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1.
J Immunother Cancer ; 8(1)2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32581053

RESUMO

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer related to asbestos exposure. The tumor microenvironment content, particularly the presence of macrophages, was described as crucial for the development of the disease. This work aimed at studying the involvement of the M-CSF (CSF-1)/IL-34/CSF-1R pathway in the formation of macrophages in MPM, using samples from patients. METHODS: Pleural effusions (PEs), frozen tumors, primary MPM cells and MPM cell lines used in this study belong to biocollections associated with clinical databases. Cytokine expressions were studied using real-time PCR and ELISA. The Cancer Genome Atlas database was used to confirm our results on an independent cohort. An original three-dimensional (3D) coculture model including MPM cells, monocytes from healthy donors and a tumor antigen-specific cytotoxic CD8 T cell clone was used. RESULTS: We observed that high interleukin (IL)-34 levels in PE were significantly associated with a shorter survival of patients. In tumors, expression of CSF1 was correlated with 'M2-like macrophages' markers, whereas this was not the case with IL34 expression, suggesting two distinct modes of action of these cytokines. Expression of IL34 was higher in MPM cells compared with primary mesothelial cells. Particularly, high expression of IL34 was observed in MPM cells with an alteration of CDKN2A. Finally, using 3D coculture model, we demonstrated the direct involvement of MPM cells in the formation of immunosuppressive macrophages, through activation of the colony stimulating factor-1 receptor (CSF1-R) pathway, causing the inhibition of cytotoxicity of tumor antigen-specific CD8+ T cells. CONCLUSIONS: The M-CSF/IL-34/CSF-1R pathway seems strongly implicated in MPM and could constitute a therapeutic target to act on immunosuppression and to support immunotherapeutic strategies.

3.
J Thorac Oncol ; 15(5): 827-842, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31945495

RESUMO

INTRODUCTION: Oncolytic immunotherapy is based on the use of nonpathogenic replicative oncolytic viruses that infect and kill tumor cells exclusively. Recently, we found that the spontaneous oncolytic activity of the Schwarz strain of measles virus (MV) against human malignant pleural mesothelioma (MPM) depends on defects in the antiviral type I interferon (IFN-I) response in tumor cells. METHODS: In this study, we studied three independent human MPM bio-collections to identify the defects in the IFN-I responses in tumor cells. RESULTS: We show that the most frequent defect is the homozygous deletions (HDs) of all the 14 IFN-I genes (IFN-α and IFN-ß) that we found in more than half of MV-sensitive MPM cell lines. These HDs occur together with the HDs of the tumor suppressor gene CDKN2A also located in the 9p21.3 chromosome region. Therefore, the IFN-I-/- MPM cell lines develop a partial and weak IFN-I response when they are exposed to the virus compared with that of normal cells and MV-resistant MPM cell lines. This response consists of the expression of a restricted number of IFN-stimulated genes that do not depend on the presence of IFN-I. In addition, the IFN-I-/- MPM cell lines infected by MV also develop a pro-inflammatory response associated with stress of the endoplasmic reticulum. CONCLUSION: Our study emphasizes the link between HDs of IFN-I encoding genes and the CDKN2A gene in MPM and sensitivity to MV oncolytic immunotherapy.

4.
Methods Mol Biol ; 2058: 127-132, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31486035

RESUMO

Oncolytic immunotherapy efficacy relies partially on the induction of immunogenic tumor cell death following infection with oncolytic viruses (OV) to induce an antitumor immune response. Here, we describe a method to determine if an OV is able to induce such an immunogenic tumor cell death. This method consists in testing whether tumor cells lysed by an OV are able to induce the maturation of human monocyte-derived immature dendritic cells (Mo-iDC).

