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1.
Acta Pharmacol Sin ; 38(6): 823-834, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28504251

RESUMEN

To achieve synergistic therapeutic efficacy and prevent cancer relapse, chemotherapy and immunotherapy have been combined as a new modality for tumor treatment. In this work, we designed a redox-responsive immunostimulatory polymeric prodrug carrier, PSSN10, for programmable co-delivery of an immune checkpoint inhibitor NLG919 (NLG) and a chemotherapeutic doxorubicin (DOX). NLG-containing PSSN10 prodrug polymers were self-assembled into nano-sized micelles that served as a carrier to load DOX (DOX/PSSN10 micelles). DOX/PSSN10 micelles displayed spherical morphology with a size of ∼170 nm. DOX was effectively loaded into PSSN10 micelles with a loading efficiency of 84.0%. In vitro DOX release studies showed that rapid drug release could be achieved in the highly redox environment after intracellular uptake by tumor cells. In 4T1.2 tumor-bearing mice, DOX/PSSN10 micelles exhibited greater accumulation of DOX and NLG in the tumor tissues compared with other organs. The PSSN10 carrier dose-dependently enhanced T-cell immune responses in the lymphocyte-Panc02 co-culture experiments, and significantly inhibited tumor growth in vivo. DOX/PSSN10 micelles showed potent cytotoxicity in vitro against 4T1.2 mouse breast cancer cells and PC-3 human prostate cancer cells comparable to that of DOX. In 4T1.2 tumor-bearing mice, DOX/PSSN10 mixed micelles (5 mg DOX/kg, iv) was more effective than DOXIL (a clinical formulation of liposomal DOX) or free DOX in inhibiting the tumor growth and prolonging the survival of the treated mice. In addition, a more immunoactive tumor microenvironment was observed in the mice treated with PSSN10 or DOX/PSSN10 micelles compared with the other treatment groups. In conclusion, systemic delivery of DOX via PSSN10 nanocarrier results in synergistic anti-tumor activity.


Asunto(s)
Antineoplásicos/farmacología , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos , Imidazoles/farmacología , Isoindoles/farmacología , Polímeros/farmacología , Profármacos/farmacología , Linfocitos T/efectos de los fármacos , Animales , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Doxorrubicina/química , Portadores de Fármacos/química , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Imidazoles/química , Inmunización , Isoindoles/química , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Micelas , Estructura Molecular , Oxidación-Reducción , Polímeros/química , Profármacos/química , Relación Estructura-Actividad , Linfocitos T/inmunología , Distribución Tisular , Células Tumorales Cultivadas
2.
Cancer Immunol Immunother ; 62(3): 553-61, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23090288

RESUMEN

In the present study, we studied the expression of T-bet, a key marker for type 1 immune responses, within the tumor microenvironment of gastric cancer, and analyzed its association with clinicopathological parameters. One hundred and fifty-two archival paraffin-embedded gastric tumor tissues were collected, and the expression of T-bet in these cancer tissue specimens was examined by immunohistochemistry. T-bet(+) tumor-infiltrating lymphocytes (TILs) in some gastric cancer tissues were further characterized by flow cytometric analysis. The density of T-bet(+) TILs in gastric cancer tissues in relation to patient's clinicopathological parameters and postoperative prognosis has been analyzed. Herein, we have found significant increases in T-bet(+) lymphocytes in tumor tissues as compared with normal stomach tissues, gastritis tissues or gastric polyp specimens. T-bet(+) cells mainly consisted of CD4(+), CD8(+) and CD56(+) TILs. In addition, lower numbers of T-bet(+) TILs were associated with poor clinicopathological parameters such as invasion to muscular layer, larger tumor size and advanced cancer stages. Moreover, patients with higher numbers of T-bet(+) TILs have longer disease-free survival and overall survival. Thus, our study supports the idea that tumor growth elicits spontaneous type 1 cellular immune responses and tumor progression is associated with suppression of antitumor immunity. T-bet expression within tumor can serve as a prognostic indicator for gastric cancer and a potential biomarker for immunotherapy.


Asunto(s)
Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias Gástricas/inmunología , Proteínas de Dominio T Box/metabolismo , Linfocitos T CD8-positivos/inmunología , Femenino , Humanos , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Persona de Mediana Edad , Pronóstico , Estómago/citología , Neoplasias Gástricas/mortalidad
3.
Onkologie ; 35(11): 700-5, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23147549

RESUMEN

Costimulatory molecule B7-H4, a member of the B7 family, negatively regulates the immune response of T cells through inhibiting their proliferation, cytokine production and cell cycle. The overexpression of B7-H4 plays an important role in initiation, progression and regression of tumors by promoting malignant transformation of epithelial cells and protecting epithelial cells from anoikis. B7-H4 expression in malignant tumors is useful for clinical diagnosis, and may provide a novel molecular target for cancer treatment.


