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1.
Cells ; 9(4)2020 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-32290265

RESUMO

Immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment providing unprecedented clinical benefits. However, many patients do not respond to ICIs as monotherapy or develop resistance. Combining ICI-based immunotherapy with chemotherapy is a promising strategy to increase response rates, but few rationale-driven chemo-immunotherapy combinations have reached the clinical arena thus far. In the present study, we show that combined anti-PDL1 and anti-PDL2 antibodies optimally synergize with cyclophosphamide but not with cisplatin, and that the magnitude and duration of the therapeutic response is dependent on the immunogenic potential of the drug and of the tumor itself. Hallmarks of successful therapeutic outcomes were the enhanced infiltration by myeloid (mainly cross-presenting dendritic cells, eosinophils, and monocytic myeloid cells) and T lymphocytes into the tumor tissue and the expansion of circulating memory pools. Overall, our results suggest that immunomodulating chemotherapy can be exploited to increase the efficacy of PD1/PDL axis inhibitors in vivo, and that the magnitude of the synergic therapeutic response is affected by tumor-intrinsic immunogenicity.


Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Feminino , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Camundongos , Modelos Animais
2.
Cancer Immunol Immunother ; 68(11): 1791-1804, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31620858

RESUMO

The perspective of combining cancer vaccines with immunomodulatory drugs is currently regarded as a highly promising approach for boosting tumor-specific T cell immunity and eradicating residual malignant cells. The efficacy of dendritic cell (DC) vaccination in combination with lenalidomide, an anticancer drug effective in several hematologic malignancies, was investigated in a follicular lymphoma (FL) model. First, we evaluated the in vitro activity of lenalidomide in modulating the immune responses of lymphocytes co-cultured with a new DC subset differentiated with IFN-α (IFN-DC) and loaded with apoptotic lymphoma cells. We next evaluated the efficacy of lenalidomide and IFN-DC-based vaccination, either alone or in combination, in hu-PBL-NOD/SCID mice bearing established human lymphoma. We found that lenalidomide reduced Treg frequency and IL-10 production in vitro, improved the formation of immune synapses of CD8 + lymphocytes with lymphoma cells and enhanced anti-lymphoma cytotoxicity. Treatment of lymphoma-bearing mice with either IFN-DC vaccination or lenalidomide led to a significant decrease in tumor growth and lymphoma cell spread. Lenalidomide treatment was shown to substantially inhibit tumor-induced neo-angiogenesis rather than to exert a direct cytotoxic effect on lymphoma cells. Notably, the combined treatment with the vaccine plus lenalidomide was more effective than either single treatment, resulting in the significant regression of established tumors and delayed tumor regrowth upon treatment discontinuation. In conclusion, our data demonstrate that IFN-DC-based vaccination plus lenalidomide exert an additive therapeutic effect in xenochimeric mice bearing established lymphoma. These results may pave the way to evaluate this combination in the clinical ground.


Assuntos
Vacinas Anticâncer/administração & dosagem , Células Dendríticas/imunologia , Sinergismo Farmacológico , Fatores Imunológicos/imunologia , Interferon-alfa/imunologia , Lenalidomida/farmacologia , Linfoma Folicular/terapia , Animais , Terapia Combinada , Feminino , Humanos , Fatores Imunológicos/farmacologia , Linfoma Folicular/imunologia , Linfoma Folicular/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID
3.
Clin Cancer Res ; 25(17): 5231-5241, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31171545