5.
Oncotarget ; 9(23): 16311-16329, 2018 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-29662647

RESUMO

Sarcomatoid mesothelioma (SM) is a devastating cancer associated with one of the poorest outcome. Therefore, representative preclinical models reproducing different tumor microenvironments (TME) observed in patients would open up new prospects for the identification of markers and evaluation of innovative therapies. Histological analyses of four original models of rat SM revealed their increasing infiltrative and metastatic potential were associated with differences in Ki67 index, blood-vessel density, and T-lymphocyte and macrophage infiltration. In comparison with the noninvasive tumor M5-T2, proteomic analysis demonstrated the three invasive tumors F4-T2, F5-T1 and M5-T1 shared in common a very significant increase in the abundance of the multifunctional proteins galectin-3, prohibitin and annexin A5, and a decrease in proteins involved in cell adhesion, tumor suppression, or epithelial differentiation. The increased metastatic potential of the F5-T1 tumor, relative to F4-T2, was associated with an increased macrophage vs T-cell infiltrate, changes in the levels of expression of a panel of cytokine genes, an increased content of proteins involved in chromatin organization, ribosome structure, splicing, or presenting anti-adhesive properties, and a decreased content of proteins involved in protection against oxidative stress, normoxia and intracellular trafficking. The most invasive tumor, M5-T1, was characterized by a pattern of specific phenotypic and molecular features affecting the presentation of MHC class I-mediated antigens and immune cell infiltration, or involved in the reorganization of the cytoskeleton and composition of the extracellular matrix. These four preclinical models and data represent a new resource available to the cancer research community to catalyze further investigations on invasiveness.

6.
Oncoimmunology ; 7(3): e1407897, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29399408

RESUMO

Oncolytic immunotherapy using oncolytic viruses (OV) has been shown to stimulate the antitumor immune response by inducing the release of tumor-associated antigens (TAA) and danger signals from the dying infected tumor cells. In this study, we sought to determine if the lysis of tumor cells induced by different OV: measles virus, vaccinia virus, vesicular stomatitis virus, herpes simplex type I virus, adenovirus or enterovirus, has consequences on the capacity of tumor cells to present TAA, such as NY-ESO-1. We show that the co-culture of NY-ESO-1neg/HLA-DP4pos melanoma cells with NY-ESO-1pos/HLA-DP4neg melanoma cells infected and killed by different OV induces an intercellular transfer of NY-ESO-1 that allows the recognition of NY-ESO-1neg/HLA-DP4pos tumor cells by an HLA-DP4/NY-ESO-1(157-170)-specific CD4+ cytotoxic T cell clone, NY67. We then confirmed this result in a second model with an HLA-DP4+ melanoma cell line that expresses a low amount of NY-ESO-1. Recognition of this cell line by the NY67 clone is largely increased in the presence of OV productive infection. Altogether, our results show for the first time another mechanism of stimulation of the anti-tumor immune response by OV, via the loading of tumor cells with TAA that sensitizes them for direct recognition by specific effector CD4+ T cells, supporting the use of OV for cancer immunotherapy.

7.
Cancer Immunol Res ; 5(11): 1029-1045, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29038298

RESUMO

Understanding how incompletely cleared primary tumors transition from minimal residual disease (MRD) into treatment-resistant, immune-invisible recurrences has major clinical significance. We show here that this transition is mediated through the subversion of two key elements of innate immunosurveillance. In the first, the role of TNFα changes from an antitumor effector against primary tumors into a growth promoter for MRD. Second, whereas primary tumors induced a natural killer (NK)-mediated cytokine response characterized by low IL6 and elevated IFNγ, PD-L1hi MRD cells promoted the secretion of IL6 but minimal IFNγ, inhibiting both NK-cell and T-cell surveillance. Tumor recurrence was promoted by trauma- or infection-like stimuli inducing VEGF and TNFα, which stimulated the growth of MRD tumors. Finally, therapies that blocked PD-1, TNFα, or NK cells delayed or prevented recurrence. These data show how innate immunosurveillance mechanisms, which control infection and growth of primary tumors, are exploited by recurrent, competent tumors and identify therapeutic targets in patients with MRD known to be at high risk of relapse. Cancer Immunol Res; 5(11); 1029-45. ©2017 AACR.


Assuntos
Células Matadoras Naturais/imunologia , Melanoma Experimental/imunologia , Recidiva Local de Neoplasia/imunologia , Neoplasias Cutâneas/imunologia , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Anticorpos/uso terapêutico , Linhagem Celular Tumoral , Citocinas/imunologia , Feminino , Ganciclovir/uso terapêutico , Vigilância Imunológica , Melanoma Experimental/terapia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Terapia Viral Oncolítica , Paclitaxel/uso terapêutico , Reoviridae , Neoplasias Cutâneas/terapia , Linfócitos T/transplante
9.
Oncoimmunology ; 6(1): e1261240, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28197384