Asunto(s)
Modelos Biológicos , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Inhibidor 1 de la Activación de Células T con Dominio V-Set/metabolismo , Biomarcadores/metabolismo , Humanos
4.
Cancer Immunol Immunother ; 60(7): 1047-55, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21519829

RESUMEN

A retrospective cohort study including 112 patients suffering from esophageal squamous cell carcinoma (ESCC) was performed to investigate the expression of B7-H4 in ESCC and determine its association with patient's clinicopathological parameters and survival. Expression levels of B7-H4 on tumor cells and densities of tumor infiltrating lymphocytes (TILs) in the surgical specimens of ESCC tissues were characterized using immunohistochemical assays. Uni- and multivariate analyses were performed to evaluate the prognostic value of B7-H4 expression levels and densities of TILs in tumor sections. Positive B7-H4 immunostaining was observed in 107 of 112 (95.5%) of ESCC tissue sections. We further divided all patients into two major subgroups, a lower B7-H4 expression group with 46 patients and a higher B7-H4 expression group with 66 patients. We found that expression levels of B7-H4 on tumor cells were significantly correlated with patient's gender (P = 0.0288), distant metastasis (P = 0.0500), and TNM stage (P = 0.0258). Moreover, tumor cell B7-H4 expression was inversely correlated with densities of CD3(+) T cells in tumor nest (P = 0.0424) and CD8(+) T cells in tumor stroma (P = 0.0229). The overall survival rate of the patients with higher B7-H4 expression was significantly worse than that of the patients with lower B7-H4 expression (P = 0.0105, Hazard Ratio: 1.854, 95%CI:1.152-2.902). Markers of cell-mediated immune responses such as CD3, CD8, and T-bet were associated with better patient survival. The present study demonstrated that B7-H4 expression in human ESCC is associated with cancer progression, reduced tumor immunosurveillance and worse patient outcomes. B7-H4 can serve as a novel prognostic predictor for human ESCC and a potential target for the immune therapy against this malignancy.


Asunto(s)
Antígeno B7-1/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidad , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/mortalidad , Linfocitos Infiltrantes de Tumor/patología , Animales , Progresión de la Enfermedad , Femenino , Humanos , Técnicas para Inmunoenzimas , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Microambiente Tumoral , Inhibidor 1 de la Activación de Células T con Dominio V-Set
5.
Cancer Immunol Immunother ; 59(8): 1163-71, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20333377

RESUMEN

B7-H3, a member of the B7-family molecules, plays an important role in adaptive immune responses, and was shown to either promote or inhibit T-cell responses in various experimental systems. B7-H3 was expressed in some human cancers and correlated with poor outcome of cancer patients. However, its exact role in cancer is not known. In the present study, we studied the expression of B7-H3 in the pathologic specimens of 102 patients treated for colorectal carcinoma (CRC) by immunohistochemistry. Strong B7-H3 expression was found in cancer tissues from 54.3% CRC patients, while minimal expression was found in adjacent normal colorectal tissues. Higher B7-H3 expression in tumor positively correlated with a more advanced tumor grade. In addition, consistent with a role of B7-H3 in suppressing tumor immune surveillance, the expression of B7-H3 in cancer cells negatively correlated with the intensity of tumor infiltrating T lymphocytes in both tumor nest and tumor stroma. Furthermore, we found that the level of soluble B7-H3 in sera from CRC patients was higher than healthy donors. TNF-alpha, an important cancer-promoting inflammatory molecule, was subsequently found to significantly increase the release of soluble B7-H3 in colon cancer cell lines. Therefore, our data suggest that both soluble and membranous B7-H3 proteins are involved in colon cancer progression and evasion of cancer immune surveillance.


Asunto(s)
Antígenos CD/inmunología , Neoplasias Colorrectales/inmunología , Vigilancia Inmunológica , Receptores Inmunológicos/inmunología , Antígenos CD/sangre , Antígenos CD/genética , Antígenos B7 , Células CACO-2 , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/fisiopatología , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Receptores Inmunológicos/sangre , Receptores Inmunológicos/genética , Factor de Necrosis Tumoral alfa/metabolismo
6.
Oncoimmunology ; 5(10): e1200778, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27853635

