Gradação de Tumores
Estadiamento de Neoplasias
Receptor de Morte Celular Programada 1/genética
Receptor de Morte Celular Programada 1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (B7-H1 Antigen); 0 (Biomarkers, Tumor); 0 (CD274 protein, human); 0 (CTLA-4 Antigen); 0 (Programmed Cell Death 1 Receptor)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15839


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[PMID]:28460462
[Au] Autor:Ness N; Andersen S; Khanehkenari MR; Nordbakken CV; Valkov A; Paulsen EE; Nordby Y; Bremnes RM; Donnem T; Busund LT; Richardsen E
[Ad] Endereço:Department of Medical Biology, UiT The Arctic University of Norway, N-9037 Tromso, Norway.
[Ti] Título:The prognostic role of immune checkpoint markers programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) in a large, multicenter prostate cancer cohort.
[So] Source:Oncotarget;8(16):26789-26801, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Programmed cell death protein 1 (PD-1) and its ligand Programmed death ligand 1 (PD-L1) have gained massive attention in cancer research due to recent availability and their targeted antitumor effects. Their role in prostate cancer is still undetermined. We constructed tissue microarrays from prostatectomy specimens from 535 prostate cancer patients. Following validation of antibodies, immunohistochemistry was used to evaluate the expression of PD-1 in lymphocytes and PD-L1 in epithelial and stromal cells of primary tumors. PD-L1 expression was commonly seen in tumor epithelial cells (92% of cases). Univariate survival analysis revealed a positive association between a high density of PD-1+ lymphocytes and worse clinical failure-free survival, limited to a trend (p = 0.084). In subgroups known to indicate unfavorable prostate cancer prognosis (Gleason grade 9, age < 65, preoperative PSA > 10, pT3) patients with high density of PD-1+ lymphocytes had a significantly higher risk of clinical failure (p = < 0.001, p = 0.025, p = 0.039 and p = 0.011, respectively). In the multivariate analysis, high density of PD-1+ lymphocytes was a significant negative independent prognostic factor for clinical failure-free survival (HR = 2.48, CI 95% 1.12-5.48, p = 0.025).
[Mh] Termos MeSH primário: Antígeno B7-H1/metabolismo
Biomarcadores Tumorais
Imunomodulação
Receptor de Morte Celular Programada 1/metabolismo
Neoplasias da Próstata/imunologia
Neoplasias da Próstata/metabolismo
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Fibroblastos Associados a Câncer/metabolismo
Seres Humanos
Imuno-Histoquímica
Imunofenotipagem
Linfócitos do Interstício Tumoral/imunologia
Linfócitos do Interstício Tumoral/metabolismo
Masculino
Meia-Idade
Gradação de Tumores
Estadiamento de Neoplasias
Prognóstico
Neoplasias da Próstata/mortalidade
Neoplasias da Próstata/patologia
Reprodutibilidade dos Testes
Análise Serial de Tecidos
Carga Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
0 (B7-H1 Antigen); 0 (Biomarkers, Tumor); 0 (CD274 protein, human); 0 (Programmed Cell Death 1 Receptor)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15817


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[PMID]:29248133
[Au] Autor:Mikkilineni L; Whitaker-Menezes D; Domingo-Vidal M; Sprandio J; Avena P; Cotzia P; Dulau-Florea A; Gong J; Uppal G; Zhan T; Leiby B; Lin Z; Pro B; Sotgia F; Lisanti MP; Martinez-Outschoorn U
[Ad] Endereço:Department of Medical Oncology, National Cancer Institute, Bethesda, MD.
[Ti] Título:Hodgkin lymphoma: A complex metabolic ecosystem with glycolytic reprogramming of the tumor microenvironment.
[So] Source:Semin Oncol;44(3):218-225, 2017 06.
