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1.
Immunity ; 48(1): 91-106.e6, 2018 01 16.
Artículo en Inglés | MEDLINE | ID: mdl-29343444

RESUMEN

CD103+ dendritic cells are critical for cross-presentation of tumor antigens. Here we have shown that during immunotherapy, large numbers of cells expressing CD103 arose in murine tumors via direct differentiation of Ly6c+ monocytic precursors. These Ly6c+CD103+ cells could derive from bone-marrow monocytic progenitors (cMoPs) or from peripheral cells present within the myeloid-derived suppressor cell (MDSC) population. Differentiation was controlled by inflammation-induced activation of the transcription factor p53, which drove upregulation of Batf3 and acquisition of the Ly6c+CD103+ phenotype. Mice with a targeted deletion of p53 in myeloid cells selectively lost the Ly6c+CD103+ population and became unable to respond to multiple forms of immunotherapy and immunogenic chemotherapy. Conversely, increasing p53 expression using a p53-agonist drug caused a sustained increase in Ly6c+CD103+ cells in tumors during immunotherapy, which markedly enhanced the efficacy and duration of response. Thus, p53-driven differentiation of Ly6c+CD103+ monocytic cells represents a potent and previously unrecognized target for immunotherapy.


Asunto(s)
Células Presentadoras de Antígenos/fisiología , Monocitos/fisiología , Células Mieloides/metabolismo , Neoplasias/inmunología , Proteína p53 Supresora de Tumor/metabolismo , Animales , Células Presentadoras de Antígenos/inmunología , Antígenos CD/metabolismo , Antígenos Ly/metabolismo , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Línea Celular , Citometría de Flujo , Humanos , Inmunoterapia/métodos , Cadenas alfa de Integrinas/metabolismo , Ratones , Monocitos/inmunología , Células Mieloides/fisiología
2.
Hepatology ; 76(2): 330-344, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-34897774

RESUMEN

BACKGROUND AND AIMS: Chimeric antigen receptor engineered T cells (CARTs) for HCC and other solid tumors are not as effective as they are for blood cancers. CARTs may lose function inside tumors due to persistent antigen engagement. The aims of this study are to develop low-affinity monoclonal antibodies (mAbs) and low-avidity CARTs for HCC and to test the hypothesis that low-avidity CARTs can resist exhaustion and maintain functions in solid tumors, generating durable antitumor effects. METHODS AND RESULTS: New human glypican-3 (hGPC3) mAbs were developed from immunized mice. We obtained three hGPC3-specific mAbs that stained HCC tumors, but not the adjacent normal liver tissues. One of them, 8F8, bound an epitope close to that of GC33, the frequently used high-affinity mAb, but with approximately 17-fold lower affinity. We then compared the 8F8 CARTs to GC33 CARTs for their in vitro function and in vivo antitumor effects. In vitro, low-avidity 8F8 CARTs killed both hGPC3high and hGPC3low HCC tumor cells to the same extent as high-avidity GC33 CARTs. 8F8 CARTs expanded and persisted to a greater extent than GC33 CARTs, resulting in durable responses against HCC xenografts. Importantly, compared with GC33 CARTs, there were 5-fold more of 8F8-BBz CARTs in the tumor mass for a longer period of time. Remarkably, the tumor-infiltrating 8F8 CARTs were less exhausted and apoptotic, and more functional than GC33 CARTs. CONCLUSION: The low-avidity 8F8-BBz CART resists exhaustion and apoptosis inside tumor lesions, demonstrating a greater therapeutic potential than high-avidity CARTs.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Glipicanos , Humanos , Neoplasias Hepáticas/patología , Ratones , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Expert Rev Mol Med ; 24: e7, 2022 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-35086597

RESUMEN

In this article, we reviewed the current literature studies and our understanding of the parameters that affect the chimeric antigen receptor T cells (CAR-T's) activation, effector function, in vivo persistence, and antitumour effects. These factors include T cell subsets and their differentiation stages, the components of chimeric antigen receptors (CAR) design, the expression promoters and delivery vectors, and the CAR-T production process. The CAR signalling and CAR-T activation were also studied in comparison to TCR. The last section of the review gave special consideration of CAR design for solid tumours, focusing on strategies to improve CAR-T tumour infiltration and survival in the hostile tumour microenvironment. With several hundred clinical trials undergoing worldwide, the pace of CAR-T immunotherapy moves from bench to bedside is unprecedented. We hope that the article will provide readers a clear and comprehensive view of this rapidly evolving field and will help scientists and physician to design effective CAR-Ts immunotherapy for solid tumours.