RESUMO

Attenuated measles virus (MV) is currently being evaluated in clinical trials as an oncolytic therapeutic agent. Originally used for its lytic activity against tumor cells, it is now admitted that the effectiveness of MV also lies in its ability to initiate antitumor immune responses through the activation of dendritic cells (DCs). In this study, we investigated the capacity of oncolytic MV to convert human blood myeloid CD1c+ DCs and plasmacytoid DCs (pDCs) into cytotoxic effectors. We found that MV induces the expression of the cytotoxic protein TNF-related apoptosis-inducing ligand (TRAIL) on the surface of DCs. We demonstrate that the secretion of interferon-α (IFN-α) by DCs in response to MV is responsible for this TRAIL expression. Several types of PRRs (pattern recognition receptors) have been implicated in MV genome recognition, including RLRs (RIG-I-like receptors) and TLRs (Toll-like receptors). We showed that CD1c+ DCs secrete modest amounts of IFN-α and express TRAIL in an RLR-dependent manner upon exposure to MV. In pDCs, MV is recognized by RLRs and also by TLR7, leading to the secretion of high amounts of IFN-α and TRAIL expression. Finally, we showed that MV-stimulated DCs induce TRAIL-mediated cell death of Jurkat cells, confirming their acquisition of cytotoxic functions. Our results demonstrate that MV can activate cytotoxic myeloid CD1c+ DCs and pDCs, which may participate to the antitumor immune response.

10.
Curr Gene Ther ; 16(6): 419-428, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28042780

RESUMO

BACKGROUND: Oncolytic viruses such as live-attenuated, vaccine strains of measles virus (MV) have recently emerged as promising cancer treatments, having shown significant antitumor activity against a large variety of human tumors. OBJECTIVE: Our study aims at determining which parameters define the sensitivity of human melanoma cells to oncolytic MV infection. METHODS: We analyzed both in vitro and in vivo the oncolytic activity of MV against a panel of human melanoma cell established in our laboratory. We tested whether either type I interferons or the interferon pathway inhibitor Ruxolitinib could modulate the sensitivity of these cells to oncolytic MV infection. RESULTS: Human melanoma cells exhibit varying levels of sensitivity to MV infection in culture and as tumor xenografts. As these differences are not explained by their expression level of the CD46 receptor, we hypothesized that antiviral immune responses may be suppressed in certain cell resulting in their inability to control infection efficiently. By analyzing the type I IFN response, we found that resistant cells had a fully functional pathway that was activated upon MV infection. On the contrary, sensitive cell showed defects in this pathway. When pre-treated with IFN-α and IFN-ß, all but one of the sensitive cell became resistant to MV. Cells resistant to MV were rendered sensitive to MV with Ruxolitinib. CONCLUSION: Type I interferon response is the main determinant for the sensitivity or resistance of melanoma to oncolytic MV infection. This will have to be taken into account for future clinical trials on oncolytic MV.


Assuntos
Interferon Tipo I/uso terapêutico , Vírus do Sarampo/genética , Melanoma/terapia , Terapia Viral Oncolítica , Animais , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Interferon Tipo I/genética , Melanoma/genética , Melanoma/virologia , Proteína Cofatora de Membrana/genética , Camundongos , Vírus Oncolíticos/genética , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Oncotarget ; 6(42): 44892-904, 2015 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-26539644

RESUMO

Attenuated measles virus (MV) is currently being evaluated as an oncolytic virus in clinical trials and could represent a new therapeutic approach for malignant pleural mesothelioma (MPM). Herein, we screened the sensitivity to MV infection and replication of twenty-two human MPM cell lines and some healthy primary cells. We show that MV replicates in fifteen of the twenty-two MPM cell lines. Despite overexpression of CD46 by a majority of MPM cell lines compared to healthy cells, we found that the sensitivity to MV replication did not correlate with this overexpression. We then evaluated the antiviral type I interferon (IFN) responses of MPM cell lines and healthy cells. We found that healthy cells and the seven insensitive MPM cell lines developed a type I IFN response in presence of the virus, thereby inhibiting replication. In contrast, eleven of the fifteen sensitive MPM cell lines were unable to develop a complete type I IFN response in presence of MV. Finally, we show that addition of type I IFN onto MV sensitive tumor cell lines inhibits replication. These results demonstrate that defects in type I IFN response are frequent in MPM and that MV takes advantage of these defects to exert oncolytic activity.