RESUMEN

Programmed Death 1 (PD-1) and T cell Ig and mucin domain-3 protein (Tim-3) are immune checkpoint receptors highly expressed on tumor infiltrating T lymphocytes (TIL). PD-1 inhibits T cell activation and type-1 T cell responses, while Tim-3 is proposed to mark more extensively exhausted cells, although the mechanisms underlying Tim-3 function are not clear. Trials of anti-PD-1 therapy have identified a large subset of non-responder patients, likely due to expression of alternative checkpoint molecules like Tim-3. We investigated the phenotypic and functional characteristics of T cells with differential expression of PD-1 (high/low) and Tim-3 (positive/negative), using TIL directly isolated from head and neck squamous cell carcinomas (HNSCC). Unexpectedly, we found that expression of Tim-3 alone does not necessarily mark TIL as dysfunctional/exhausted. In Tim-3-TIL, PD-1 levels correlate with T cell dysfunction, with a PD-1low/intermed phenotype identifying recently activated and still functional cells, whereas PD-1hiTim-3- T cells are actually exhausted. Nonetheless, PD-1intermed cells are still potently suppressed by PD-L1. PD-1 expression was associated with reduced phosphorylation of ribosomal protein S6 (pS6), whereas Tim-3 expression was associated with increased pS6. Using a novel mouse model for inducible Tim-3 expression, we confirmed that expression of Tim-3 does not necessarily render T cells refractory to further activation. These results suggest the existence of PD-1 and Tim-3 crosstalk in regulating antitumor T cell responses, with important implications for anti-PD-1 immunotherapy.

7.
World J Gastroenterol ; 21(31): 9403-12, 2015 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-26309367

RESUMEN

AIM: To determine the relationship between CD11c expression level and prognosis in patients with gastric cancer (GC). METHODS: This retrospective survival study was performed from July 31, 2008 to June 30, 2014. Our study inclusion criteria included all the patients with GC who underwent surgical resection between January 1998 and December 2009 in the Third Affiliated Hospital of Soochow University. CD11c expression levels in 140 patients with GC at different UICC stages were evaluated using immunohistochemistry, and GC tissues from 16 cases were further verified by qRT-PCR. The χ (2) test was used to compare the patient- and disease-related factors between the low CD11c expression group and the high expression group. Univariate probabilities of overall survival (OS) and disease-free survival (DFS) were assessed using the Kaplan-Meier method. The log rank test was used to compare survival curves. Different multivariate COX models were used to estimate the association between CD11c expression and both death and recurrence risk in GC patients. RESULTS: The average CD11c expression level was 5.1 ± 1.8/high power field (HPF) in 10 gastritis samples, 4.5 ± 2.3/HPF in 10 gastric polyp samples and 9.7 ± 6.3/HPF in 140 gastric cancer samples, respectively. The CD11c expression level was significantly decreased from UICC stage I to stage IV (stage I: 16.0 ± 7.4, stage II: 10.4 ± 5.5, stage III: 9.4 ± 6.1, stage IV: 5.3 ± 3.2, P < 0.001). Patients in the high CD11c expression group had a greater 3- and 5-year OS probability and longer median survival time compared with the low CD11c expression group, (67.7% vs 39.2%; 51.4% vs 29.0%; 67.0 mo vs 28.0 mo; χ(2) = 6.80, P = 0.009), and had a greater 3- and 5-year DFS probability and longer median DFS time (63.7% vs 24.0%; 49.1% vs 11.9%; 64.0 mo vs 18.0 mo; χ (2) = 15.39, P < 0.001). Patients with high CD11c high expression had a reduced risk of death (HR = 0.56, 95%CI: 0.33-0.98, P < 0.05) and relapse (HR = 0.39, 95%CI: 0.23-0.67, P < 0.01) compared with patients with low CD11c expression after adjustment of potential confounders, with the exception of tumor size. However, the protective effect related to death (HR = 0.90, 95%CI: 0.49-1.67, P = 0.749) and relapse (HR = 0.65, 95%CI: 0.36-1.19, P = 0.160) disappeared when tumor size was incorporated into the model. CONCLUSION: High expression of CD11c decreased the risk of death and relapse, and may be regarded as an alternative indicator of favorable prognosis in patients with GC.


Asunto(s)
Biomarcadores de Tumor/análisis , Antígeno CD11c/análisis , Neoplasias Gástricas/inmunología , Biomarcadores de Tumor/genética , Antígeno CD11c/genética , Distribución de Chi-Cuadrado , China , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Gastrectomía , Hospitales Universitarios , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Análisis Multivariante , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios Retrospectivos , Factores de Riesgo , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugía , Factores de Tiempo , Resultado del Tratamiento , Regulación hacia Arriba
8.
Cancer Biol Med ; 10(3): 131-7, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24379987

RESUMEN

MicroRNAs (miRNAs) are small, non-coding single-stranded RNAs that can modulate target gene expression at post-transcriptional level and participate in cell proliferation, differentiation, and apoptosis. T cells have important functions in acquired immune response; miRNAs regulate this immune response by targeting the mRNAs of genes involved in T cell development, proliferation, differentiation, and function. For instance, miR-181 family members function in progression by targeting Bcl2 and CD69, among others. MiR-17 to miR-92 clusters function by binding to CREB1, PTEN, and Bim. Considering that the suppression of T cell-mediated immune responses against tumor cells is involved in cancer progression, we should investigate the mechanism by which miRNA regulates T cells to develop new approaches for cancer treatment.