Asunto(s)
Neoplasias , Receptores Quiméricos de Antígenos , Humanos , Inmunoterapia , Inmunoterapia Adoptiva , Neoplasias/genética , Neoplasias/terapia , Receptores de Antígenos de Linfocitos T/genética , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/metabolismo , Microambiente Tumoral/genética
4.
Hepatology ; 68(2): 574-589, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29443377

RESUMEN

Hepatocellular carcinoma (HCC) is the major form of liver cancer for which there is no effective therapy. Genetic modification with T-cell receptors (TCRs) specific for HCC-associated antigens, such as α-fetoprotein (AFP), can potentially redirect human T cells to specifically recognize and kill HCC tumor cells to achieve antitumor effects. In this study, using lentivector and peptide immunization, we identified a population of cluster of differentiation 8 (CD8) T cells in human leukocyte antigen (HLA)-A2 transgenic AAD mice that recognized AFP158 epitope on human HCC cells. Adoptive transfer of the AFP158 -specific mouse CD8 T cells eradicated HepG2 tumor xenografts as large as 2 cm in diameter in immunocompromised nonobese diabetic severe combined immunodeficient gamma knockout (NSG) mice. We then established T-cell hybridoma clones from the AFP158 -specific mouse CD8 T cells and identified three sets of paired TCR genes out of five hybridomas. Expression of the murine TCR genes redirected primary human T cells to bind HLA-A2/AFP158 tetramer. TCR gene-engineered human T (TCR-T) cells also specifically recognized HLA-A2+ AFP+ HepG2 HCC tumor cells and produced effector cytokines. Importantly, the TCR-T cells could specifically kill HLA-A2+ AFP+ HepG2 tumor cells without significant toxicity to normal primary hepatocytes in vitro. Adoptive transfer of the AFP-specific TCR-T cells could eradicate HepG2 tumors in NSG mice. CONCLUSION: We have identified AFP-specific murine TCR genes that can redirect human T cells to specifically recognize and kill HCC tumor cells, and those AFP158 -specific TCRs have a great potential to engineer a patient's autologous T cells to treat HCC tumors. (Hepatology 2018).


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Carcinoma Hepatocelular/inmunología , Inmunoterapia/métodos , Neoplasias Hepáticas/inmunología , alfa-Fetoproteínas/inmunología , Animales , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral , Ensayo de Inmunoadsorción Enzimática , Femenino , Antígeno HLA-A2/inmunología , Células Hep G2 , Humanos , Ratones , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T/inmunología
5.
Immunity ; 33(6): 942-54, 2010 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-21145762

RESUMEN

Foxp3(+) regulatory T (Treg) cells can undergo reprogramming into a phenotype expressing proinflammatory cytokines. However, the biologic significance of this conversion remains unclear. We show that large numbers of Treg cells undergo rapid reprogramming into activated T helper cells after vaccination with antigen plus Toll-like receptor 9 (TLR-9) ligand. Helper activity from converted Treg cells proved essential during initial priming of CD8(+) T cells to a new cross-presented antigen. Help from Treg cells was dependent on CD40L, and (unlike help from conventional non-Treg CD4(+) cells) did not require preactivation or prior exposure to antigen. In hosts with established tumors, Treg cell reprogramming was suppressed by tumor-induced indoleamine 2,3-dioxygenase (IDO) and vaccination failed because of lack of help. Treg cell reprogramming, vaccine efficacy, and antitumor CD8(+) T cell responses were restored by pharmacologic inhibition of IDO. Reprogrammed Treg cells can thus participate as previously unrecognized drivers of certain early CD8(+) T cell responses.