Assuntos
Interferon Tipo I/metabolismo , Vírus do Sarampo/crescimento & desenvolvimento , Mesotelioma/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/crescimento & desenvolvimento , Neoplasias Pleurais/terapia , Replicação Viral , Antígenos CD/metabolismo , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Interações Hospedeiro-Patógeno , Humanos , Interferon Tipo I/imunologia , Vírus do Sarampo/imunologia , Vírus do Sarampo/metabolismo , Proteína Cofatora de Membrana/metabolismo , Mesotelioma/imunologia , Mesotelioma/metabolismo , Mesotelioma/virologia , Vírus Oncolíticos/imunologia , Vírus Oncolíticos/metabolismo , Neoplasias Pleurais/imunologia , Neoplasias Pleurais/metabolismo , Neoplasias Pleurais/virologia , Receptores de Superfície Celular/metabolismo , Transdução de Sinais , Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária , Fatores de Tempo
12.
Oncolytic Virother ; 4: 133-40, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-27512676

RESUMO

Cancer virotherapy is an attractive alternative to conventional treatments because it offers a wide range of antitumor effects due to 1) the diversity of the oncolytic viruses that are now available and 2) their multifaceted activities against both tumor cells and tumor vessels, in addition to their ability to induce antitumor immune responses. In this review, we summarize preclinical and clinical data regarding the targeting of malignant mesothelioma (MM) by oncolytic viruses. We also discuss the potential of other oncolytic viruses that have already shown antitumor effects against several malignancies in advanced clinical trials but are yet to be tested against MM cells. Finally, we review how the activation of the immune system and combinations with other types of anticancer treatments could support the development of oncolytic virotherapy for the treatment of MM.

13.
Mol Ther ; 23(5): 845-856, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25544599

RESUMO

We used a VSV-cDNA library to treat recurrent melanoma, identifying immunogenic antigens, allowing us to target recurrences with immunotherapy or chemotherapy. Primary B16 melanoma tumors were induced to regress by frontline therapy. Mice with recurrent tumors were treated with VSV-cDNA immunotherapy. A Th17 recall response was used to screen the VSV-cDNA library for individual viruses encoding rejection antigens, subsequently targeted using immunotherapy or chemotherapy. Recurrent tumors were effectively treated with a VSV-cDNA library using cDNA from recurrent B16 tumors. Recurrence-associated rejection antigens identified included Topoisomerase-IIα, YB-1, cdc7 kinase, and BRAF. Fourteen out of 16 recurrent tumors carried BRAF mutations (595-605 region) following frontline therapy, even though the parental B16 tumors were BRAF wild type. The emergence of mutated BRAF-containing recurrences served as an excellent target for BRAF-specific immune-(VSV-BRAF), or chemo-(PLX-4720) therapies. Successful PLX-4720 therapy of recurrent tumors was associated with the development of a broad spectrum of T-cell responses. VSV-cDNA technology can be used to identify recurrence specific antigens. Emergence of mutated BRAF may be a major effector of melanoma recurrence which could serve as a target for chemo or immune therapy. This study suggests a rationale for offering patients with initially wild-type BRAF melanomas an additional biopsy to screen for mutant BRAF upon recurrence.


Assuntos
Melanoma/genética , Melanoma/patologia , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Antígenos de Neoplasias/imunologia , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Sequência de Bases , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Ganciclovir/farmacologia , Expressão Gênica , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/farmacologia , Masculino , Melanoma/tratamento farmacológico , Melanoma/imunologia , Melanoma Experimental , Camundongos , Dados de Sequência Molecular , Recidiva Local de Neoplasia , Proteínas Proto-Oncogênicas B-raf/química , Timidina Quinase/genética
14.
Oncoimmunology ; 3: e27811, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25339997

RESUMO

Monitoring and treating dormant tumors represents a major clinical challenge. We have recently found that early recurring tumors elicit an innate immune response that can be detected systemically. We also demonstrated that it may be possible to target minimal residual disease before or after immune evasion with carefully timed, rational therapeutic approaches.