9.
Zhonghua Wei Chang Wai Ke Za Zhi ; 13(5): 366-70, 2010 May.
Artículo en Zh | MEDLINE | ID: mdl-20499308

RESUMEN

OBJECTIVE: To investigate the influence of co-stimulatory molecules B7-H4 expression on prognosis of gastric cancer patients treated by cytokine-induced killer cells (CIK cells) adoptive immunotherapy. METHODS: Clinical data of 156 cases of gastric cancer patients were retrospectively analyzed. Patients were divided into chemotherapy group(n=81) and chemotherapy combined with CIK cell therapy group(n=75). B7-H4 expression was detected in the surgical specimens of gastric cancer patients by immunohistochemistry assay. Disease-free survival was compared between the chemotherapy group and the CIK group at different expression levels of B7-H4. RESULTS: The difference was not statistically significant in all clinical and pathological data between the chemotherapy group and the CIK treatment group (P>0.05). The postoperative median tumor-free survival in two groups was 18.0 and 45.0 months, respectively, and the difference was statistically significant (chi(2)=11.631, P=0.001). The postoperative median survival time was 27.0 and 49.0 months, respectively, and the difference was statistically significant (chi(2)=10.907, P=0.001). In 86 patients with low B7-H4 expression, the median tumor-free survival time was 32.0 and 62.0 months, respectively, and the difference was statistically significant (chi(2)=4.663,P=0.03). In 70 patients with high B7-H4 expression, the median tumor-free survival time was 11.0 and 18.0 months, respectively, and the difference was statistically significant (chi(2)=11.971, P=0.001). CONCLUSION: The median tumor-free survival time of patients with gastric cancer may be further improved by chemotherapy combined with CIK cell therapy, regardless of the level of B7-H4 expression.


Asunto(s)
Antígeno B7-1/metabolismo , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/metabolismo , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Células Asesinas Inducidas por Citocinas , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunoterapia Adoptiva , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Neoplasias Gástricas/terapia , Inhibidor 1 de la Activación de Células T con Dominio V-Set
10.
World J Gastroenterol ; 16(48): 6155-62, 2010 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-21182234

RESUMEN

AIM: to analyze the correlation between cytokine-induced killer (cik) cells adoptive immunotherapy and cancer-related death in gastric cancer patients. methods: One hundred and fifty-six gastric cancer patients after operation at the Third Affiliated Hospital of Soochow University were enrolled in this study. Their clinical data including demographic characteristics, operation time, tumor size, pathological type and staging, tumor metastasis, outcome of chemotherapy or CIK cells adoptive immunotherapy, survival time or time of death were collected with a standard structured questionnaire. Kaplan-Meier method was used to estimate the median survival time, and the 2- and 5- year survival rates. Hazard risk (HR) and 95% confidence interval (95% CI) of CIK cells adoptive immunotherapy for gastric cancer were calculated using the two-stage time-dependent covariates Cox model. RESULTS: the survival time of gastric cancer patients was longer after CIK cells adoptive immunotherapy than after chemotherapy (χ(2) = 10.907, P = 0.001). The median survival time of gastric cancer patients was also longer after CIK cells adoptive immunotherapy than after chemotherapy (49 mo vs 27 mo, P < 0.05). The 2- and 5-year survival rates of gastric cancer patients were significantly higher after CIK cells adoptive immunotherapy than after chemotherapy (73.5% vs 52.6%, 40.4% vs 23.9%, P < 0.05). A significant difference was observed in the survival curve for patients who received CIK cells adoptive immunotherapy (0, 1-10, 11-25, and over 25 frequencies) (χ(2) = 14.534, P = 0.002). The frequencies of CIK cells adoptive immunotherapy were significantly related with the decreasing risk of death in gastric cancer patients after adjustment for sex and age of the patients, tumor stage and relapse (HR = 0.54, 95% CI: 0.36-0.80) when the first stage Cox model was used to define the subjects who remained alive beyond 36 mo as survivors. However, no correlation was observed between the frequencies of death in CIK cells adoptive immunotherapy and the risk of gastric cancer patients (HR = 1.09, 95% CI: 0.63-0.89) when the second stage Cox model was used to define the subjects who survived for more than 36 mo as survivors. CONCLUSION: the survival time of the gastric cancer patients treated with chemotherapy combined with CIK cells adoptive immunotherapy is significantly longer than that of the patients treated with chemotherapy alone and increasing the frequency of CIK cells adoptive immunotherapy seems to benefit patients more.


Asunto(s)
Células Asesinas Inducidas por Citocinas/inmunología , Inmunoterapia Adoptiva/métodos , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/terapia , Tasa de Supervivencia , Adulto , Anciano , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/patología , Encuestas y Cuestionarios
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