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1.
Anticancer Res ; 41(2): 1047-1053, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33517314

RESUMO

BACKGROUND/AIM: We aimed to predict the prognosis of endometrial carcinoma by combining traditional histological classification with the status of tumor-infiltrating lymphocytes (TILs). PATIENTS AND METHODS: All patients with endometrial carcinoma, treated at our hospital, were classified into four categories-Category I: Type I positive for TILs; category II: type I negative for TILs; category III: type II positive for TILs; and category IV: type II negative for TILs. Prognoses were compared across all the categories. Positivity for TILs was defined as a continuously formed thick zone of TILs at the invasive front. RESULTS: Multivariate analyses of progression-free and overall survival indicated that category classification was an independent prognostic factor, with hazard ratios of 3.127, 3.483, and 8.459 for progression-free survival, and 3.444, 4.374, and 11.058 for OS for patients in categories II, III, and IV, respectively. CONCLUSION: Combining traditional histological classification with TIL status might better predict prognosis of endometrial carcinoma.


Assuntos
Neoplasias do Endométrio/imunologia , Neoplasias do Endométrio/patologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Neoplasias do Endométrio/mortalidade , Feminino , Humanos , Análise Multivariada , Gradação de Tumores , Prognóstico , Análise de Sobrevida
2.
Anticancer Res ; 41(1): 219-226, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33419816

RESUMO

BACKGROUND: Extramammary Paget's disease (EMPD) is a type of carcinoma that usually progresses slowly but may cause metastasis and subsequent death of patients. We investigated the relationship between the expression of programmed death-ligand 1 (PD-L1)/programmed death-ligand 2 (PD-L2) and stromal CD8+ tumor-infiltrating lymphocytes (TILs) in EMPD and clinicopathological findings, including prognosis. MATERIALS AND METHODS: We examined 47 cases of EMPD and performed immunohistochemical staining of formalin-fixed paraffin-embedded full-face sections. RESULTS: PD-L1 expression in tumor cells was observed in 13 cases (27.7%) while PD-L2 expression was observed in 21 cases (44.7%). The cumulative postoperative recurrence-free rate in the group with positivity for PD-L1 and/or PD-L2 with a low CD8+ TIL count was significantly lower than that of the corresponding group with a high CD8+ TIL count and of the PD-L1- and PD-L2-negative group (p=0.026). CONCLUSION: The expression of PD-L1/PD-L2 in tumor cells was shown to be a factor for poor prognosis.


Assuntos
Antígeno B7-H1/genética , Biomarcadores Tumorais , Expressão Gênica , Doença de Paget Extramamária/genética , Doença de Paget Extramamária/mortalidade , Proteína 2 Ligante de Morte Celular Programada 1/genética , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Doença de Paget Extramamária/imunologia , Doença de Paget Extramamária/patologia , Prognóstico , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo
3.
Anticancer Res ; 41(1): 249-258, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33419819

RESUMO

BACKGROUND/AIM: Peritumoral ectopic lymphoid-like structures and tertiary lymphoid structures (TLS), have been identified in various cancers. However, evidence for the role of TLS in endometrial cancer (EC) is lacking. We found a cluster of peritumoral lymphocytes with band-like structures (PLB) in the forefront of EC and analyzed their association with the clinical outcome. MATERIALS AND METHODS: This was a single-center, retrospective cohort study. We evaluated peritumoral lymphoid cells using conventional hematoxylin-eosin and immunohistochemical staining by semi-quantitative digital analysis. RESULTS: A total of 85 cases were included and the presence of PLB was examined. A strong correlation was observed between the density of PLB and progression-free survival (very low, low vs. intermediate, high; HR=0.22; 95%CI=0.093-0.52; p<0.001) and overall survival (very low, low vs. intermediate, high; HR=0.259; 95%CI=0.091-0.73; p=0.011). CONCLUSION: PLB in type II EC show a strong association with fatal outcome.