16.
Nat Med ; 19(12): 1625-1631, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24240185

RESUMO

Tumor recurrence represents a major clinical challenge. Our data show that emergent recurrent tumors acquire a phenotype radically different from that of their originating primary tumors. This phenotype allows them to evade a host-derived innate immune response elicited by the progression from minimal residual disease (MRD) to actively growing recurrence. Screening for this innate response predicted accurately in which mice recurrence would occur. Premature induction of recurrence resensitized MRD to the primary therapy, suggesting a possible paradigm shift for clinical treatment of dormant disease in which the current expectant approach is replaced with active attempts to uncover MRD before evolution of the escape phenotype is complete. By combining screening with second-line treatments targeting innate insensitivity, up to 100% of mice that would have otherwise relapsed were cured. These data may open new avenues for early detection and appropriately timed, highly targeted treatment of tumor recurrence irrespective of tumor type or frontline treatment.


Assuntos
Imunidade Inata/fisiologia , Melanoma Experimental/diagnóstico , Recidiva Local de Neoplasia/diagnóstico , Neoplasias Cutâneas/diagnóstico , Linfócitos T/imunologia , Evasão Tumoral/fisiologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Detecção Precoce de Câncer/métodos , Feminino , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/imunologia , Neoplasia Residual , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Células Tumorais Cultivadas
17.
Mol Ther ; 21(8): 1507-16, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23752316

RESUMO

Aggressive regrowth of recurrent tumors following treatment-induced dormancy represents a major clinical challenge for treatment of malignant disease. We reported previously that recurrent prostate tumors, which underwent complete macroscopic regression followed by aggressive regrowth, could be cured with a vesicular stomatitis virus (VSV)-expressed cDNA library derived from recurrent tumor cells. By screening the protective, recurrence-derived VSV-cDNA library, here we identify topoisomerase-IIα (TOPO-IIα) as a recurrence-specific tumor antigen against which tolerance can be broken. Tumor recurrences, in two different types of tumor (prostate and melanoma), which had evaded two different frontline treatments (immunotherapy or chemotherapy), significantly overexpressed TOPO-IIα compared with their primary tumor counterparts, which conferred a novel sensitivity to doxorubicin (DOX) chemotherapy upon the recurrent tumors. This was exploited in vivo using combination therapies to cure mice, which would otherwise have relapsed, after suboptimal primary therapy in both models. Our data show that recurrent tumors-across histologies and primary treatments-express distinct antigens compared with the primary tumor which can be identified using the VSV-cDNA library technology. These results suggest that it may be possible to design a few common second-line therapies against a variety of tumor recurrences, in some cases using agents with no obvious activity against the primary tumor.


Assuntos
Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Neoplasias/genética , Neoplasias/imunologia , Animais , Antibióticos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , DNA Topoisomerases Tipo II/genética , DNA Topoisomerases Tipo II/imunologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Modelos Animais de Doenças , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Epitopos/genética , Epitopos/imunologia , Expressão Gênica , Biblioteca Gênica , Terapia Genética , Vetores Genéticos/genética , Humanos , Imunoterapia , Masculino , Melanoma/genética , Melanoma/imunologia , Camundongos , Neoplasias/mortalidade , Neoplasias/terapia , Fenótipo , Neoplasias da Próstata/genética , Neoplasias da Próstata/imunologia , Recidiva , Inibidores da Topoisomerase II/farmacologia , Evasão Tumoral/genética , Evasão Tumoral/imunologia , Vírus da Estomatite Vesicular Indiana/genética
18.
Biomed Res Int ; 2013: 387362, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23586034

RESUMO

Lung and colorectal cancers are responsible for approximately 2 million deaths each year worldwide. Despite continual improvements, clinical management of these diseases remains challenging and development of novel therapies with increased efficacy is critical to address these major public health issues. Oncolytic viruses have shown promising results against cancers that are resistant to conventional anticancer therapies. Vaccine strains of measles virus (MV) exhibit such natural antitumor properties by preferentially targeting cancer cells. We tested the ability of live-attenuated Schwarz strain of MV to specifically infect tumor cells derived from human lung and colorectal adenocarcinomas and demonstrated that live-attenuated MV exhibits oncolytic properties against these two aggressive neoplasms. We also showed that Schwarz MV was able to prevent uncontrollable growth of large, established lung and colorectal adenocarcinoma xenografts in nude mice. Moreover, MV oncolysis is associated with in vivo activation of caspase-3 in colorectal cancer model, as shown by immunohistochemical staining. Our results provide new arguments for the use of MV as an antitumor therapy against aggressive human malignancies.