[Is] ISSN:1532-8708
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Twenty percent of patients with classical Hodgkin Lymphoma (cHL) have aggressive disease defined as relapsed or refractory disease to initial therapy. At present we cannot identify these patients pre-treatment. The microenvironment is very important in cHL because non-cancer cells constitute the majority of the cells in these tumors. Non-cancer intra-tumoral cells, such as tumor-associated macrophages (TAMs) have been shown to promote tumor growth in cHL via crosstalk with the cancer cells. Metabolic heterogeneity is defined as high mitochondrial metabolism in some tumor cells and glycolysis in others. We hypothesized that there are metabolic differences between cancer cells and non-cancer tumor cells, such as TAMs and tumor-infiltrating lymphocytes in cHL and that greater metabolic differences between cancer cells and TAMs are associated with poor outcomes. METHODS: A case-control study was conducted with 22 tissue samples of cHL at diagnosis from a single institution. The case samples were from 11 patients with aggressive cHL who had relapsed after standard treatment with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) or were refractory to this treatment. The control samples were from 11 patients with cHL who achieved a remission and never relapsed after ABVD. Reactive non-cancerous lymph nodes from four subjects served as additional controls. Samples were stained by immunohistochemistry for three metabolic markers: translocase of the outer mitochondrial membrane 20 (TOMM20), monocarboxylate transporter 1 (MCT1), and monocarboxylate transporter 4 (MCT4). TOMM20 is a marker of mitochondrial oxidative phosphorylation (OXPHOS) metabolism. Monocarboxylate transporter 1 (MCT1) is the main importer of lactate into cells and is a marker of OXPHOS. Monocarboxylate transporter 4 (MCT4) is the main lactate exporter out of cells and is a marker of glycolysis. The immunoreactivity for TOMM20, MCT1, and MCT4 was scored based on staining intensity and percentage of positive cells, as follows: 0 for no detectable staining in > 50% of cells; 1+ for faint to moderate staining in > 50% of cells, and 2+ for high or strong staining in > 50% of cells. RESULTS: TOMM20, MCT1, and MCT4 expression was significantly different in Hodgkin and Reed Sternberg (HRS) cells, which are the cancerous cells in cHL compared with TAMs and tumor-associated lymphocytes. HRS have high expression of TOMM20 and MCT1, while TAMs have absent expression of TOMM20 and MCT1 in all but two cases. Tumor-infiltrating lymphocytes have low TOMM20 expression and absent MCT1 expression. Conversely, high MCT4 expression was found in TAMs, but absent in HRS cells in all but one case. Tumor-infiltrating lymphocytes had absent MCT4 expression. Reactive lymph nodes in contrast to cHL tumors had low TOMM20, MCT1, and MCT4 expression in lymphocytes and macrophages. High TOMM20 and MCT1 expression in cancer cells with high MCT4 expression in TAMs is a signature of high metabolic heterogeneity between cancer cells and the tumor microenvironment. A high metabolic heterogeneity signature was associated with relapsed or refractory cHL with a hazard ratio of 5.87 (1.16-29.71; two-sided P < .05) compared with the low metabolic heterogeneity signature. CONCLUSION: Aggressive cHL exhibits features of metabolic heterogeneity with high mitochondrial metabolism in cancer cells and high glycolysis in TAMs, which is not seen in reactive lymph nodes. Future studies will need to confirm the value of these markers as prognostic and predictive biomarkers in clinical practice. Treatment intensity may be tailored in the future to the metabolic profile of the tumor microenvironment and drugs that target metabolic heterogeneity may be valuable in this disease.
[Mh] Termos MeSH primário: Glicólise
Doença de Hodgkin/metabolismo
Proteínas de Membrana Transportadoras/metabolismo
Mitocôndrias/metabolismo
Transportadores de Ácidos Monocarboxílicos/metabolismo
Recidiva Local de Neoplasia/metabolismo
Fosforilação Oxidativa
Receptores de Superfície Celular/metabolismo
Células de Reed-Sternberg/metabolismo
Simportadores/metabolismo
Microambiente Tumoral
[Mh] Termos MeSH secundário: Adulto
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Bleomicina/administração & dosagem
Estudos de Casos e Controles
Dacarbazina/administração & dosagem
Doxorrubicina/administração & dosagem
Feminino
Doença de Hodgkin/tratamento farmacológico
Seres Humanos
Imuno-Histoquímica
Linfócitos do Interstício Tumoral/metabolismo
Macrófagos/metabolismo
Masculino
Meia-Idade
Proteínas Musculares/metabolismo
Indução de Remissão
Vimblastina/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Membrane Transport Proteins); 0 (Monocarboxylic Acid Transporters); 0 (Muscle Proteins); 0 (Receptors, Cell Surface); 0 (SLC16A4 protein, human); 0 (Symporters); 0 (TOMM20 protein, human); 0 (monocarboxylate transport protein 1); 11056-06-7 (Bleomycin); 5V9KLZ54CY (Vinblastine); 7GR28W0FJI (Dacarbazine); 80168379AG (Doxorubicin)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171218
[St] Status:MEDLINE


  7 / 5068 MEDLINE  
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[PMID]:29324844
[Au] Autor:Barakat DJ; Suresh R; Barberi T; Pienta KJ; Simons BW; Friedman AD
[Ad] Endereço:Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
[Ti] Título:Absence of myeloid Klf4 reduces prostate cancer growth with pro-atherosclerotic activation of tumor myeloid cells and infiltration of CD8 T cells.
