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1.
PLoS One ; 15(11): e0242191, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33180829

RESUMO

The enhancer of zeste homolog 2 (EZH2) plays a critical role in different components of anti-tumor immunity. However, the specific role of EZH2 in modulating MHC Class I antigen presentation and T cell infiltration have not been investigated in HCC. This study analyzed the expression and clinical significance of EZH2 in HCC. The EZH2 genetic alterations were identified using cBioPortal. The EZH2 mRNA and protein levels were found to be significantly higher in HCC than in adjacent normal liver tissues in multiple datasets from the GEO and TCGA databases. High expression of EZH2 was significantly correlated with poor overall survival, disease-specific survival, progression-free survival, and relapse-free survival in almost all patients with HCC. The gene set variance analysis (GSVA) showed that the expression of EZH2 is positively correlated with an immunosuppressive microenvironment and negatively correlated with major MHC class I antigen presentation molecules. Gene set enrichment analysis (GSEA) showed that high EZH2 expression is positively associated with the MYC and glycolysis signaling pathway and negatively associated with the interferon-gamma signaling pathway in HCC tissues. These findings demonstrate that EZH2 is a potential prognostic biomarker and therapeutic target in HCC.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Neoplasias Hepáticas/genética , Biomarcadores Tumorais/imunologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Microambiente Tumoral/imunologia
2.
Cancer Treat Rev ; 91: 102115, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33130422

RESUMO

Sarcomas are a heterogenous group of mesenchymal cancers comprising over 100 subtypes. Current chemotherapy for all but a very few subtypes has limited efficacy, resulting in 5-year relative survival rates of 16% for metastatic patients. While sarcomas have often been regarded as an "immune cold" tumor category, recent biomarker studies have confirmed a great deal of immune heterogeneity across sarcoma subtypes. Reports from the first generation of clinical trials treating sarcomas with immunotherapy demonstrate a few positive responses, supporting efforts to stratify patients to optimize response rates. This review summarizes recent advances in knowledge around immune biomarker expression in sarcomas, the potential use of new technologies to complement these study results, and clinical trials particularly of immune checkpoint inhibitor therapy in sarcomas. Each of the immune biomarkers assessed was reviewed for subtype-specific expression patterns and correlation with prognosis. Overall, there is extensive heterogeneity of immune biomarker presence across sarcoma subtypes, and no consensus on the prognostic effect of these biomarkers. New technologies such as multiplex immunohistochemistry and high plex in situ profiling may offer more insights into the sarcoma microenvironment. To date, clinical trials using immune checkpoint inhibitor monotherapy have not shown compelling clinical benefits. Combination therapy with dual checkpoint inhibitors or in combinations with other agents has yielded more promising results in dedifferentiated liposarcoma, undifferentiated pleomorphic sarcoma, angiosarcoma and alveolar soft-part sarcoma. Better understanding of the sarcoma immune status through biomarkers may help decipher the reasons behind differential responses to immunotherapy.


Assuntos
Biomarcadores Tumorais/imunologia , Imunoterapia , Sarcoma/terapia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Humanos , Pessoa de Meia-Idade , Prognóstico , Sarcoma/tratamento farmacológico , Sarcoma/imunologia , Adulto Jovem
3.
Medicine (Baltimore) ; 99(46): e23024, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33181667

RESUMO

Transforming growth factor-beta (TGF-ß2) is an important cytokine regulating immune cell function. However, whether TGF-ß2 controls the invasion of colorectal cancer (CRC) by immune cells is unknown. Therefore, we evaluated the expression of TGF-ß2 using multiple databases and determined the relationship between TGF-ß2 expression and tumor immune infiltration defined by a set of genetic markers. The analysis demonstrated that the expression of TGF-ß2 is closely related to the outcome of many cancers, and this correlation was particularly strong in CRC. In addition, the increased expression of TGF-ß2 was significantly associated with the expression of various markers of specific immune cell subpopulations, and overexpression of TGF-ß2 was closely related to the prognosis of colon cancer patients. Moreover, TGF-ß2 was related to the prognosis and infiltration of the tumor by immune cells in CRC patients. The obtained results indicate that TGF-ß2 is a critical factor regulating the recruitment of immune cells and controls their infiltration into colorectal tumors. Thus, high expression of TGF-ß2 not only facilitates the prognosis in CRC patients, but also may provide a new target for the treatment of CRC.