Asunto(s)
Linfocitos T CD8-positivos/metabolismo , Reactividad Cruzada , Melanoma Experimental/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Reguladores/metabolismo , Traslado Adoptivo , Animales , Antígenos/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Transdiferenciación Celular/efectos de los fármacos , Células Cultivadas , Reactividad Cruzada/efectos de los fármacos , Factores de Transcripción Forkhead/biosíntesis , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Activación de Linfocitos/efectos de los fármacos , Melanoma Experimental/tratamiento farmacológico , Ratones , Ratones Endogámicos , Oligodesoxirribonucleótidos/administración & dosificación , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/patología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Receptor Toll-Like 9/inmunología , Triptófano/análogos & derivados , Triptófano/farmacología
6.
Metab Brain Dis ; 34(1): 213-221, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30443767

RESUMEN

Hepatic encephalopathy (HE) is a serious complication of liver disease. To establish a model for predicting 3-month mortality in patients with HE in China. This retrospective study included 609 patients with HE admitted to the Peoples' Hospital, Liaocheng City, China (August 2006 to January 2016). Patients were allocated to a modeling (n = 409) or validation (n = 200) group. Demographic/clinical characteristics, laboratory test results, Model for End Stage Liver Disease (MELD) score and Child-Turcotte-Pugh (CTP) score were extracted from medical records. A model for predicting death within 3 months after admission was established using logistic regression analysis (modeling group). Model validity (validation group) was assessed using receiver operating characteristic (ROC) curve analysis. 270/409(66.0%) patients died in the modeling group and 142/203(70.0%) died in the validation group. Compared with survivors, patients who died had more severe HE, and higher MELD score, CTP score, incidence of complications including hepatorenal syndrome (HRS) and upper gastrointestinal bleeding, and values for laboratory parameters including red blood cell count(RBC) and total bilirubin(TBIL)(P < 0.05). Regression analysis revealed RBC, TBIL, HE stage, HRS and upper gastrointestinal bleeding as independent factors associated with death (P < 0.05). The area under the ROC curve (AUC) for the model was 0.931.The model had a higher Youden index than MELD or CTP scores and predicted death in the validation group with a sensitivity of 83.1% and specificity of 93.4%. The established model has superior performance to MELD and CTP scores for predicting mortality in patients with HE.


Asunto(s)
Encefalopatía Hepática/mortalidad , Adulto , Anciano , China , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Teóricos , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos
7.
J Med Virol ; 95(10): e29162, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37812034

Asunto(s)
Mentores , Ciencia , Humanos
8.
Mol Cell Biochem ; 424(1-2): 195-201, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27822662

RESUMEN

Altered microRNA expression is associated with tumor proliferation, metastasis, and tumorigenesis. In this study, we studied the role of miR-3117 in hepatocellular carcinoma (HCC) cell proliferation and found that miR-3117 was upregulated in HCC tissues and cells. MTT assay, soft agar growth assay, BrdU assay, and cell cycle assay revealed that miR-3117 overexpression promoted HCC HepG2 cell proliferation and that knockdown of miR-3117 suppressed HepG2 proliferation. Mechanism analysis suggested PH domain and leucine-rich repeat protein phosphatase-like (PHLPPL) as the target of miR-3117. Luciferase reporter assay suggested that miR-3117 directly binds to the 3'UTR of PHLPPL. Double knockdown of miR-3117 and PHLPPL copied the phenotypes caused by miR-3117 overexpression, suggesting that miR-3117 contributes to the proliferation of HepG2 by targeting PHLPPL. Our study provided a target for HCC therapy.


Asunto(s)
Carcinoma Hepatocelular/metabolismo , Proliferación Celular , Neoplasias Hepáticas/metabolismo , MicroARNs/metabolismo , Proteínas de Neoplasias/metabolismo , Fosfoproteínas Fosfatasas/metabolismo , ARN Neoplásico/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , MicroARNs/genética , Proteínas de Neoplasias/genética , Fosfoproteínas Fosfatasas/genética , ARN Neoplásico/genética
9.
Hepatology ; 59(4): 1448-58, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24122861