RESUMO

PURPOSE: This study was aimed at evaluating the feasibility, safety, immunologic and clinical responses in patients with follicular lymphoma treated with monocyte-derived dendritic cells generated in the presence of IFNα and GM-CSF (IFN-DC) in combination with low doses of rituximab. PATIENTS AND METHODS: Firstly, we analyzed in vitro and in vivo the immunologic properties of IFN-DC against follicular lymphoma. Thus, we performed a phase I trial in 8 patients with refractory and relapsed follicular lymphoma based on sequential intranodal injections of low-dose of rituximab and unloaded IFN-DC and report the safety, clinical, and immunologic results of the enrolled patients. RESULTS: Preclinical studies indicated that IFN-DC can synergize with rituximab leading to increased cytotoxicity and T-cell tumor infiltration. The clinical evaluation showed that the combined treatment was totally safe. The overall response rate was 50%, PET-negative complete response rate 37%, and remission is still ongoing in 2/4 of responding patients (median follow-up 26 months, range 11-47). Notably, following the combined therapy all patients showed induction/enhancement of T-cell responses by CD107 degranulation or IFNγ ELISPOT assay against patient-specific tumor IGHV sequences. CONCLUSIONS: These results represent the proof-of-principle on the effectiveness of unloaded IFN-DC in inducing durable clinical responses and promoting induction of tumor-specific peripheral T cells, thus suggesting the occurrence of an effective endogenous antitumor vaccination. The overall findings indicate that some unique properties of IFN-DC can be successfully exploited to induce/enhance antitumor responses, thus representing a valuable antitumor strategy for novel and more effective combination therapies in patients with cancer.


Assuntos
Células Dendríticas/transplante , Imunoterapia Adotiva/métodos , Linfoma Folicular/terapia , Recidiva Local de Neoplasia/terapia , Rituximab/administração & dosagem , Adulto , Idoso , Animais , Antineoplásicos Imunológicos/administração & dosagem , Terapia Combinada , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Injeções Intralinfáticas , Interferon-alfa/farmacologia , Linfoma Folicular/imunologia , Linfoma Folicular/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Indução de Remissão , Terapia de Salvação , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Immunol ; 197(3): 795-806, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27357153

RESUMO

Follicular lymphoma (FL) is the most common form of indolent non-Hodgkin lymphoma. This malignancy is considered virtually incurable, with high response rates to therapy but frequent relapses. We investigated the ability of monocyte-derived dendritic cells generated in the presence of IFN-α and GM-CSF (IFN-DC) and loaded with apoptotic lymphoma cells to activate immune responses against FL cells, with the ultimate goal of designing novel patient-specific vaccination strategies for the treatment of FL. In this article, we show that apoptotic tumor cell-loaded IFN-DC from FL patients, which were cultured for 2 wk with autologous lymphocytes, led to Th1 response skewing, based on significantly higher levels of IFN-γ production and a remarkable increase in CD8(+) and NK cell frequency, consistent with the detection of enhanced cytotoxic effector function toward autologous FL cells. IFN-DC were found to promote efficient NK cell activation, increased expression of cytotoxicity receptors, and extensive IFN-γ production in the virtual absence of IL-10. Moreover, direct recognition and killing of primary autologous lymphoma cells by activated NK cells from FL patients was also demonstrated. A critical role was demonstrated for MHC class I-related chain A and B and membrane-bound IL-15 in IFN-DC-mediated NK cell activation and early IFN-γ production. The overall results indicate that IFN-DC loaded with autologous apoptotic FL cells represent a valuable tool for improving the potency of therapeutic cancer vaccines through the efficient induction of NK cell activation and promotion of CD8(+) T cell antitumor immunity.


Assuntos
Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária/imunologia , Linfoma Folicular , Apoptose/imunologia , Western Blotting , Técnicas de Cocultura , Citotoxicidade Imunológica , ELISPOT , Citometria de Fluxo , Humanos , Interferon-alfa/imunologia , Células Tumorais Cultivadas
5.
Blood ; 119(6): 1407-17, 2012 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-22184405

RESUMO

Cross-presentation allows antigen-presenting cells to present exogenous antigens to CD8(+) T cells, playing an essential role in controlling infections and tumor development. IFN-α induces the rapid differentiation of human mono-cytes into dendritic cells, known as IFN-DCs, highly efficient in mediating cross-presentation, as well as the cross-priming of CD8(+) T cells. Here, we have investigated the mechanisms underlying the cross-presentation ability of IFN-DCs by studying the intracellular sorting of soluble ovalbumin and nonstructural-3 protein of hepatitis C virus. Our results demonstrate that, independently from the route and mechanism of antigen entry, IFN-DCs are extraordinarily competent in preserving internalized proteins from early degradation and in routing antigens toward the MHC class-I processing pathway, allowing long-lasting, cross-priming capacity. In IFN-DCs, both early and recycling endosomes function as key compartments for the storage of both antigens and MHC-class I molecules and for proteasome- and transporter-associated with Ag processing-dependent auxiliary cross-presentation pathways. Because IFN-DCs closely resemble human DCs naturally occurring in vivo in response to infections and other danger signals, these findings may have important implications for the design of vaccination strategies in neoplastic or chronic infectious diseases.