[So] Source:PLoS One;13(1):e0191188, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The microenvironment of prostate cancer often includes abundant tumor-associated macrophages (TAMs), with their acquisition of an M2 phenotype correlating with local aggressiveness and metastasis. Tumor-derived M-CSF contributes to TAM M2 polarization, and M-CSF receptor inhibition slows prostate cancer growth in model systems. As additional cytokines can direct TAM M2 polarization, targeting downstream transcription factors could avoid resistance. Klf4 and C/EBPß each contribute to monocyte development, and reduced expression of macrophage Klf4 or C/EBPß favors their adoption of a pro-inflammatory M1 state. We find that a Hi-Myc C57BL/6 prostate cancer line grows more slowly in syngeneic Klf4(f/f);Lys-Cre compared with Klf4(f/f) mice when inoculated subcutaneously, but grows equally rapidly in C/EBPß(f/f);Lys-Cre and C/EBPß(f/f) hosts. In the absence of myeloid Klf4, TAMs have reduced expression of surface mannose receptor and Fizz1 mRNA, both M2 markers. Global gene expression analysis further revealed activation of pro-inflammatory, pro-atherosclerotic pathways. Analysis of tumor-infiltrating lymphocytes (TILs) demonstrated markedly increased activated CD8 T cell numbers, and CD8 T cell depletion obviated the inhibitory effect of myeloid Klf4 deletion on prostate cancer growth. These findings suggest that reducing expression or activity of the Klf4 transcription factor in tumor myeloid cells may contribute to prostate cancer therapy.
[Mh] Termos MeSH primário: Fatores de Transcrição Kruppel-Like/deficiência
Neoplasias da Próstata/metabolismo
Neoplasias da Próstata/patologia
[Mh] Termos MeSH secundário: Animais
Aterosclerose/etiologia
Proteína beta Intensificadora de Ligação a CCAAT/deficiência
Proteína beta Intensificadora de Ligação a CCAAT/genética
Antígeno CD11c/metabolismo
Linfócitos T CD8-Positivos/imunologia
Linfócitos T CD8-Positivos/patologia
Linhagem Celular Tumoral
Fatores de Transcrição Kruppel-Like/genética
Lectinas Tipo C/metabolismo
Linfócitos do Interstício Tumoral
Macrófagos/imunologia
Macrófagos/metabolismo
Macrófagos/patologia
Masculino
Lectinas de Ligação a Manose/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Células Mieloides/imunologia
Células Mieloides/metabolismo
Células Mieloides/patologia
Neoplasias da Próstata/genética
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
RNA Neoplásico/genética
RNA Neoplásico/metabolismo
Receptores de Superfície Celular/metabolismo
Microambiente Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (CCAAT-Enhancer-Binding Protein-beta); 0 (CD11c Antigen); 0 (GKLF protein); 0 (Kruppel-Like Transcription Factors); 0 (Lectins, C-Type); 0 (Mannose-Binding Lectins); 0 (RNA, Messenger); 0 (RNA, Neoplasm); 0 (Receptors, Cell Surface); 0 (mannose receptor)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180112
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191188


  8 / 5068 MEDLINE  
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[PMID]:29320521
[Au] Autor:Ziai J; Gilbert HN; Foreman O; Eastham-Anderson J; Chu F; Huseni M; Kim JM
[Ad] Endereço:Department of Pathology, Genentech, Inc., South San Francisco, California, United States of America.