RESUMEN

UNLABELLED: Immunization with effective cancer vaccines can offer a much needed adjuvant therapy to fill the treatment gap after liver resection to prevent relapse of hepatocellular carcinoma (HCC). However, current HCC cancer vaccines are mostly based on native shared-self/tumor antigens that are only able to induce weak immune responses. In this study we investigated whether the HCC-associated self/tumor antigen of alpha-fetoprotein (AFP) could be engineered to create an effective vaccine to break immune tolerance and potently activate CD8 T cells to prevent clinically relevant carcinogen-induced autochthonous HCC in mice. We found that the approach of computer-guided methodical epitope-optimization created a highly immunogenic AFP and that immunization with lentivector expressing the epitope-optimized AFP, but not wild-type AFP, potently activated CD8 T cells. Critically, the activated CD8 T cells not only cross-recognized short synthetic wild-type AFP peptides, but also recognized and killed tumor cells expressing wild-type AFP protein. Immunization with lentivector expressing optimized AFP, but not native AFP, completely protected mice from tumor challenge and reduced the incidence of carcinogen-induced autochthonous HCC. In addition, prime-boost immunization with the optimized AFP significantly increased the frequency of AFP-specific memory CD8 T cells in the liver that were highly effective against emerging HCC tumor cells, further enhancing the tumor prevention of carcinogen-induced autochthonous HCC. CONCLUSIONS: Epitope-optimization is required to break immune tolerance and potently activate AFP-specific CD8 T cells, generating effective antitumor effect to prevent clinically relevant carcinogen-induced autochthonous HCC in mice. Our study provides a practical roadmap to develop effective human HCC vaccines that may result in an improved outcome compared to the current HCC vaccines based on wild-type AFP.


Asunto(s)
Vacunas contra el Cáncer/uso terapéutico , Carcinoma Hepatocelular/prevención & control , Epítopos , Neoplasias Hepáticas/prevención & control , alfa-Fetoproteínas/genética , Animales , Linfocitos T CD8-positivos/patología , Carcinógenos , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/inmunología , Modelos Animales de Enfermedad , Tolerancia Inmunológica/fisiología , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/inmunología , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Resultado del Tratamiento
10.
J Immunol ; 190(11): 5866-73, 2013 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-23610140

RESUMEN

Cancer vaccines, to date, have shown limited effect to control the growth of established tumors due largely to effector failure of the antitumor immune responses. Tumor lesion is characterized as chronic indolent inflammation in which the effector function of tumor-infiltrating lymphocytes (TILs) is severely impaired. In this study, we investigated whether the effector function of CD8 TILs could be rescued by converting the chronic inflammation milieu to acute inflammation within tumors. We found that injection of TLR3/9 ligands (polyI:C/CpG) into a tumor during the effector phase of lentivector (lv) immunization effectively rescued the function of lv-activated CD8 TILs and decreased the percentage of T regulatory within the tumor, resulting in a marked improvement in the antitumor efficacy of lv immunization. Mechanistically, rescue of the effector function of CD8 TILs by TLR3/9 ligands is most likely dependent on production, within a tumor, of type-1 IFN that can mature and activate tumor-infiltrating dendritic cells. The effector function of CD8 TILs could not be rescued in mice lacking intact type I IFN signaling. These findings have important implications for tumor immunotherapy, suggesting that type I IFN-mediated activation of tumor-infiltrating dendritic cells within a tumor will most likely restore/enhance the effector function of CD8 TILs and thus improve the antitumor efficacy of current cancer vaccines.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias/inmunología , Animales , Linfocitos T CD8-positivos/metabolismo , Vacunas contra el Cáncer , Línea Celular Tumoral , Citocinas/biosíntesis , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Vectores Genéticos , Humanos , Interferón Tipo I/metabolismo , Lentivirus , Ligandos , Linfocitos Infiltrantes de Tumor/metabolismo , Ratones , Modelos Biológicos , Neoplasias/metabolismo , Receptores de Interferón/metabolismo , Transducción de Señal , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Receptores Toll-Like/metabolismo
11.
J Immunol ; 188(10): 4819-27, 2012 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-22504640