Assuntos
Neoplasias do Colo/mortalidade , Neoplasias Colorretais/mortalidade , Imunidade Celular/genética , Linfócitos/imunologia , Fator de Crescimento Transformador beta2/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Neoplasias do Colo/genética , Neoplasias do Colo/imunologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Humanos , Estimativa de Kaplan-Meier , Prognóstico
4.
Nat Commun ; 11(1): 5332, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087697

RESUMO

Cytotoxic T lymphocyte (CTL)-based cancer immunotherapies have shown great promise for inducing clinical regressions by targeting tumor-associated antigens (TAA). To expand the TAA landscape of pancreatic ductal adenocarcinoma (PDAC), we performed tandem mass spectrometry analysis of HLA class I-bound peptides from 35 PDAC patient tumors. This identified a shared HLA-A*0101 restricted peptide derived from co-transcriptional activator Vestigial-like 1 (VGLL1) as a putative TAA demonstrating overexpression in multiple tumor types and low or absent expression in essential normal tissues. Here we show that VGLL1-specific CTLs expanded from the blood of a PDAC patient could recognize and kill in an antigen-specific manner a majority of HLA-A*0101 allogeneic tumor cell lines derived not only from PDAC, but also bladder, ovarian, gastric, lung, and basal-like breast cancers. Gene expression profiling reveals VGLL1 as a member of a unique group of cancer-placenta antigens (CPA) that may constitute immunotherapeutic targets for patients with multiple cancer types.


Assuntos
Antígenos de Neoplasias/imunologia , Neoplasias da Mama/imunologia , Proteínas de Ligação a DNA/imunologia , Neoplasias Pancreáticas/imunologia , Fatores de Transcrição/imunologia , Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/terapia , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Proteínas de Ligação a DNA/genética , Feminino , Perfilação da Expressão Gênica , Antígeno HLA-A1/imunologia , Humanos , Imunoterapia Adotiva , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Placenta/imunologia , Gravidez , Prognóstico , Linfócitos T Citotóxicos/imunologia , Fatores de Transcrição/genética
5.
PLoS One ; 15(10): e0240331, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33031392

RESUMO

OBJECTIVE: Melanoma is rare but dangerous skin cancer, and it can spread rather quickly in the advanced stages of the tumor. Abundant evidence suggests the relationship between tumor development and progression and the immune system. A robust gene risk model could provide an accurate prediction of clinical outcomes. The present study aimed to explore a robust signature of immune-related gene pairs (IRGPs) for estimating overall survival (OS) in malignant melanoma. METHODS: Clinical and genetic data of skin cutaneous melanoma (SKCM) patients from The Cancer Genome Atlas (TCGA) was performed as a training dataset to identify candidate IRGPs for the prognosis of melanoma. Two independent datasets from the Gene Expression Omnibus (GEO) database (GSE65904) and TCGA dataset (TCGA-UVM) were selected for external validation. Univariate and multivariate Cox regression analyses were then performed to explore the prognostic power of the IRGPs signature and other clinical factors. CIBERSORTx was applied to estimate the fractions of infiltrated immune cells in bulk tumor tissues. RESULTS: A signature consisted of 33 IRGPs was established which was significantly associated with patients' survival in the TCGA-SKCM dataset (P = 2.0×10-16, Hazard Ratio (HR) = 4.220 (2.909 to 6.122)). We found the IRGPs signature exhibited an independent prognostic factor in all the three independent cohorts in both the univariate and multivariate Cox analysis (P<0.01). The prognostic efficacy of the signature remained unaffected regardless of whether BRAF or NRAS was mutated. As expected, the results were verified in the GSE65904 dataset and the TCGA-UVM dataset. We found an apparent shorter OS in patients of the high-risk group in the GSE65904 dataset (P = 2.1×10-3; HR = 1.988 (1.309 to 3.020)). The trend in the results of the survival analysis in TCGA-UVM was as we expected, but the result was not statistically significant (P = 0.117, HR = 4.263 (1.407 to 12.91)). CD8 T cells, activated dendritic cells (DCs), regulatory T cells (Tregs), and activated CD4 memory T cells presented a significantly lower fraction in the high-risk group in the TCGA-SKCM dataset(P <0.01). CONCLUSION: The results of the present study support the IRGPs signature as a promising marker for prognosis prediction in melanoma.


Assuntos
Melanoma/patologia , Neoplasias Cutâneas/patologia , Área Sob a Curva , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Bases de Dados Genéticas , Feminino , GTP Fosfo-Hidrolases/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/genética , Melanoma/imunologia , Melanoma/mortalidade , Proteínas de Membrana/genética , Mutação , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas B-raf/genética , Curva ROC , Fatores de Risco , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
6.
J Cancer Res Ther ; 16(4): 731-736, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32930111