[Ti] Título:CD8+ T cell infiltration in breast and colon cancer: A histologic and statistical analysis.
[So] Source:PLoS One;13(1):e0190158, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The prevalence of cytotoxic tumor infiltrating lymphocytes (TILs) has demonstrated prognostic value in multiple tumor types. In particular, CD8 counts (in combination with CD3 and CD45RO) have been shown to be superior to traditional UICC staging in colon cancer patients and higher total CD8 counts have been associated with better survival in breast cancer patients. However, immune infiltrate heterogeneity can lead to potentially significant misrepresentations of marker prevalence in routine histologic sections. We examined step sections of breast and colorectal cancer samples for CD8+ T cell prevalence by standard chromogenic immunohistochemistry to determine marker variability and inform practice of T cell biomarker assessment in formalin-fixed, paraffin-embedded (FFPE) tissue samples. Stained sections were digitally imaged and CD8+ lymphocytes within defined regions of interest (ROI) including the tumor and surrounding stroma were enumerated. Statistical analyses of CD8+ cell count variability using a linear model/ANOVA framework between patients as well as between levels within a patient sample were performed. Our results show that CD8+ T-cell distribution is highly homogeneous within a standard tissue sample in both colorectal and breast carcinomas. As such, cytotoxic T cell prevalence by immunohistochemistry on a single level or even from a subsample of biopsy fragments taken from that level can be considered representative of cytotoxic T cell infiltration for the entire tumor section within the block. These findings support the technical validity of biomarker strategies relying on CD8 immunohistochemistry.
[Mh] Termos MeSH primário: Neoplasias da Mama/imunologia
Linfócitos T CD8-Positivos/patologia
Carcinoma/imunologia
Neoplasias Colorretais/imunologia
Linfócitos do Interstício Tumoral/patologia
Subpopulações de Linfócitos T/patologia
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Biópsia/métodos
Neoplasias da Mama/patologia
Linfócitos T CD8-Positivos/imunologia
Carcinoma/patologia
Neoplasias Colorretais/patologia
Simulação por Computador
Citotoxicidade Imunológica
Feminino
Técnicas Histológicas
Seres Humanos
Processamento de Imagem Assistida por Computador
Contagem de Linfócitos
Linfócitos do Interstício Tumoral/imunologia
Masculino
Meia-Idade
Prognóstico
Curva ROC
Subpopulações de Linfócitos T/imunologia
Linfócitos T Citotóxicos/imunologia
Linfócitos T Citotóxicos/patologia
Microambiente Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180111
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190158


  9 / 5068 MEDLINE  
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[PMID]:27776338
[Au] Autor:Hong AM; Vilain RE; Romanes S; Yang J; Smith E; Jones D; Scolyer RA; Lee CS; Zhang M; Rose B
[Ad] Endereço:Sydney Medical School, The University of Sydney, NSW, Australia.
[Ti] Título:PD-L1 expression in tonsillar cancer is associated with human papillomavirus positivity and improved survival: implications for anti-PD1 clinical trials.
[So] Source:Oncotarget;7(47):77010-77020, 2016 Nov 22.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In this study, we examined PD-L1 expression by immunohistochemistry in 99 patients with tonsillar cancer and known human papillomavirus (HPV) status to assess its clinical significance. We showed that the pattern of PD-L1 expression is strongly related to HPV status. The PD-L1 positivity rate was 83.3% in HPV-positive cases and 56.9% in HPV-negative cases (p < 0.05). Patients with HPV-positive/PD-L1-positive cancer had significantly better event free survival and overall survival compared with patients with HPV-negative/PD-L1-negative cancer. Relative to those patients with HPV-negative/PD-L1-negative disease who had the highest risk of death, patients with HPV-positive/PD-L1-positive cancers had a 2.85 fold lower risk of developing an event (HR 0.35, 95% CI: 0.16-0.79) and a 4.5 fold lower risk of death (HR =0.22, 95% CI: 0.09-0.53). Our findings will help to guide future clinical trial design in immunotherapy based on PD-L1 expression in tonsillar cancer.