RESUMEN

A major problem with current cancer vaccines is that the induction of CD8 immune responses is rarely associated with antitumor benefits, mainly owing to multiple immune suppressions in established tumor lesions. In this study, we investigated if and how activation of endogenous CD4 T cells could be achieved to influence the suppressive tumor milieu and antitumor effect. We engineered a lentivector (lv) to express a nominal fusion Ag composed of hepatitis B surface protein and IgG2a Fc fragment (HBS-Fc-lv) to increase the magnitude of CD8 response but, more importantly, to induce effective coactivation of CD4 T cells. We found that, remarkably, immunization with HBS-Fc-lv caused significant regression of established tumors. Immunologic analysis revealed that, compared with HBS-lv without Fc fragment, immunization with HBS-Fc-lv markedly increased the number of functional CD8 and CD4 T cells and the level of Th1/Tc1-like cytokines in the tumor while substantially decreasing the regulatory T cell ratio. The favorable immunologic changes in tumor lesions and the improvement of antitumor effects from HBS-Fc-lv immunization were dependent on the CD4 activation, which was Fc receptor mediated. Adoptive transfer of CD4 T cells from the HBS-Fc-lv-immunized mice could activate endogenous CD8 T cells in an IFN-γ-dependent manner. We conclude that endogenous CD4 T cells can be activated by lv expressing Fc-tagged Ag to provide another layer of help--that is, creating a Th1/Tc1-like proinflammatory milieu within the tumor lesion to boost the effector phase of immune responses in enhancing the antitumor effect.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/uso terapéutico , Vectores Genéticos/uso terapéutico , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Activación de Linfocitos/inmunología , Melanoma Experimental/inmunología , Melanoma Experimental/terapia , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/trasplante , Vacunas contra el Cáncer/inmunología , Vectores Genéticos/inmunología , Células HEK293 , Antígenos de Superficie de la Hepatitis B/genética , Antígenos de Superficie de la Hepatitis B/uso terapéutico , Humanos , Fragmentos Fc de Inmunoglobulinas/administración & dosificación , Fragmentos Fc de Inmunoglobulinas/metabolismo , Inflamación/inmunología , Inflamación/patología , Inflamación/terapia , Lentivirus/genética , Lentivirus/inmunología , Activación de Linfocitos/genética , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/uso terapéutico , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/patología
12.
Signal Transduct Target Ther ; 9(1): 101, 2024 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-38643203

RESUMEN

Strategies to improve T cell therapy efficacy in solid tumors such as hepatocellular carcinoma (HCC) are urgently needed. The common cytokine receptor γ chain (γc) family cytokines such as IL-2, IL-7, IL-15 and IL-21 play fundamental roles in T cell development, differentiation and effector phases. This study aims to determine the combination effects of IL-21 in T cell therapy against HCC and investigate optimized strategies to utilize the effect of IL-21 signal in T cell therapy. The antitumor function of AFP-specific T cell receptor-engineered T cells (TCR-T) was augmented by exogenous IL-21 in vitro and in vivo. IL-21 enhanced proliferation capacity, promoted memory differentiation, downregulated PD-1 expression and alleviated apoptosis in TCR-T after activation. A novel engineered IL-21 receptor was established, and TCR-T armed with the novel engineered IL-21 receptors (IL-21R-TCR-T) showed upregulated phosphorylated STAT3 expression without exogenous IL-21 ligand. IL-21R-TCR-T showed better proliferation upon activation and superior antitumor function in vitro and in vivo. IL-21R-TCR-T exhibited a less differentiated, exhausted and apoptotic phenotype than conventional TCR-T upon repetitive tumor antigen stimulation. The novel IL-21 receptor in our study programs powerful TCR-T and can avoid side effects induced by IL-21 systemic utilization. The novel IL-21 receptor creates new opportunities for next-generation TCR-T against HCC.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/metabolismo , Subunidad gamma Común de Receptores de Interleucina/metabolismo , Receptores de Interleucina-21/genética , Receptores de Interleucina-21/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T CD8-positivos
13.
Mol Cancer ; 12(1): 103, 2013 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-24020520

RESUMEN

Oncolytic viruses (OVs) are tumor-selective, multi-mechanistic antitumor agents. They kill infected cancer and associated endothelial cells via direct oncolysis, and uninfected cells via tumor vasculature targeting and bystander effect. Multimodal immunogenic cell death (ICD) together with autophagy often induced by OVs not only presents potent danger signals to dendritic cells but also efficiently cross-present tumor-associated antigens from cancer cells to dendritic cells to T cells to induce adaptive antitumor immunity. With this favorable immune backdrop, genetic engineering of OVs and rational combinations further potentiate OVs as cancer vaccines. OVs armed with GM-CSF (such as T-VEC and Pexa-Vec) or other immunostimulatory genes, induce potent anti-tumor immunity in both animal models and human patients. Combination with other immunotherapy regimens improve overall therapeutic efficacy. Coadministration with a HDAC inhibitor inhibits innate immunity transiently to promote infection and spread of OVs, and significantly enhances anti-tumor immunity and improves the therapeutic index. Local administration or OV mediated-expression of ligands for Toll-like receptors can rescue the function of tumor-infiltrating CD8+ T cells inhibited by the immunosuppressive tumor microenvironment and thus enhances the antitumor effect. Combination with cyclophosphamide further induces ICD, depletes Treg, and thus potentiates antitumor immunity. In summary, OVs properly armed or in rational combinations are potent therapeutic cancer vaccines.