RESUMO

Background: Chronic state of inflammation is an important factor in advanced cancer which is used by tumor cells for maintaining survival and growth. Hematological parameters such as neutrophil/lymphocyte ratio (NLR), thrombocyte/lymphocyte ratio (TLR), and lymphocyte/monocyte ratio (LMR) are reliable indicators of systemic inflammation. We aimed to elucidate the effect of hematological parameters and clinical features of patients on the prognosis of advanced-stage non-small cell lung cancer (NSCLC). Methods: We included 102 Stage IV NSCLC patients who presented to the oncology clinic between 2010 and 2016. Pretreatment clinical parameters and NLR, TLR, and LMR were retrieved from the medical records. The cutoff values, calculated with receiver operating curve analysis, for NLR, LMR, and TLR were 2.5, 3, and 183, respectively. All patients were divided into two groups according to cutoff values and analyzed accordingly. Results: Median overall survival and progression-free survival were 10 and 6 months, respectively. In univariate analysis, high NLR, high TLR, and low LMR were found to be significantly associated with survival. Among clinical parameters having eastern cooperative oncology group performance score 0-1, older age (≥70 years) single metastatic disease was prognostic. In multivariate Cox regression analysis, only the number of metastatic lesions and LMR were found to be independent predictors for survival. Conclusion: Among hematological parameters, only LMR was found to be an independent predictor of survival in patients with advanced-stage NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Inflamação/sangue , Neoplasias Pulmonares/patologia , Neutrófilos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/imunologia , Plaquetas/imunologia , Plaquetas/patologia , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/imunologia , Feminino , Humanos , Inflamação/patologia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/patologia , Metástase Neoplásica , Prognóstico , Estudos Retrospectivos
7.
Proc Natl Acad Sci U S A ; 117(38): 23684-23694, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32907939

RESUMO

Immune checkpoint blockade (ICB) is efficacious in many diverse cancer types, but not all patients respond. It is important to understand the mechanisms driving resistance to these treatments and to identify predictive biomarkers of response to provide best treatment options for all patients. Here we introduce a resection and response-assessment approach for studying the tumor microenvironment before or shortly after treatment initiation to identify predictive biomarkers differentiating responders from nonresponders. Our approach builds on a bilateral tumor implantation technique in a murine metastatic breast cancer model (E0771) coupled with anti-PD-1 therapy. Using our model, we show that tumors from mice responding to ICB therapy had significantly higher CD8+ T cells and fewer Gr1+CD11b+ myeloid-derived suppressor cells (MDSCs) at early time points following therapy initiation. RNA sequencing on the intratumoral CD8+ T cells identified the presence of T cell exhaustion pathways in nonresponding tumors and T cell activation in responding tumors. Strikingly, we showed that our derived response and resistance signatures significantly segregate patients by survival and associate with patient response to ICB. Furthermore, we identified decreased expression of CXCR3 in nonresponding mice and showed that tumors grown in Cxcr3 -/- mice had an elevated resistance rate to anti-PD-1 treatment. Our findings suggest that the resection and response tumor model can be used to identify response and resistance biomarkers to ICB therapy and guide the use of combination therapy to further boost the antitumor efficacy of ICB.


Assuntos
Neoplasias da Mama , Imunoterapia , Neoplasias Mamárias Experimentais , Microambiente Tumoral/imunologia , Animais , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/terapia , Linfócitos T CD8-Positivos/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/terapia , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Transcriptoma/imunologia
8.
FEBS J ; 287(17): 3677-3680, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32738184

RESUMO

Coronavirus disease 2019 (COVID-19), the highly contagious illness caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread across the globe, becoming one of the most challenging public health crisis of our times. SARS-CoV-2 can cause severe disease associated with multiple organ damage. Cancer patients have a higher risk of SARS-CoV-2 infection and death. While the virus uses angiotensin-converting enzyme 2 (ACE2) as the primary entry receptor, the recent experimental and clinical findings suggest that some tumor markers, including CD147 (basigin), can provide an additional entry for SARS-CoV-2 infection through binding to the viral spike (S) protein. In the absence of specific viral drugs, blocking of CD147 might be a way to prevent virus invasion. Identifying other target proteins is of high importance as targeting the alternative receptors for SARS-CoV-2 might open up a promising avenue for the treatment of COVID-19 patients, including those who have cancer.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Basigina/antagonistas & inibidores , Biomarcadores Tumorais/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , /genética , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Basigina/genética , Basigina/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , /imunologia , Ensaios Clínicos como Assunto , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/virologia , Ligação Proteica , Receptores Virais/genética , Receptores Virais/metabolismo , /imunologia , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo
9.
Cancer Sci ; 111(10): 3426-3434, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32726495

RESUMO

Immune-based tumor characteristics in the context of tumor heterogeneity are associated with suppression as well as promotion of cancer progression in various tumor types. As immunity typically functions based on intercellular contacts and short-distance cytokine communications, the location and spatial relationships of the tumor immune microenvironment can provide a framework to understand the biology and potential predictive biomarkers related to disease outcomes. Immune spatial analysis is a newly emerging form of cancer research based on recent methodological advances in in situ single-cell analysis, where cell-cell interaction and the tissue architecture can be analyzed in relation to phenotyping the tumor immune heterogeneity. Spatial characteristics of tumors can be stratified into the tissue architecture level and the single-cell level. At the tissue architecture level, the prognostic significance of the density of immune cell lineages, particularly T cells, is leveraged by understanding longitudinal changes in cell distribution in the tissue architecture such as intra-tumoral and peri-tumoral regions, and invasive margins. At the single-cell level, the proximity of the tumor to the immune cells correlates with disease aggressiveness and therapeutic resistance, providing evidence to understand biological interactions and characteristics of the tumor immune microenvironment. In this review, we summarize recent findings regarding spatial information of the tumor immune microenvironment and review advances and challenges in spatial single-cell analysis toward developing tissue-based biomarkers rooted in the immune spatial landscape.