[Mh] Termos MeSH primário: Antígeno B7-H1/metabolismo
Infecções por Papillomavirus/metabolismo
Neoplasias Tonsilares/metabolismo
Neoplasias Tonsilares/virologia
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Feminino
Seres Humanos
Linfócitos do Interstício Tumoral
Masculino
Meia-Idade
Infecções por Papillomavirus/patologia
Prognóstico
Fumar/metabolismo
Análise de Sobrevida
Neoplasias Tonsilares/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (B7-H1 Antigen); 0 (CD274 protein, human)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.12776


  10 / 5068 MEDLINE  
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[PMID]:28470686
[Au] Autor:Sideras K; Biermann K; Yap K; Mancham S; Boor PPC; Hansen BE; Stoop HJA; Peppelenbosch MP; van Eijck CH; Sleijfer S; Kwekkeboom J; Bruno MJ
[Ad] Endereço:Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
[Ti] Título:Tumor cell expression of immune inhibitory molecules and tumor-infiltrating lymphocyte count predict cancer-specific survival in pancreatic and ampullary cancer.
[So] Source:Int J Cancer;141(3):572-582, 2017 08 01.
[Is] ISSN:1097-0215
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Understanding the mechanisms of immune resistance in pancreatic and ampullary cancers is crucial for the development of suitable biomarkers and effective immunotherapeutics. Our aim was to examine the expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM, IDO and HLA-G, as well as CD8+ and FoxP3+ tumor infiltrating lymphocytes (TIL), in pancreatic and ampullary cancers, and to relate their individual, as well as their combined expression, to cancer survival. Tumor tissue from 224 patients with resected pancreatic (n = 148) and ampullary (n = 76) cancer was used to construct tissue-microarrays. Expression of immune inhibitory molecules and TIL was examined by immunohistochemistry. We show that immune inhibitory molecules are prevalently expressed. Moreover, high tumor expression of PD-L1 (p = 0.002), Gal-9 (p = 0.003), HVEM (p = 0.001), IDO (p = 0.049), HLA-G (p = 0.004) and high CD8/FoxP3 TIL ratio (p = 0.006) were associated with improved cancer-specific survival. All immune biomarkers, with the exception of IDO, were individually predictive of cancer-specific survival when adjusted for clinicopathologic characteristics. For every additional immune biomarker present survival was almost two-fold prolonged (HR 0.57 95%CI 0.47-0.69, p < 0.0001). When patients with pancreatic and ampullary cancer were analyzed separately the results were similar. We conclude that pancreas and ampullary cancers are rich in expression of immune-inhibitory molecules. These molecules can be targets for future immunotherapeutics, as well as form powerful immunological biomarkers. We propose that such immune biomarker panels be included in future prospective immunotherapy trials.
[Mh] Termos MeSH primário: Antígeno B7-H1/metabolismo
Neoplasias do Ducto Colédoco/mortalidade
Galanina/metabolismo
Antígenos HLA-G/metabolismo
Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo
Linfócitos do Interstício Tumoral/imunologia
Neoplasias Pancreáticas/mortalidade
Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Ampola Hepatopancreática/imunologia
Ampola Hepatopancreática/metabolismo
Biomarcadores Tumorais/metabolismo
Neoplasias do Ducto Colédoco/imunologia
Neoplasias do Ducto Colédoco/metabolismo
Feminino
Seres Humanos
Linfócitos do Interstício Tumoral/metabolismo
Linfócitos do Interstício Tumoral/patologia
Masculino
Meia-Idade
Neoplasias Pancreáticas/imunologia
Neoplasias Pancreáticas/metabolismo
Prognóstico
Estudos Retrospectivos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (B7-H1 Antigen); 0 (Biomarkers, Tumor); 0 (CD274 protein, human); 0 (GAL protein, human); 0 (HLA-G Antigens); 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase); 0 (Receptors, Tumor Necrosis Factor, Member 14); 0 (TNFRSF14 protein, human); 88813-36-9 (Galanin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:180208
[Lr] Data última revisão:
180208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1002/ijc.30760



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