Assuntos
Adenocarcinoma/terapia , Neoplasias Colorretais/terapia , Neoplasias Pulmonares/terapia , Terapia Viral Oncolítica , Vacinas Atenuadas/administração & dosagem , Adenocarcinoma/patologia , Adenocarcinoma/virologia , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Neoplasias Colorretais/virologia , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/virologia , Sarampo/prevenção & controle , Sarampo/virologia , Vacina contra Sarampo/administração & dosagem , Vírus do Sarampo/patogenicidade , Camundongos , Transplante Heterólogo
19.
Clin Cancer Res ; 19(5): 1147-58, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23339127

RESUMO

PURPOSE: Plasmacytoid dendritic cells (pDC) are antigen-presenting cells specialized in antiviral response. The measles virus vaccine is proposed as an antitumor agent to target and specifically kill tumor cells without infecting healthy cells. EXPERIMENTAL DESIGN: Here, we investigated, in vitro, the effects of measles virus vaccine-infected tumor cells on the phenotype and functions of human pDC. We studied maturation and tumor antigen cross-presentation by pDC, exposed either to the virus alone, or to measles virus vaccine-infected or UV-irradiated tumor cells. RESULTS: We found that only measles virus vaccine-infected cells induced pDC maturation with a strong production of IFN-α, whereas UV-irradiated tumor cells were unable to activate pDC. This IFN-α production was triggered by the interaction of measles virus vaccine single-stranded RNA (ssRNA) with TLR7. We observed that measles virus vaccine-infected tumor cells were phagocytosed by pDC. Interestingly, we showed cross-presentation of the tumor antigen NYESO-1 to a specific CD8(+) T-cell clone when pDC were cocultured with measles virus vaccine-infected tumor cells, whereas pDC were unable to cross-present NYESO-1 after coculture with UV-irradiated tumor cells. CONCLUSIONS: Altogether, our results suggest that the use of measles virus vaccine in antitumor virotherapy induces immunogenic tumor cell death, allowing pDC to mature, produce high amounts of IFN-α, and cross-present tumor antigen, thus representing a mode of recruiting these antigen-presenting cells in the immune response. Clin Cancer Res; 19(5); 1147-58. ©2012 AACR.


Assuntos
Antígenos de Neoplasias/imunologia , Apresentação Cruzada/imunologia , Células Dendríticas/imunologia , Vacina contra Sarampo/farmacologia , Neoplasias/imunologia , Terapia Viral Oncolítica , Fagocitose/imunologia , Western Blotting , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Proliferação de Células , Células Cultivadas , Células Dendríticas/metabolismo , Células Dendríticas/virologia , Imunofluorescência , Humanos , Interferon-alfa/metabolismo , Interleucina-3/farmacologia , Proteína Cofatora de Membrana/imunologia , Proteína Cofatora de Membrana/metabolismo , Neoplasias/terapia , Neoplasias/virologia , RNA Mensageiro/genética , RNA Viral/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptor 7 Toll-Like/metabolismo
20.
Biol Res ; 45(1): 33-43, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22688982

RESUMO

Dendritic cells (DCs) are professional antigen-presenting cells involved in the control and initiation of immune responses. In vivo, DCs exposed at the periphery to maturation stimuli migrate to lymph nodes, where they receive secondary signals from CD4+ T helper cells. These DCs become able to initiate CD8+ cytotoxic T lymphocyte (CTL) responses. However, in vitro investigations concerning human monocyte-derived DCs have never focused on their functional properties after such sequential maturation. Here, we studied human DC phenotypes and functions according to this sequential exposure to maturation stimuli. As first signals, we used TNF-α/polyI:C mimicking inflammatory and pathogen stimuli and, as second signals, we compared activated CD4+ T helper cells to a combination of CD40-L/ IFN-γ. Our results show that a sequential activation with activated CD4+ T cells dramatically increased the maturation of DCs in terms of their phenotype and cytokine secretion compared to DCs activated with maturation stimuli delivered simultaneously. Furthermore, this sequential maturation led to the induction of CTL with a long-term effector and central memory phenotypes. Thus, sequential delivery of maturation stimuli, which includes CD4+ T cells, should be considered in the future to improve the induction of long-term CTL memory in DC-based immunotherapy.


Assuntos
Antígenos CD4/análise , Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Memória Imunológica/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Células Cultivadas , Células Dendríticas/citologia , Humanos , Imunofenotipagem , Imunoterapia , Interferon gama/imunologia , Ativação Linfocitária , Fator de Necrose Tumoral alfa/imunologia
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