Assuntos
Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/patologia , Linfócitos do Interstício Tumoral/patologia , Microambiente Tumoral , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Terapia Combinada , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/terapia , Feminino , Imunofluorescência , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/metabolismo , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos
4.
Gene ; 764: 145105, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32882333

RESUMO

Sarcoma (SARC) represents a group of highly histological and molecular heterogeneous rare malignant tumors with poor prognosis. There are few proposed classifiers for predicting patient's outcome. The Cancer Proteome Atlas (TPCA) and The Cancer Genome Atlas (TCGA) databases provide multi-omics datasets that enable a comprehensive investigation for this disease. The proteomic expression profile of SARC patients along with the clinical information was downloaded. 55 proteins were found to be associated with overall survival (OS) of patients using univariate Cox regression analysis. We developed a prognostic risk signature that comprises seven proteins (AMPKALPHA, CHK1, S6, ARID1A, RBM15, ACETYLATUBULINLYS40, and MSH6) with robust predictive performance using multivariate Cox stepwise regression analysis. Additionally, the signature could be an independent prognostic predictor after adjusting for clinicopathological parameters. Patients in high-risk group also have worse progression free intervals (PFI) than that of patients in low-risk group, but not for disease free intervals (DFI). The signature was validated using transcriptomic profile of SARC patients from TCGA. Potential mechanisms between high- and low-risk groups were identified using differentially expressed genes (DEGs) analysis. These DEGs were primarily enriched in RAS and MPAK signaling pathways. The signature protein molecules are candidate biomarkers for SARC, and the analysis of computational biology in tumor infiltrating lymphocytes and immune checkpoint molecules revealed distinctly immune landscapes of high- and low-risk patients. Together, we constructed a prognostic signature for predicting outcomes for SARC integrating proteomic and transcriptomic profiles, this might have value in guiding clinical practice.


Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Testes Genéticos/métodos , Sarcoma/mortalidade , Microambiente Tumoral/imunologia , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Conjuntos de Dados como Assunto , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Intervalo Livre de Progressão , Mapeamento de Interação de Proteínas , Proteômica , Curva ROC , Sarcoma/tratamento farmacológico , Sarcoma/genética , Sarcoma/imunologia , Transcriptoma/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
5.
Medicine (Baltimore) ; 99(50): e23418, 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33327268

RESUMO

BACKGROUND: Triple negative breast cancer affects 10% to 20% of all women diagnosed with breast cancer. Due to its characteristics, treatment strategies are limited and metastatic recurrences are common in the first 5 years after treatment. However, not all patients affected by this disease develop metastases. Tumor-infiltrating lymphocytes have shown to be reliable predictive biomarkers of treatment response and metastatic recurrences. However, we need to develop simpler and faster ways to predict response to cytotoxic treatment and the possibility of eventual cancer relapse by identifying new biomarkers. Recently, new studies are emerging, suggesting a predictive role of circulating blood cells in different types of cancer. In this study, we will assess the correlation between tumor-infiltrating lymphocytes and different elements of the blood count in patients diagnosed with triple negative breast cancer. METHODS: The main objective of this study is to evaluate the correlation between the peripheral neutrophil-to-lymphocyte ratio and the amount of tumor-infiltrating lymphocytes, assessed in triple negative breast cancer patients at diagnosis. Secondary objectives include evaluation of the correlation between tumor-infiltrating lymphocytes at diagnosis and the baseline absolute neutrophil, lymphocyte, and platelet counts, as well as the platelet-to-lymphocyte ratio. The triple negative breast cancer patients will be enrolled in the PERCEPTION trial during the first year after the treatment completion. Two supplementary blood tests, at 12 months after the end of treatment and at the time of the first metastatic recurrence, will be performed. DISCUSSION: The discovery of new prognostic and predictive biomarkers is crucial for triple negative breast cancer. We set up the PERCEPTION clinical trial in order to evaluate certain blood counts as early biomarkers and to assess their correlation with tumor-infiltrating lymphocytes. Demonstration of comparative predictive and/or prognostic capacities of peripheral blood counts and tumor-infiltrating lymphocytes would allow introduction of the former as simple and cheap biomarkers in triple negative breast cancer patient management. TRIAL REGISTRATION: The PERCEPTION study has been registered in the French National Agency of Medical Security registry on the 2nd of July 2019 under the number 2019-A01861-56 and in the ClinicalTrials.org registry under the number NCT04068623.