Assuntos
Antígenos/metabolismo , Apresentação Cruzada/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Interferon-alfa/farmacologia , Antígenos/imunologia , Western Blotting , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Apresentação Cruzada/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Endossomos/química , Endossomos/metabolismo , Citometria de Fluxo , Hepacivirus/imunologia , Hepacivirus/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Microscopia Confocal , Ovalbumina/imunologia , Ovalbumina/metabolismo , Ovalbumina/farmacocinética , Proteínas não Estruturais Virais/imunologia , Proteínas não Estruturais Virais/metabolismo , Proteínas não Estruturais Virais/farmacocinética
6.
PLoS One ; 6(2): e17364, 2011 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-21387004

RESUMO

IFN-α exerts multiple effects leading to immune protection against pathogens and cancer as well to autoimmune reactions by acting on monocytes and dendritic cells. We analyzed the versatility of human monocytes conditioned by IFN-α towards dendritic cell differentiation (IFN-DC) in shaping the autologous T-helper response. Priming of naïve CD4 T cells with autologous IFN-DC in the presence of either SEA or anti-CD3, resulted, in addition to a prominent expansion of CXCR3+ IFN-γ-producing CD4 Th1 cells, in the emergence of two distinct subsets of IL-17-producing CD4 T cells: i) a predominant Th17 population selectively producing IL-17 and expressing CCR6; ii) a minor Th1/Th17 population, producing both IL-17 and IFN-γ. After phagocytosis of apoptotic cells, IFN-DC induced Th17 cell expansion and IL-17 release. Notably, the use of neutralizing antibodies revealed that IL-23 was an essential cytokine in mediating Th17 cell development by IFN-DC. The demonstration of the IFN-DC-induced expansion of both Th1 and Th17 cell populations reveals the intrinsic plasticity of these DC in orienting the immune response and provides a mechanistic link between IFN-α and the onset of autoimmune phenomena, which have been correlated with both IL-17 production and exposure to IFN-α.


Assuntos
Interferon-alfa/farmacologia , Interleucina-12/fisiologia , Interleucina-23/fisiologia , Monócitos/efeitos dos fármacos , Células Th1/fisiologia , Células Th17/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/fisiologia , Diferenciação Celular/efeitos dos fármacos , Polaridade Celular/efeitos dos fármacos , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Células Dendríticas/fisiologia , Humanos , Interleucina-12/metabolismo , Interleucina-23/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/fisiologia , Modelos Biológicos , Monócitos/metabolismo , Monócitos/fisiologia , Células Th1/efeitos dos fármacos , Células Th17/metabolismo , Células Th17/fisiologia , Células Th17/transplante
7.
Virology ; 395(1): 45-55, 2009 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-19800648

RESUMO

Here we report a novel strategy for the induction of CD8(+) T cell adaptive immune response against viral and tumor antigens. This approach relies on high levels of incorporation in HIV-1 VLPs of a mutant of HIV-1 Nef (Nef(mut)) which can act as anchoring element for foreign proteins. By in vitro assay, we found that VLP-associated Nef(mut) is efficiently cross-presented by antigen presenting cells. Inoculation in mice of VLPs incorporating the HPV-16 E7 protein fused to Nef(mut) led to an anti-E7 CD8(+) T cell response much stronger than that elicited by E7 recombinant protein inoculated with incomplete Freund's adjuvant and correlating with well-detectable anti-E7 CTL activity. Most relevantly, mice immunized with Nef(mut)-E7 VLPs developed a protective immune response against tumors induced by E7 expressing tumor cells. These results make Nef(mut) VLPs a promising candidate for new vaccine strategies focused on the induction of CD8(+) T cell immunity.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/imunologia , Proteínas Oncogênicas Virais/imunologia , Produtos do Gene nef do Vírus da Imunodeficiência Humana/imunologia , Imunidade Adaptativa , Animais , Linhagem Celular , Apresentação Cruzada , HIV-1/imunologia , Papillomavirus Humano 16/imunologia , Humanos , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas E7 de Papillomavirus , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/imunologia , Proteínas Recombinantes de Fusão/imunologia , Vírus da Estomatite Vesicular Indiana/imunologia , Proteínas do Envelope Viral/imunologia
8.
J Leukoc Biol ; 82(5): 1136-42, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17656653