Asunto(s)
Vacunas contra el Cáncer/inmunología , Neoplasias/terapia , Virus Oncolíticos/inmunología , Animales , Antígenos de Neoplasias/inmunología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Muerte Celular , Terapia Combinada , Reactividad Cruzada , Ciclofosfamida/farmacología , Ciclofosfamida/uso terapéutico , Citotoxicidad Inmunológica , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Neoplasias/inmunología
14.
J Immunol ; 187(4): 1788-96, 2011 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-21746967

RESUMEN

Most cancer vaccines, to date, fail to control established tumors. However, their application in preventing tumors is another question that is understudied. In the current study, we investigated the CD8 memory T cell responses of lentivector (lv) immunization and its potential to prevent melanoma using both transplantable B16 tumor and autochthonous melanoma models. We found that lv-expressing xenogenic human gp100 could induce potent CD8 responses that cross-react with mouse gp100. Importantly, the lv-primed CD8 response consisted of a high number of memory precursors and could be further increased by recombinant vaccinia virus vector (vv) boost, resulting in enhanced CD8 memory response. These long-lasting CD8 memory T cells played a critical role in immune surveillance and could rapidly respond and expand after sensing B16 tumor cells to prevent tumor establishment. Although CD8 response plays a dominant role after lv immunization, both CD4 and CD8 T cells are responsible for the immune prevention. In addition, we surprisingly found that CD4 help was not only critical for generating primary CD8 responses, but also important for secondary CD8 responses of vv boost. CD4 depletion prior to lv prime or prior to vv boost substantially reduced the magnitude of secondary CD8 effector and memory responses, and severely compromised the effect of cancer immune prevention. More importantly, the CD8 memory response from lv-vv prime-boost immunization could effectively prevent autochthonous melanoma in tumor-prone transgenic mice, providing a strong evidence that lv-vv prime-boost strategy is an effective approach for cancer immune prevention.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/farmacología , Vectores Genéticos , Inmunización Secundaria , Memoria Inmunológica , Lentivirus , Melanoma/prevención & control , Virus Vaccinia , Antígeno gp100 del Melanoma/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Vacunas contra el Cáncer/inmunología , Línea Celular Tumoral , Humanos , Melanoma/genética , Melanoma/inmunología , Ratones , Ratones Transgénicos , Neoplasias Experimentales/genética , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/prevención & control , Antígeno gp100 del Melanoma/genética
16.
Front Immunol ; 14: 1114770, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37215108

RESUMEN

Background: The overall 5-year survival rate of hepatocellular carcinoma (HCC), a major form of liver cancer, is merely 20%, underscoring the need for more effective therapies. We recently identified T cell receptors (TCR) specific for the HLA-A2/alpha fetoprotein amino acids 158-166 (AFP158) and showed that these TCR engineered T cells could control HCC xenografts in NSG mice. However, their efficacy was limited by poor expansion, loss of function, and short persistence of the TCR T cells. Here, we studied whether overexpression of c-Jun, a transcription factor required for T cell activation, in the TCR T cells could enhance their expansion, function, and persistence in HCC tumor models. Methods: Recombinant lentiviral vectors (lv), expressing either the HLA-A2/AFP158-specific TCR or both the TCR and c-Jun (TCR-JUN), were constructed and used to transduce primary human T cells to generate the TCR or TCR-JUN T cells, respectively. We compared the expansion, effector function, and exhaustion status of the TCR and TCR-JUN T cells in vitro after HCC tumor stimulation. Additionally, we studied the persistence and antitumor effects of the TCR and TCR-JUN T cells using the HCC xenografts in NSG mice. Results: We could effectively transduce primary human T cells to express both TCR and c-Jun. Compared to the HLA-A2/AFP158 TCR T cells, the TCR-JUN T cells have better expansion potential in culture, with enhanced functional capacity against HCC tumor cells. In addition, the TCR-JUN T cells were less apoptotic and more resistant to exhaustion after HepG2 tumor stimulation. In the HCC xenograft tumor model, c-Jun overexpression enhanced the TCR T cell expansion and increased the overall survival rate of the treated mice. Importantly, the TCR-JUN T cells were less exhausted in the tumor lesions and demonstrated enhanced tumor infiltration, functionality, and persistence. Conclusion: c-Jun overexpression can enhance the expansion, function, and persistence of the A2/AFP158 TCR engineered T cells. The c-Jun gene co-delivery has the potential to enhance the antitumor efficacy of AFP specific TCR T cells when treating patients with HCC.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Ratones , Animales , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/metabolismo , alfa-Fetoproteínas/genética , Antígeno HLA-A2/genética , Antígeno HLA-A2/metabolismo , Genes jun , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T
17.
J Clin Invest ; 133(11)2023 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-37040183