Assuntos
Plaquetas/metabolismo , Neoplasias da Mama/sangue , Linfócitos do Interstício Tumoral/metabolismo , Neutrófilos/metabolismo , Neoplasias de Mama Triplo Negativas/sangue , Adolescente , Adulto , Biomarcadores Tumorais/sangue , Neoplasias da Mama/mortalidade , Feminino , Humanos , Contagem de Linfócitos , Linfócitos/metabolismo , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/mortalidade , Contagem de Plaquetas , Valor Preditivo dos Testes , Prognóstico , Neoplasias de Mama Triplo Negativas/mortalidade , Adulto Jovem
6.
Tumour Biol ; 42(11): 1010428320971404, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33169632

RESUMO

Ovarian cancer is the most lethal of gynecological cancers with 5-year survival rate of ca. 45%. The most common histologic subtype is high-grade serous carcinoma, which typically is presented with advanced stage and development of chemoresistance. Therefore, new treatment options, including immunotherapies, are needed. Understanding the features of the immune cell populations in the tumor microenvironment is essential for developing personalized treatments and finding predictive biomarkers. Digital image analysis may enhance the accuracy and reliability of immune cell infiltration assessment in the tumor microenvironment. The aim of this study was to characterize tumor microenvironment in a retrospective cohort of high-grade serous carcinoma samples with whole-slide imaging and digital image analysis. Formalin-fixed paraffin-embedded high-grade serous carcinoma tumor tissue samples (n = 67) were analyzed for six immunohistochemical stainings: CD4, CD8, FoxP3, granzyme B, CD68, and CD163. The stained sample slides were scanned into a digital format and assessed using QuPath 0.1.2 and ImageJ software. Staining patterns were associated with clinicopathological data. The higher numbers of intraepithelial CD8+, CD163+, and granzyme B+ immune cells were associated with survival benefit when analyzed individually, while high levels of both CD8+ and granzyme B+ tumor-infiltrating lymphocytes were an independent prognostic factor in the Cox multivariate regression analysis (median progression-free survival; hazard ratio = 0.287, p = 0.002). Specimens taken after administration of neoadjuvant chemotherapy presented with lower FoxP3+ tumor-infiltrating lymphocyte density (Fisher's exact test, p = 0.013). However, none of the studied immunomarkers was associated with overall survival or clinical factors. Tumors having high amount of both intraepithelial CD8+ and granzyme B+ tumor-infiltrating lymphocytes showed better progression-free survival, possibly reflecting an activated immune state in the tumor microenvironment. The combined positivity of CD8 and granzyme B warrants further investigation with respect to predicting response to immune therapy. Neoadjuvant chemotherapy may have an effect on the tumor microenvironment and therefore on the response to immuno-oncologic or chemotherapy treatments.


Assuntos
Antígenos CD8/sangue , Carcinoma Epitelial do Ovário/sangue , Granzimas/sangue , Linfócitos do Interstício Tumoral/metabolismo , Adulto , Idoso , Antígenos CD/sangue , Antígenos de Diferenciação Mielomonocítica/sangue , Antígenos CD4/sangue , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/epidemiologia , Carcinoma Epitelial do Ovário/patologia , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Fatores de Transcrição Forkhead/sangue , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Receptores de Superfície Celular/sangue , Microambiente Tumoral/efeitos dos fármacos
7.
Jpn J Clin Oncol ; 50(11): 1290-1297, 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33089868