RESUMO

The functional consequences of treating human monocytes with purified and chemically characterized Candida albicans beta-glucan -- a major microbial pathogen associated molecular pattern -- on their differentiation into dendritic cells (DC) were investigated. We show here that beta-glucan-treated monocytes differentiated into mature DC (Glu-MoDC) with altered phenotype and functional behavior, similarly to DC derived from C. albicans germ-tubes-infected monocytes (Gt-MoDC). They failed to express CD1a and to up-regulate CD80 and DR molecules. Moreover, they produced IL-10 but not IL-12 and primed naive T cells without inducing their functional polarization into effector cells. Since C. albicans beta-glucan is a mixture of both beta-(1,3) and beta-(1,6) glucan, we investigated their relative contribution by the use of non-Candida beta-glucan structural analogs. We found that high molecular weight (MW) glucans beta-(1,6) pustulan and beta-(1,3) curdlan totally mimicked the effect of C. albicans beta-glucan, while the low MW beta-(1,3) glucan laminarin did not have any effect. Because beta-glucan is a common constituent of all fungi and is abundantly released in vivo during systemic fungal infection, this novel effect of beta-glucan has potential implications for host-parasite relationship in candidiasis and other mycoses. In particular, our data suggest that beta-glucan could bias noninfected, bystander monocytes, thus aggravating the general immunodeficiency, predisposing to systemic fungal infection.


Assuntos
Candida albicans/imunologia , Diferenciação Celular , Parede Celular/metabolismo , Células Dendríticas/citologia , Monócitos/citologia , beta-Glucanas/farmacologia , Apresentação de Antígeno , Candidíase/imunologia , Candidíase/metabolismo , Candidíase/patologia , Proliferação de Células , Parede Celular/imunologia , Células Cultivadas , Citocinas/metabolismo , Células Dendríticas/fisiologia , Humanos , Monócitos/fisiologia , Fenótipo , Linfócitos T/imunologia , Linfócitos T/metabolismo
9.
Eur J Immunol ; 36(8): 2046-60, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16856207

RESUMO

Dendritic cells (DC) generated after a short-term exposure of monocytes to IFN-alpha and GM-CSF (IFN-DC) are highly effective in inducing cross-priming of CD8(+ )T cells against viral antigens. We have investigated the mechanisms responsible for the special attitude of these DC and compared their activity with that of reference DC. Antigen uptake and endosomal processing capabilities were similar for IFN-DC and IL-4-derived DC. Both DC types efficiently cross-presented soluble HCV NS3 protein to the specific CD8(+) T cell clone, even though IFN-DC were superior in cross-presenting low amounts of viral antigens. Moreover, when DC were pulsed with inactivated HIV-1 and injected into hu-PBL-SCID mice, the generation of virus-specific CD8(+ )T cells was markedly higher in animals immunized with IFN-DC than in mice immunized with CD40L-matured IL-4-DC. Of interest, in experiments with purified CD8(+ )T cells, IFN-DC were superior with respect to CD40L-matured IL-4-DC in inducing in vitro cross-priming of HIV-specific CD8(+ )T cells. This property correlated with enhanced potential to express the specific subunits of the IL-23 and IL-27 cytokines. These results suggest that IFN-DC are directly licensed for an efficient CD8(+) T cell priming by mechanisms likely involving enhanced antigen presentation and special attitude to produce IL-12 family cytokines.


Assuntos
Antígenos Virais/imunologia , Linfócitos T CD8-Positivos/imunologia , Apresentação Cruzada/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Interferon-alfa/imunologia , Animais , Formação de Anticorpos/imunologia , Apresentação de Antígeno , Linfócitos T CD4-Positivos/imunologia , Ligante de CD40/imunologia , Diferenciação Celular , Células Cultivadas , Técnicas de Cocultura , Células Dendríticas/citologia , Endossomos/imunologia , HIV-1/imunologia , Humanos , Interferon-alfa/genética , Interleucinas/metabolismo , Camundongos , Fenótipo , Solubilidade , Fatores de Tempo
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