Assuntos
Neoplasias/imunologia , Neoplasias/patologia , Biomarcadores Tumorais/imunologia , Humanos , Prognóstico , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
10.
Eur J Cancer ; 136: 7-15, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32622323

RESUMO

BACKGROUND: Tumour infiltrating lymphocytes (TILs) are an established prognostic biomarker for triple-negative breast cancer (TNBC). We evaluated the role of programmed cell-death ligand-1 (PD-L1), CD8 and FOXP3 expression in refining a prognostic model for non-metastatic TNBC beyond classic factors and TILs. METHODS: Primary tumour samples from 244 early patients with TNBC, all treated with surgery and chemotherapy, were collected. Stromal TILs were evaluated on haematoxylin-eosin slides according to guidelines. PD-L1, CD8 and FOXP3 were assessed by immunohistochemistry and evaluated by digital pathology. RESULTS: TILs, PD-L1, CD8 and FOXP3 were positively correlated with each other (P < 0.001). TILs were confirmed as an independent prognostic factor. When PD-L1, CD8 and FOXP3 were added to multivariable models including classic factors (age, stage, histologic grade) and TILs, PD-L1 provided the largest amount of additional prognostic information: likelihood ratio χ2 4.60, P = 0.032 (in a model including classic factors and TILs 10% increments) and likelihood ratio χ2 6.50, P = 0.011 (in a model including classic factors and TILs >30% versus <30%). In the subset of patients treated with neoadjuvant chemotherapy, FOXP3 provided further prognostic information beyond classic factors, TILs and pathological complete response (pCR) (likelihood ratio χ2 5.01, P = 0.025). For patients who did not achieve a pCR, the expression of CD8 and PD-L1 was significantly increased from baseline to residual disease. CONCLUSIONS: Beyond clinicopathological factors and TILs, other immune biomarkers may add prognostic information for early TNBC. The increased PD-L1 expression on residual disease after neoadjuvant chemotherapy strengthens the rationale of testing immune checkpoint inhibitors in the post-neoadjuvant setting.


Assuntos
Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias de Mama Triplo Negativas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Antígenos CD8/análise , Antígenos CD8/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Estudos de Coortes , Feminino , Fatores de Transcrição Forkhead/análise , Humanos , Imuno-Histoquímica/métodos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Neoplasia Residual , Valor Preditivo dos Testes , Prognóstico , Medição de Risco/métodos , Fatores de Risco , Padrão de Cuidado , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/terapia
11.
Breast Cancer Res Treat ; 183(2): 347-354, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32621251

RESUMO

PURPOSE: The prognostic role of tumor-infiltrating lymphocytes (TILs) in ER+/HER2- breast cancer (BC) is debated. We evaluated the association of TILs and clinico-pathological features with distant disease-free survival (DDFS) in patients with ER+/HER2- BC treated at a single institution. PATIENTS AND METHODS: A mono-institutional case-cohort series of 987 patients with early ER+/HER2- BC was retrospectively analyzed. TILs were considered both as continuous variable, and dichotomized in low (< 5%) vs high (≥ 5%). The main outcome was DDFS. Median follow-up was 7.5 years (0.1-10). Univariate and multivariable Cox proportional hazards regression with inverse sub-cohort sampling probability weighting were used to evaluate the risk across groups. RESULTS: Median TIL count was 2% (Q1-Q3 1-4%). Higher TILs were positively associated with number of lymph nodes involved (p = 0.003), tumor grade (p < 0.0001), peritumoral vascular invasion (p = 0.003), higher Ki-67 (p = 0.0001), luminal B subtype (p < 0.0001), and chemotherapy use (p < 0.00019). In multivariable regression analysis, only higher Ki-67 expression retained significant association with TILs. At univariate Cox regression analysis, TIL expression (≥ 5% vs. < 5%) was not associated with DDFS (HR 1.08, 95% CI 0.80-1.46, p = 0.62). In patients treated with adjuvant chemotherapy, high TILs were associated with better DDFS (HR 0.52, 95%CI 0.33-0.83, p = 0.006), particularly in the group with Ki-67 ≥ 20% (HR 0.50, 95%CI 0.29-0.86, p = 0.01). CONCLUSION: High TILs in ER+/HER2- BC are significantly associated with clinico-pathological features of dismal outcome. TIL prognostic value seems different in patients treated with or without chemotherapy. Our findings suggest that the high-risk subgroup might be more immunogenic, thus deserving the exploration of immunotherapy approaches.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/imunologia , Quimioterapia Adjuvante/métodos , Receptor alfa de Estrogênio/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Receptor ErbB-2/metabolismo , Adulto , Idoso , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida
12.
J Cancer Res Ther ; 16(3): 624-629, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32719278