RESUMO

OBJECTIVE: To evaluate proteins related to tumor immune response and treatment outcome from radiotherapy for uterine cervical cancer patients. METHODS: We performed a retrospective immunohistochemical staining of 81 patients with uterine cervical cancer who underwent definitive radiotherapy. We examined the expression of programmed death ligand 1, human leukocyte antigen class I, tumor-infiltrating CD8+, and forkhead box P3+ (FoxP3+) T cells in tumor tissues. RESULTS: In biopsy specimen, patients with a higher number of CD8+ T cells and FoxP3+ T cells had a better disease-specific survival than patients with a lower number of CD8+ T cells and FoxP3+ cells (P = 0.018 and P = 0.009). Multivariate analysis showed that equivalent dose in 2 Gy fractions (EQD2) of the minimum dose to 90% of the high-risk clinical target volume, FoxP3+ T cells and expression of human leukocyte antigen class I were significant prognostic factors. When the EQD2 is 70 Gy or more, a higher local control rate is obtained regardless of the number of CD8- or FoxP3-positive cells. When EQD2 is <70 Gy, the number of CD8-positive cells has a significant impact on treatment outcome: the recurrence rate (local recurrence rate + distant metastasis rate) was 46.2% in the group with a CD8 value of 230 or higher, whereas the recurrence rate was 75.7% in the group with a CD8 value of less than 230. CONCLUSION: The combination of CD8 or FoxP3 with EQD2 can be potentially useful to predict the treatment results of radiotherapy for cervical cancer, leading to individualized optimal selection of treatment for cervical cancer.


Assuntos
Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/imunologia , Intervalo Livre de Doença , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Análise Multivariada , Recidiva Local de Neoplasia/patologia , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias do Colo do Útero/patologia
8.
Minerva Med ; 111(4): 337-343, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33032394

RESUMO

BACKGROUND: Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) are considered have a prognostic value in several malignancies. This study investigated the correlation between PD-L1 expression of tumor cells with the degree of stromal TILs in colorectal adenocarcinoma. METHODS: A cross sectional study design performed by taking 52 colorectal adenocarcinoma samples. The specimens were stained by immunohistochemical procedure using PD-L1 rabbit monoclonal antibody and the degrees of TILs were assessed base on hematoxylin and eosin (H&E) staining. RESULTS: From a total of 52 samples, the positive PD-L1 expression of tumor cells were 44 (84.6%) samples with 22 (50.0%), 18 (40.9%) and 4 (9.1%) samples had low-, moderate-, and high-degree TILs, respectively. While the negative PD-L1 expression were eight (15.4%) samples with 1 (12.5%), three (37.5%) and four (50.0%) samples had low-, moderate-, and high-degree TILs, respectively. A value of P=0.017 (P<0.05) was obtained by the Chi-square test. CONCLUSIONS: This study concluded that there was a significant correlation between PD-L1 expression of tumor cells and the degree of TILs in colorectal adenocarcinoma. This result indicated that the degree of TILs had the potential to be used as a predictive factor for PD-L1 expression of tumor cells in colorectal adenocarcinoma.


Assuntos
Adenocarcinoma/patologia , Antígeno B7-H1/biossíntese , Neoplasias Colorretais/patologia , Linfócitos do Interstício Tumoral/metabolismo , Adulto , Correlação de Dados , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
9.
PLoS Med ; 17(9): e1003292, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32970670

RESUMO

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


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Repetições de Microssatélites/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Estudos de Casos e Controles , Quimioterapia Adjuvante , Neoplasias Colorretais/metabolismo , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Instabilidade de Microssatélites , Repetições de Microssatélites/imunologia , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Espanha , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
10.
PLoS One ; 15(8): e0237465, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32785290

RESUMO

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


Assuntos
Antígeno CTLA-4/metabolismo , Carcinoma de Células Escamosas/patologia , Fatores de Transcrição Forkhead/metabolismo , Neoplasias Bucais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Feminino , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/metabolismo , Neoplasias Bucais/mortalidade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Taxa de Sobrevida , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo
11.
Cancer Invest ; 38(7): 406-414, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32762373