RESUMEN

Many patients with hepatocellular carcinoma (HCC) do not respond to the first-line immune checkpoint inhibitor treatment. Immunization with effective cancer vaccines is an attractive alternative approach to immunotherapy. However, its efficacy remains insufficiently evaluated in preclinical studies. Here, we investigated HCC-associated self/tumor antigen, α-fetoprotein-based (AFP-based) vaccine immunization for treating AFP (+) HCC mouse models. We found that AFP immunization effectively induced AFP-specific CD8+ T cells in vivo. However, these CD8+ T cells expressed exhaustion markers, including PD1, LAG3, and Tim3. Furthermore, the AFP vaccine effectively prevented c-MYC/Mcl1 HCC initiation when administered before tumor formation, while it was ineffective against full-blown c-MYC/Mcl1 tumors. Similarly, anti-PD1 and anti-PD-L1 monotherapy showed no efficacy in this murine HCC model. In striking contrast, AFP immunization combined with anti-PD-L1 treatment triggered significant inhibition of HCC progression in most liver tumor nodules, while in combination with anti-PD1, it induced slower tumor progression. Mechanistically, we demonstrated that HCC-intrinsic PD-L1 expression was the primary target of anti-PD-L1 in this combination therapy. Notably, the combination therapy had a similar therapeutic effect in the cMet/ß-catenin mouse HCC model. These findings suggest that combining the AFP vaccine and immune checkpoint inhibitors may be effective for AFP (+) HCC treatment.


Asunto(s)
Vacunas contra el Cáncer , Carcinoma Hepatocelular , Neoplasias Hepáticas , Ratones , Animales , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , alfa-Fetoproteínas/genética , alfa-Fetoproteínas/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Linfocitos T CD8-positivos , Vacunas contra el Cáncer/uso terapéutico
18.
J Immunol ; 185(9): 5082-92, 2010 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-20926790

RESUMEN

Despite intensive effort, the antitumor efficacy of tumor vaccines remains limited in treating established tumors regardless of the potent systemic tumor-specific immune response and the increases of tumor infiltration of T effector cells. In the current study, we demonstrated that although lentivector (lv) immunization markedly increased Ag-dependent tumor infiltration of CD8 and CD4 T cells and generated Ag-specific antitumor effect, it simultaneously increased the absolute number of myeloid-derived suppressor cells and regulatory T cells in the tumor lesions. In addition, lv immunization induced expression of programmed death-ligand 1 in the tumor lesions. Furthermore, the tumor-infiltrating CD8 T cells expressed high levels of programmed death-1 and were partially dysfunctional, producing lower amounts of effector cytokines and possessing a reduced cytotoxicity. Together, these immune-suppression mechanisms in the tumor microenvironment pose a major obstacle to effective tumor immunotherapy and may explain the limited antitumor efficacy of lv immunization. The loss of effector function in the tumor microenvironment is reversible, and the effector function of CD8 T cells in the tumor could be partially rescued by blocking programmed death-1 and programmed death-ligand 1 pathway in vitro and in vivo, resulting in enhanced antitumor efficacy of lv immunization. These data suggest that immunization alone may exacerbate immune suppression in the tumor lesions and that methods to improve the tumor microenvironment and to rescue the effector functions of tumor-infiltrating T cells should be incorporated into immunization strategies to achieve enhanced antitumor efficacy.