RESUMO

Objective: Thyroglobulin antibodies (TgAb) are detected in thyroid cancer patients up to 25%. We investigated the prognostic value of TgAb positivity in patients with papillary thyroid carcinoma (PTC) after initial therapy. Patients and Methods: A database of 109 consecutive patients who underwent total thyroidectomy and therapeutic lateral neck dissection followed by remnant ablation for PTC between January 1989 and December 2014 was reviewed We recorded the patients' all serum Tg and TgAb levels over time to establish changing trends. Patients were classified as either positive or negative according to serum TgAb levels. The recurrence or persistence rates in both groups were compared. Results: Of the 109 patients enrolled 14 patients had TgAb positivity. Thirty-two (29.3%) showed disease recurrence or persistent disease during 101 months of follow-up. Twenty-seven of 95 patients (28.4%) with negative TgAb had persistent or recurrent disease, whereas 5 of 14 patients (35.7%) with positive TgAb had persistence or recurrence (P = 0.57). No significant difference in disease-free survival (115.3 ± 10.8 vs. 224.1 ± 16.6 months, P = 0.78) and overall survival (P = 0.59) was observed between TgAb positive and TgAb negative patients. Conclusions: TgAb status is not useful as a prognostic and predictive factor for clinical outcomes in patients with PTC in our experience.


Assuntos
Autoanticorpos/sangue , Carcinoma Papilar/sangue , Recidiva Local de Neoplasia/sangue , Tireoglobulina/imunologia , Câncer Papilífero da Tireoide/sangue , Adolescente , Adulto , Idoso , Autoanticorpos/imunologia , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/imunologia , Carcinoma Papilar/diagnóstico , Carcinoma Papilar/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/imunologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Câncer Papilífero da Tireoide/diagnóstico , Câncer Papilífero da Tireoide/imunologia , Adulto Jovem
13.
Int J Clin Oncol ; 25(10): 1861-1869, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32656742

RESUMO

BACKGROUND: The blockade of cell surface PD-1 ((sur)PD-1) by monoclonal antibodies, represented by nivolumab, provides the strategy to treat advanced malignant melanoma (AMM). The intracellular presence of PD-1 molecules have been reported in some T cell subsets, however, their kinetic association with those expressed on the cell surface, let alone their significance in antitumor immunity has been ill-investigated. METHODS: Intracellular PD-1 expression status in T cell subsets in AMM cases during nivolumab administration was chronologically characterized. The kinetics of PD-1 molecules within AMM-derived T cells was assessed in vitro in conjunction with their functional properties. RESULTS: Increase in (sur)PD-1 and intracellular PD-1 ((int)PD-1+) expression was characteristic for AMM T cells. After short-term culture, virtually (sur)PD-1- nivolumab-treated AMM T cells restore (sur)PD-1 expression, which could not be explained by the detachment of nivolumab from PD-1 epitopes alone. The blockade of trans-Golgi network resulted in the decrease in the extent of (sur)PD-1 recovery, suggesting the translocation of accumulated (int)PD-1 to the cell surface. Antigen-specific PD-1+ T cells significantly increased in (int)PD-1+ cells after treatment. In addition, a surge in (int)PD-1+CD4+ T cells was observed prior to the emergence of skin rash as an immune-related adverse event (irAE). CONCLUSIONS: Accumulated (int)PD-1 in T cells may contribute to enhanced immune evasion in AMM. Evaluation of intracellular PD-1 expression would be useful for better management of nivolumab-treated AMM patients in view of predicting treatment response and the incidence of irAE. Our findings further support the necessity of periodical administration of nivolumab for treating AMM.


Assuntos
Melanoma/imunologia , Nivolumabe/farmacologia , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/metabolismo , Evasão Tumoral/imunologia , Antineoplásicos Imunológicos/farmacologia , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Humanos , Imunoterapia/efeitos adversos , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Evasão Tumoral/efeitos dos fármacos
14.
Breast Cancer Res ; 22(1): 73, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32605588