RESUMO

BACKGROUND: Programmed death 1 (PD-1) and its ligand PD-L1 play a key dysfunction of T lymphocytes. The purpose of this study was to assess and compare the prognostic role of tumor- TILs and its relationship with PD-L1 expression in stage II and III colon cancer. METHODS: Immunohistochemisty was used to assess the densities of CD8+, CD4+, and FOXP3+ cells, and PD-L1 expression in intraepithelial tumor site from 58 stage II and III colon cancers. These were evaluated for association with histopathologic features and overall survival. RESULTS: PD-L1-positive tumors contained a higher number of CD8+ TILs with statistical significance (p = 0.001). CD4+ TILs showed positive correlation with PD-L1 expression (p = 0.034). There were no associations between PD-L1 expression and FOXP3+ TILs. Microsatellite instability (MSI)-high status (p = 0.001; Odd ration 18.0; 95% CI = 4.3-74.8) was the strongest prognostic factor along with mucinous/poor cell differentiation, CD8 and right tumor location was associated with PD-L1 expression (p = 0.024, 0.035 and 0.033, respectively). CONCLUSION: This study demonstrated that PD-L1 expression was associated with MSI-high, increased CD8+ TILs, mucinous and poor cell differentiation, and right-sided tumor location.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias do Colo/mortalidade , Neoplasias do Colo/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Análise de Sobrevida
12.
Proc Natl Acad Sci U S A ; 117(37): 22910-22919, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32859758

RESUMO

Lymphocyte-based immunotherapy has emerged as a breakthrough in cancer therapy for both hematologic and solid malignancies. In a subpopulation of cancer patients, this powerful therapeutic modality converts malignancy to clinically manageable disease. However, the T cell- and chimeric antigen receptor T (CAR-T) cell-mediated antimetastatic activity, especially their impacts on microscopic metastatic lesions, has not yet been investigated. Here we report a living zebrafish model that allows us to visualize the metastatic cancer cell killing effect by tumor- infiltrating lymphocytes (TILs) and CAR-T cells in vivo at the single-cell level. In a freshly isolated primary human melanoma, specific TILs effectively eliminated metastatic cancer cells in the living body. This potent metastasis-eradicating effect was validated using a human lymphoma model with CAR-T cells. Furthermore, cancer-associated fibroblasts protected metastatic cancer cells from T cell-mediated killing. Our data provide an in vivo platform to validate antimetastatic effects by human T cell-mediated immunotherapy. This unique technology may serve as a precision medicine platform for assessing anticancer effects of cellular immunotherapy in vivo before administration to human cancer patients.


Assuntos
Imunoterapia/métodos , Linfócitos do Interstício Tumoral/metabolismo , Análise de Célula Única/métodos , Animais , Linhagem Celular Tumoral , Citotoxicidade Imunológica/imunologia , Imunoterapia Adotiva/métodos , Ativação Linfocitária/fisiologia , Modelos Animais , Metástase Neoplásica/patologia , Neoplasias/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Peixe-Zebra
13.
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
14.
Anticancer Res ; 40(6): 3395-3400, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487636