Asunto(s)
Antígenos de Superficie/inmunología , Proteínas Reguladoras de la Apoptosis/inmunología , Vacunas contra el Cáncer/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias Experimentales/inmunología , Linfocitos T/inmunología , Traslado Adoptivo , Animales , Antígenos de Neoplasias/inmunología , Antígenos de Superficie/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Separación Celular , Citometría de Flujo , Vectores Genéticos , Tolerancia Inmunológica/inmunología , Inmunoterapia/métodos , Lentivirus , Linfocitos Infiltrantes de Tumor/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neoplasias Experimentales/terapia , Receptor de Muerte Celular Programada 1 , Linfocitos T/metabolismo
19.
Front Immunol ; 13: 1032403, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36325345

RESUMEN

The overall efficacy of chimeric antigen receptor modified T cells (CARTs) remain limited in solid tumors despite intensive studies that aim at targeting multiple antigens, enhancing migration, reducing tonic signaling, and improving tumor microenvironment. On the other hand, how the affinity and engaging kinetics of antigen-binding domain (ABD) affects the CART's efficacy has not been carefully investigated. In this article, we first analyzed 38 published solid tumor CART trials and correlated the response rate to their ABD affinity. Not surprisingly, majority (25 trials) of the CARTs utilized high-affinity ABDs, but generated merely 5.7% response rate. In contrast, 35% of the patients treated with the CARTs built from moderate-affinity ABDs had clinical responses. Thus, CARTs with moderate-affinity ABDs not only have less off-target toxicity, but also are more effective. We then reviewed the effects of ABD affinity on the biology and function of CARTs, providing further evidence that moderate-affinity ABDs may be better in CART development. In the end, we propose that a fast-on/fast-off (high Kon and Koff ) kinetics of CART-target engagement in solid tumor allow CARTs to generate sufficient signaling to kill tumor cells without being driven to exhaustion. We believe that studying the ABD affinity and the kinetics of CART-tumor interaction may hold a key to designing effective CARTs for solid tumors.


Asunto(s)
Neoplasias , Receptores Quiméricos de Antígenos , Humanos , Receptores de Antígenos de Linfocitos T , Inmunoterapia Adoptiva/efectos adversos , Receptores Quiméricos de Antígenos/genética , Linfocitos T , Microambiente Tumoral
20.
Blood ; 113(24): 6102-11, 2009 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-19366986

RESUMEN

The immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) is expressed by a subset of murine plasmacytoid DCs (pDCs) in tumor-draining lymph nodes (TDLNs), where it can potently activate Foxp3+ regulatory T cells (Tregs). We now show that IDO functions as a molecular switch in TDLNs, maintaining Tregs in their normal suppressive phenotype when IDO was active, but allowing inflammation-induced conversion of Tregs to a polyfunctional T-helper phenotype similar to proinflammatory T-helper-17 (TH17) cells when IDO was blocked. In vitro, conversion of Tregs to the TH17-like phenotype was driven by antigen-activated effector T cells and required interleukin-6 (IL-6) produced by activated pDCs. IDO regulated this conversion by dominantly suppressing production of IL-6 in pDCs, in a GCN2-kinase dependent fashion. In vivo, using a model of established B16 melanoma, the combination of an IDO-inhibitor drug plus antitumor vaccine caused up-regulation of IL-6 in pDCs and in situ conversion of a majority of Tregs to the TH17 phenotype, with marked enhancement of CD8+ T-cell activation and antitumor efficacy. Thus, Tregs in TDLNs can be actively reprogrammed in situ into T-helper cells, without the need for physical depletion, and IDO serves as a key regulator of this critical conversion.


Asunto(s)
Factores de Transcripción Forkhead/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/fisiología , Ganglios Linfáticos/inmunología , Melanoma Experimental/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología , Traslado Adoptivo , Animales , Western Blotting , Vacunas contra el Cáncer/uso terapéutico , Pollos , Células Dendríticas/inmunología , Inmunofenotipificación , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Ganglios Linfáticos/enzimología , Activación de Linfocitos , Melanoma Experimental/enzimología , Melanoma Experimental/patología , Ratones , Ratones Noqueados , Ratones Transgénicos , Ovalbúmina/fisiología , Receptores de Antígenos de Linfocitos T/fisiología , Linfocitos T Colaboradores-Inductores/patología
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