RESUMO

BACKGROUND: Studies on tumor-secreted microRNAs point to a functional role of these in cellular communication and reprogramming of the tumor microenvironment. Uptake of tumor-secreted microRNAs by neighboring cells may result in the silencing of mRNA targets and, in turn, modulation of the transcriptome. Studying miRNAs externalized from tumors could improve cancer patient diagnosis and disease monitoring and help to pinpoint which miRNA-gene interactions are central for tumor properties such as invasiveness and metastasis. METHODS: Using a bioinformatics approach, we analyzed the profiles of secreted tumor and normal interstitial fluid (IF) microRNAs, from women with breast cancer (BC). We carried out differential abundance analysis (DAA), to obtain miRNAs, which were enriched or depleted in IFs, from patients with different clinical traits. Subsequently, miRNA family enrichment analysis was performed to assess whether any families were over-represented in the specific sets. We identified dysregulated genes in tumor tissues from the same cohort of patients and constructed weighted gene co-expression networks, to extract sets of co-expressed genes and co-abundant miRNAs. Lastly, we integrated miRNAs and mRNAs to obtain interaction networks and supported our findings using prediction tools and cancer gene databases. RESULTS: Network analysis showed co-expressed genes and miRNA regulators, associated with tumor lymphocyte infiltration. All of the genes were involved in immune system processes, and many had previously been associated with cancer immunity. A subset of these, BTLA, CXCL13, IL7R, LAMP3, and LTB, was linked to the presence of tertiary lymphoid structures and high endothelial venules within tumors. Co-abundant tumor interstitial fluid miRNAs within this network, including miR-146a and miR-494, were annotated as negative regulators of immune-stimulatory responses. One co-expression network encompassed differences between BC subtypes. Genes differentially co-expressed between luminal B and triple-negative breast cancer (TNBC) were connected with sphingolipid metabolism and predicted to be co-regulated by miR-23a. Co-expressed genes and TIF miRNAs associated with tumor grade were BTRC, CHST1, miR-10a/b, miR-107, miR-301a, and miR-454. CONCLUSION: Integration of IF miRNAs and mRNAs unveiled networks associated with patient clinicopathological traits, and underlined molecular mechanisms, specific to BC sub-groups. Our results highlight the benefits of an integrative approach to biomarker discovery, placing secreted miRNAs within a biological context.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , MicroRNAs/genética , Neoplasias de Mama Triplo Negativas/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Líquido Extracelular/metabolismo , Feminino , Seguimentos , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Linfócitos do Interstício Tumoral/metabolismo , MicroRNAs/metabolismo , Gradação de Tumores , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
15.
BMC Cancer ; 20(1): 542, 2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32522170

RESUMO

BACKGROUND: Novel biomarkers are required to discern between breast tumors that should be targeted for treatment from those that would never become clinically apparent and/or life threatening for patients. Moreover, therapeutics that specifically target breast cancer (BC) cells with tumor-initiating capacity to prevent recurrence are an unmet need. We investigated the clinical importance of LGR5 in BC and ductal carcinoma in situ (DCIS) to explore LGR5 as a biomarker and a therapeutic target. METHODS: We stained BC (n = 401) and DCIS (n = 119) tissue microarrays with an antibody against LGR5. We examined an LGR5 knockdown ER- cell line that was orthotopically transplanted and used for in vitro colony assays. We also determined the tumor-initiating role of Lgr5 in lineage-tracing experiments. Lastly, we transplanted ER- patient-derived xenografts into mice that were subsequently treated with a LGR5 antibody drug conjugate (anti-LGR5-ADC). RESULTS: LGR5 expression correlated with small tumor size, lower grade, lymph node negativity, and ER-positivity. ER+ patients with LGR5high tumors rarely had recurrence, while high-grade ER- patients with LGR5high expression recurred and died due to BC more often. Intriguingly, all the DCIS patients who later died of BC had LGR5-positive tumors. Colony assays and xenograft experiments substantiated a role for LGR5 in ER- tumor initiation and subsequent growth, which was further validated by lineage-tracing experiments in ER- /triple-negative BC mouse models. Importantly, by utilizing LGR5high patient-derived xenografts, we showed that anti-LGR5-ADC should be considered as a therapeutic for high-grade ER- BC. CONCLUSION: LGR5 has distinct roles in ER- vs. ER+ BC with potential clinical applicability as a biomarker to identify patients in need of therapy and could serve as a therapeutic target for high-grade ER- BC.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/química , Carcinoma Intraductal não Infiltrante/química , Receptores Acoplados a Proteínas-G/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/diagnóstico , Carcinoma Intraductal não Infiltrante/mortalidade , Carcinoma Intraductal não Infiltrante/patologia , Linhagem Celular Tumoral , Feminino , Xenoenxertos , Humanos , Camundongos , Pessoa de Meia-Idade , Prognóstico , RNA Neoplásico/isolamento & purificação , Reação em Cadeia da Polimerase em Tempo Real , Receptor ErbB-2/análise , Receptores Acoplados a Proteínas-G/imunologia , Análise Serial de Tecidos/métodos
16.
Medicine (Baltimore) ; 99(25): e20617, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32569190