RESUMO

AIM: To investigate whether tumor-infiltrating lymphocyte (TIL) scoring based on 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) can predict the pathological response to neoadjuvant chemotherapy. PATIENTS AND METHODS: A total of 261 patients with breast cancer underwent complete resection after neoadjuvant chemotherapy. PET-TIL score was calculated using tumor size, Ki-67 labeling index, and maximum standardized uptake value (SUVmax) on FDG PET/CT. The efficacy of the PET-TIL score in predicting the pathological complete response (pCR) was retrospectively evaluated. RESULTS: pCR rates were 11.4%, 58.6%, and 38.8% in luminal, human epidermal growth factor receptor 2 (HER2)-positive, and triple-negative breast cancer, respectively. The corresponding median PET-TIL scores were 28, 37, and 45. pCR rates were 20.0% and 44.2% in the low and high PET-TIL score groups, respectively (p<0.001). HER2-positive and triple-negative subtypes and high PET-TIL score were independent predictors for pCR. CONCLUSION: PET-TIL score can predict pCR after neoadjuvant chemotherapy in breast cancer.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Fluordesoxiglucose F18 , Linfócitos do Interstício Tumoral/patologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Feminino , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Pessoa de Meia-Idade , Terapia Neoadjuvante , Gradação de Tumores , Estadiamento de Neoplasias , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Prognóstico , Curva ROC , Resultado do Tratamento , Microambiente Tumoral , Adulto Jovem
15.
PLoS One ; 15(6): e0233676, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32484812

RESUMO

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


Assuntos
Carcinoma de Células de Transição/patologia , Linfócitos do Interstício Tumoral/imunologia , Índice Mitótico , Recidiva Local de Neoplasia/diagnóstico , Neoplasias da Bexiga Urinária/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/imunologia , Progressão da Doença , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Estimativa de Kaplan-Meier , Antígeno Ki-67/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia , Estadiamento de Neoplasias , Prognóstico , Reprodutibilidade dos Testes , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/mortalidade
16.
J Cancer Res Ther ; 16(2): 320-326, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32474519

RESUMO

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


Assuntos
Adenocarcinoma de Pulmão/imunologia , Biomarcadores Tumorais/genética , Biologia Computacional/métodos , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Evasão Tumoral/imunologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Idoso , Algoritmos , Biomarcadores Tumorais/imunologia , Estudos de Casos e Controles , Estudos de Coortes , Bases de Dados Genéticas , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Evasão Tumoral/genética
17.
J Cancer Res Clin Oncol ; 146(9): 2319-2327, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32592066

RESUMO

PURPOSE: Lymphocyte activation gene-3 (LAG3) is an immunosuppressive checkpoint molecule expressed on T cells. The frequency and distribution of LAG3 expression in oesophageal adenocarcinoma (EAC) is unknown. Aim of the study was the evaluation and distribution of LAG3 on tumour infiltrating lymphocytes (TILs) and correlation with clinico-pathological and molecular data. METHODS: We analysed tumor tissue samples using immunohistochemistry, multi-colour immunofluorescence and mRNA in-situ technology. The analyses were performed on a multi-spot tissue microarray (TMA) with 165 samples, followed by an evaluation on a single-spot TMA with 477 samples. These results were correlated with clinical and molecular tumour data. RESULTS: LAG3 expression on TILs was detectable in 10.5% on the multi-spot TMA and 11.4% on the single-spot TMA. There was a strong correlation between protein expression and mRNA expression (p < 0.001) in TILs. LAG 3 expression was correlated with CD4+ and CD8+ T-cells within the tumor (p < 0.001). LAG3 expression showed an improved overall survival (OS) compared to patients without LAG3 expression (median OS 70.2 vs. 26.9 months; p = 0.046). The effect was even clearer in the group of patients with tumour stages > pT2 (70.2 vs 25.0 months; p = 0.037). CONCLUSION: This is the first description of LAG3 expression on TILs in EAC, underscoring the importance of immunomodulation in EAC. Our data suggest an impact of LAG3 in a relevant subset of EAC. Therapeutic studies investigating the efficacy of LAG3 inhibition in EAC will also provide predictive evidence and relevance of the immunohistochemical determination of LAG3 expression.


Assuntos
Adenocarcinoma/metabolismo , Antígenos CD/metabolismo , Neoplasias Esofágicas/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , RNA Mensageiro/metabolismo , Adenocarcinoma/patologia , Idoso , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Neoplasias Esofágicas/patologia , Feminino , Humanos , Ativação Linfocitária/fisiologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Estadiamento de Neoplasias/métodos
18.
Cancer Sci ; 111(9): 3132-3141, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32579769

RESUMO

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


Assuntos
Antineoplásicos Imunológicos/farmacologia , Neoplasias Esofágicas/etiologia , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/etiologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/patologia , Humanos , Imunomodulação/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Mutação , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Células Supressoras Mieloides/patologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo
19.
Cancer Immunol Immunother ; 69(11): 2275-2289, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32504248

RESUMO

Due to its high ability to disseminate, ovarian cancer remains one of the largest threats to women's health, worldwide. Evidence showed that the immune cells infiltrating the tumor microenvironment are crucial in mediating metastasis. Therefore, it is necessary to understand which types of immune cells are involved in metastasis, and to determine the mechanisms by which they influence the process. By immunohistochemistry, we found that higher concentrations of intratumoral CD8+ T cells were found to be correlated with an advanced grade and stage of ovarian cancer. Additionally, the infiltration of stromal CD8+ T cells was also significantly higher in tissues with advanced stages and metastatic tumors. A positive correlation between the infiltration of FoxP3+ Treg cells and histological grade was also observed, regardless of location. PD-L1 expression in metastatic tumors was also higher than that in paired primary ovarian tumors. Transwell migration and invasion assays revealed the increased migration and invasion of ovarian cancer cell lines (A2780CP and ES2) and ascites-derived ovarian cancer cells following co-culturing with CD8+ T cells. Enhanced expression of MMP-9, uPA, VEGF, bFGF, IL-8, IL-10, and PD-L1 by cancer cells following co-culturing with CD8+ T cells were also detected by qPCR, ELISA or flow cytometry. In conclusion, our findings suggest that the infiltrated T cells could promote the development of ovarian cancer, and provide another mechanism of immune evasion mediated by T cells.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma Epitelial do Ovário/patologia , Linfócitos do Interstício Tumoral/imunologia , Invasividade Neoplásica/patologia , Evasão Tumoral/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Epitelial do Ovário/imunologia , Carcinoma Epitelial do Ovário/metabolismo , Feminino , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Células Tumorais Cultivadas , Microambiente Tumoral/imunologia , Adulto Jovem
20.
Cancer Immunol Immunother ; 69(11): 2371-2380, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32524362

RESUMO

Natural killer (NK) cells, a predominant innate lymphocyte subset, mediates eradicating malignant cells. Purinergic signaling by ectonucleotidase CD39 can suppress T-cell response in caner. However, the role of CD39 in NK cells has not been fully elucidated. Here, we characterized CD39 expression on NK cells and its clinical relevance in esophageal squamous cell carcinoma (ESCC). Peripheral blood and tissue samples were collected from 36 ESCC patients. We observed that the proportion of NK cells significantly decreased but CD39 was obviously up-regulated on NK cells from cancerous tissues compared to paired peripheral blood in ESCC patients. Furthermore, tumor-infiltrating NK cells with high CD39 expression exhibited a phenotype of functional impairment. In vitro, conditioned media of ESCC cell lines could induce CD39 expression on peripheral NK cells from healthy donors. IL-6 was identified as the major cytokine produced by ESCC cell lines and also elevated in both tumor tissues and blood serum from ESCC patients. Recombinant IL-6 significantly induced surface CD39 expression in human NK cells, while IL-6-receptor antagonist tocilizumab prevented this effect. Finally, tumor-infiltrating CD39+ NK cells were correlated with poor prognosis in ESCC patients. Thus, tumor-derived IL-6 might impair NK cell functions through induction of CD39 expression. CD39+ NK cells may serve as a potential prognostic biomarker for ESCC patients.


Assuntos
Apirase/imunologia , Neoplasias Esofágicas/imunologia , Carcinoma de Células Escamosas do Esôfago/imunologia , Interleucina-6/imunologia , Células Matadoras Naturais/imunologia , Apirase/biossíntese , Feminino , Humanos , Interleucina-6/metabolismo , Células Matadoras Naturais/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Prognóstico , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologia
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