RESUMO

BACKGROUND: Colorectal cancer (CRC) has been divided into 4 consensus molecular subtypes (CMSs), of which CMS4 has the mesenchymal identity and the highest relapse rate. Our goal is to develop a prognostic signature by integrating the immune system and mesenchymal modalities involved in CMS4. METHODS: The gene expression profiles collected from 5 public datasets were applied to this study, including 1280 samples totally. Network analysis was applied to integrate the mesenchymal modalities and immune signature to establish an immune-based prognostic signature for CRC (IPSCRC). RESULTS: We identified 6 immune genes as key factors of CMS4 and established the IPSCRC. The IPSCRC could significantly divide patients into high- and low- risk groups in terms of relapse-free survival (RFS) and overall survival (OS) and in discovery (RFS: P < .0001) and 4 independent validation sets (RFS range: P = .01 to <.0001; OS range: P = .02-.0004). After stage stratification, the IPSCRC could still distinguish poor prognosis patients in discovery (RFS: P = .04) and validation cohorts (RFS range: P = .04-.007) within stage II in terms of RFS. Further, in multivariate analysis, the IPSCRC remained an independent predictor of prognosis. Moreover, Macrophage M2 was significantly enriched in the high-risk group, while plasma cells enriched in the low-risk group. CONCLUSION: We propose an immune-based signature identified by network analysis, which is a promising prognostic biomarker and help for the selection of CRC patients who might benefit from more rigorous therapies. Further prospective studies are warranted to test and validate its efficiency for clinical application.


Assuntos
Neoplasias Colorretais/genética , Células-Tronco Mesenquimais/citologia , Transcriptoma/imunologia , Biomarcadores Tumorais/imunologia , Estudos de Coortes , Neoplasias Colorretais/classificação , Neoplasias Colorretais/imunologia , Feminino , Humanos , Masculino , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia
17.
Medicine (Baltimore) ; 99(25): e20738, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32569215

RESUMO

There is a discordance in the immunohistochemical markers between primary breast cancer and recurrent or metastatic breast cancer. This study aimed to assess the recent trends and prognostic features in the treatment of recurrent or metastatic breast cancerOverall, 107 patients were identified from January 2001 to August 2018 at the Peking Union Medical College Hospital, Beijing, and People's Republic of China to obtain a cohort of breast carcinoma patients who were confirmed to have recurrent or metastatic breast cancer by histopathology. We evaluated patient and tumor characteristics and examined the relationships between these factors and prognosis.The estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) positivity, and Ki67 index in primary breast cancer were 63.6% (68/107), 58.9% (63/107), 19.8% (21/106) and 75.8% (75/99), respectively, while those in recurrent or metastatic lesions were 60.6% (65/107) (P = .672), 46.7% (50/107) (P = 0.013), 23.8% (25/105) (P = 0.482)and 83.5%(81/97)(P = 0.178), respectively. The discordance rate of HER2 expression was 10.6% (11/104), while that of PR expression was 23.3% (21/90). HER2 was the most stable biomarker. The discordance rates for luminal A and HER2 were as high as 100% and 25%, respectively, while the luminal B and triple negative values were as low as 8.3% and 5.3%, respectively.ER and PR positivity and the Ki-67 index tended to increase due to recurrence or metastases; however, the discordance for PR and Ki-67 was high. PR is more variable than ER in the expression of primary and recurrent or metastatic breast cancer. The expression of HER2 receptor was the most stable and the discordance rate of triple negative breast cancer was the lowest. Therefore, although changes in biomarkers are due to recurrence or metastasis, pathological confirmation and exploration of markers are very important.


Assuntos
Neoplasias da Mama/imunologia , Recidiva Local de Neoplasia/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Feminino , Humanos , Antígeno Ki-67/imunologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Prognóstico , Receptor ErbB-2/imunologia , Receptores Estrogênicos/imunologia , Receptores de Progesterona/imunologia , Estudos Retrospectivos , Adulto Jovem
18.
Technol Cancer Res Treat ; 19: 1533033820936682, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32583730

RESUMO

BACKGROUND: Disabled homolog 2-interacting protein is a new member of the Ras GTPase superfamily involved in the regulation of cell proliferation, apoptosis, and metastasis. However, the expression of disabled homolog 2-interacting protein in renal cell carcinoma, its correlation with cancer prognosis, and tumor infiltrating lymphocytes remains unclear. METHODS: The expression of disabled homolog 2-interacting protein was analyzed by UALCAN database, GEPIA database and the evaluation of disabled homolog 2-interacting protein effects on clinical prognosis. Prognostic factor analysis was used to identify the correlations between disabled homolog 2-interacting protein and cancer immune infiltration via the TIMER database. In addition, COXPRESdb database was used to analyze the enrichment of disabled homolog 2-interacting protein co-expression genes. RESULTS: Compared to the normal tissues, the messenger RNA expression levels of DAB2IP are higher in 8 while lower in 15 types of tumor tissues. Furthermore, disabled homolog 2-interacting protein has high expression in kidney chromophobe and low expression in both kidney renal clear cell carcinoma and kidney renal papillary cell carcinoma. The messenger RNA expression levels of disabled homolog 2-interacting protein decrease gradually due to the increasing tumor staging which positively correlates with disease-free survival and overall survival in both kidney renal clear cell carcinoma and kidney renal papillary cell carcinoma. The expression levels of disabled homolog 2-interacting protein also positively correlate with the tumor purity of kidney chromophobe, kidney renal clear cell carcinoma, and kidney renal papillary cell carcinoma samples. Besides, the expression of disabled homolog 2-interacting protein in renal cell carcinoma has negative correlation with the immune infiltration, and the immune infiltration of B cells and CD8+ T cells affects the prognosis of kidney renal papillary cell carcinoma. Enrichment analysis of disabled homolog 2-interacting protein co-expressed genes suggested that its biological role was mainly in regulating GTPase activity. CONCLUSIONS: These findings suggest that disabled homolog 2-interacting protein functions as a tumor suppressor in the progression of renal cell carcinoma, and the expression of disabled homolog 2-interacting protein is related to the immune infiltrating cells and affects the survival of renal cell carcinoma. Disabled homolog 2-interacting protein can be a novel clinical biomarker for patients with renal cell carcinoma, which also provides new insights for the future treatments of renal cell carcinoma.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Renais/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/patologia , Linfócitos do Interstício Tumoral/imunologia , Mutação , Proteínas Ativadoras de ras GTPase/genética , Biomarcadores Tumorais/imunologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Perfilação da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Prognóstico , Curva ROC , Taxa de Sobrevida , Transcriptoma , Proteínas Ativadoras de ras GTPase/imunologia
19.
Technol Cancer Res Treat ; 19: 1533033820935860, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32588760

RESUMO

BACKGROUND: Recent studies have confirmed that immune-associated genes perform a crucial function in recurrence and metastasis of thyroid carcinoma. A reliable immune-related prognostic signature for patients with thyroid cancer is needed. This study constructed a novel immune-related prognostic signature for thyroid cancer and evaluated its prognostic value by bioinformatics analysis. METHODS: In this study, we anatomized differentially expressed immune-associated genes from The Cancer Genome Atlas database. The samples from The Cancer Genome Atlas database were randomly divided into training set and test set. A novel immune-related prognostic signature for thyroid cancer was developed by least absolute shrinkage and selection operator and Cox regression analysis: Risk score = (0.6846 × expression value of C-X-C motif chemokine ligand 5 [CXCL5]) + (1.1556 × expression value of Azurocidin 1 [AZU1]) + (-0.3156 × expression value of nucleotide binding oligomerization domain containing 1 [NOD1] + (0.0542 × expression value of TNF Receptor Superfamily Member 11b [TNFRSF11B]) + (0.0952 × expression value of VGF nerve growth factor inducible [VGF]). The established prognostic signature was evaluated based on training set and test set by survival curves, receiver-operator characteristic curves, risk score, survival status, heatmap, and independent prognostic analysis. Meanwhile, we appraised the correlation between target immune-associated genes and clinical stage, tumor-infiltrating immune cells respectively. RESULTS: Five immune-associated genes were used for constructing an immune-related prognostic signature by least absolute shrinkage and selection operator, univariate, and multivariate analysis. Survival curves, receiver-operator characteristic curves, and independent prognostic analysis showed the signature had significant prediction value. Clinical and immune cell correlation analyses indicated that target immune-associated genes may participate in tumor immune infiltration and tumor progression. CONCLUSIONS: We constructed a novel 5 immune-associated genes signature for predicting the prognosis of patients with thyroid cancer, which may help clinical workers evaluate individualized therapy and prognosis.


Assuntos
Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Regulação Neoplásica da Expressão Gênica , Linfócitos do Interstício Tumoral/imunologia , Neoplasias da Glândula Tireoide/patologia , Estudos de Casos e Controles , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Taxa de Sobrevida , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/imunologia , Transcriptoma
20.
Nat Rev Clin Oncol ; 17(9): 555-568, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32528101

RESUMO

With advances in tumour biology and immunology that continue to refine our understanding of cancer, therapies are now being developed to treat cancers on the basis of specific molecular alterations and markers of immune phenotypes that transcend specific tumour histologies. With the landmark approvals of pembrolizumab for the treatment of patients whose tumours have high microsatellite instability and larotrectinib and entrectinib for those harbouring NTRK fusions, a regulatory pathway has been created to facilitate the approval of histology-agnostic indications. Negative results presented in the past few years, however, highlight the intrinsic complexities faced by drug developers pursuing histology-agnostic therapeutic agents. When patient selection and statistical analysis involve multiple potentially heterogeneous histologies, guidance is needed to navigate the challenges posed by trial design. Additionally, as new therapeutic agents are tested and post-approval data become available, the regulatory framework for acting on these data requires further optimization. In this Review, we summarize the development and testing of approved histology-agnostic therapeutic agents and present data on other agents currently under development. Finally, we discuss the challenges intrinsic to histology-agnostic drug development in oncology, including biological, regulatory, design and statistical considerations.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Desenvolvimento de Medicamentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Biomarcadores Tumorais/imunologia , Ensaios Clínicos como Assunto , Humanos , Neoplasias/imunologia , Neoplasias/patologia , Medicina de Precisão
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