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1.
Blood ; 118(18): 4853-62, 2011 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-21908423

RESUMO

Regulatory T cells (Tregs) may impede cancer vaccine efficacy in hematologic malignancies and cancer. CCR4 antagonists, an emergent class of Treg inhibitor, have been shown to block recruitment of Tregs mediated by CCL22 and CCL17. Our aim was to demonstrate the ability of a CCR4 antagonist (a small chemical molecule identified in silico) when combined with vaccines to break peripheral tolerance controlled by Tregs, a prerequisite for the induction of CD8(+) T cells against self Ags. Immunization of transgenic or normal mice expressing tumor-associated self Ags (Her2/neu, OVA, gp100) with a CCR4 antagonist combined with various vaccines led to the induction of effector CD8(+) T cells and partial inhibition of tumor growth expressing self Ags in both prophylactic and therapeutic settings. The CCR4 antagonist was more efficient than cyclophosphamide to elicit anti-self CD8(+) T cells. We also showed that the population of Tregs expressing CCR4 corresponded to memory (CD44(high)) and activated (ICOS(+)) Tregs, an important population to be targeted to modulate Treg activity. CCR4 antagonist represents a competitive class of Treg inhibitor able to induce functional anti-self CD8(+) T cells and tumor growth inhibition when combined with vaccines. High expression of CCR4 on human Tregs also supports the clinical development of this strategy.


Assuntos
Autoantígenos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Vacinas Anticâncer/administração & dosagem , Neoplasias/terapia , Receptores CCR4/antagonistas & inibidores , Evasão Tumoral/efeitos dos fármacos , Animais , Antígenos de Neoplasias/imunologia , Antineoplásicos/administração & dosagem , Autoantígenos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Terapia Combinada , Modelos Animais de Doenças , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Especificidade do Receptor de Antígeno de Linfócitos T/efeitos dos fármacos , Especificidade do Receptor de Antígeno de Linfócitos T/imunologia , Evasão Tumoral/imunologia
2.
Sci Transl Med ; 13(600)2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193612

RESUMO

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance toward self-nucleic acids, autoantibody production, interferon expression and signaling, and a defect in the regulatory T (Treg) cell compartment. In this work, we identified that platelets from patients with active SLE preferentially interacted with Treg cells via the P-selectin/P-selectin glycoprotein ligand-1 (PSGL-1) axis. Selectin interaction with PSGL-1 blocked the regulatory and suppressive properties of Treg cells and particularly follicular Treg cells by triggering Syk phosphorylation and an increase in intracytosolic calcium. Mechanistically, P-selectin engagement on Treg cells induced a down-regulation of the transforming growth factor-ß axis, altering the phenotype of Treg cells and limiting their immunosuppressive responses. In patients with SLE, we found an up-regulation of P- and E-selectin both on microparticles and in their soluble forms that correlated with disease activity. Last, blocking P-selectin in a mouse model of SLE improved cardinal features of the disease, such as anti-dsDNA antibody concentrations and kidney pathology. Overall, our results identify a P-selectin-dependent pathway that is active in patients with SLE and validate it as a potential therapeutic avenue.


Assuntos
Lúpus Eritematoso Sistêmico , Linfócitos T Reguladores , Animais , Humanos , Camundongos , Selectinas , Fator de Crescimento Transformador beta
3.
Clin Cancer Res ; 22(16): 4133-44, 2016 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-27006496

RESUMO

PURPOSE: E75, a peptide derived from the Her2/neu protein, is the most clinically advanced vaccine approach against breast cancer. In this study, we aimed to optimize the E75 vaccine using a delivery vector targeting dendritic cells, the B-subunit of Shiga toxin (STxB), and to assess the role of various parameters (Her2/neu expression, combination with trastuzumab) in the efficacy of this cancer vaccine in a relevant preclinical model. EXPERIMENTAL DESIGN: We compared the differential ability of the free E75 peptide or the STxB-E75 vaccine to elicit CD8(+) T cells, and the impact of the vaccine on murine HLA-A2 tumors expressing low or high levels of Her2/neu. RESULTS: STxB-E75 synergized with granulocyte macrophage colony-stimulating factors and CpG and proved to be more efficient than the free E75 peptide in the induction of multifunctional and high-avidity E75-specific anti-CD8(+) T cells resulting in a potent tumor protection in HLA-A2 transgenic mice. High expression of HER2/neu inhibited the expression of HLA-class I molecules, leading to a poor recognition of human or murine tumors by E75-specific cytotoxic CD8(+) T cells. In line with these results, STxB-E75 preferentially inhibited the growth of HLA-A2 tumors expressing low levels of Her2/neu. Coadministration of anti-Her2/neu mAb potentiated this effect. CONCLUSIONS: STxB-E75 vaccine is a potent candidate to be tested in patients with low Her2/neu-expressing tumors. It could also be indicated in patients expressing high levels of Her2/neu and low intratumoral T-cell infiltration to boost the recruitment of T cells-a key parameter in the efficacy of anti-Her2/neu mAb therapy. Clin Cancer Res; 22(16); 4133-44. ©2016 AACR.


Assuntos
Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Antígeno HLA-A2/genética , Antígeno HLA-A2/imunologia , Neoplasias/genética , Neoplasias/imunologia , Receptor ErbB-2/imunologia , Animais , Antígenos de Neoplasias/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Epitopos de Linfócito T/imunologia , Humanos , Melanoma Experimental , Camundongos , Camundongos Transgênicos , Neoplasias/patologia , Neoplasias/terapia , Fragmentos de Peptídeos/imunologia , Receptor ErbB-2/genética , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Sci Transl Med ; 5(172): 172ra20, 2013 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-23408053

RESUMO

Although many human cancers are located in mucosal sites, most cancer vaccines are tested against subcutaneous tumors in preclinical models. We therefore wondered whether mucosa-specific homing instructions to the immune system might influence mucosal tumor outgrowth. We showed that the growth of orthotopic head and neck or lung cancers was inhibited when a cancer vaccine was delivered by the intranasal mucosal route but not the intramuscular route. This antitumor effect was dependent on CD8⁺ T cells. Indeed, only intranasal vaccination elicited mucosal-specific CD8⁺ T cells expressing the mucosal integrin CD49a. Blockade of CD49a decreased intratumoral CD8⁺ T cell infiltration and the efficacy of cancer vaccine on mucosal tumor. We then showed that after intranasal vaccination, dendritic cells from lung parenchyma, but not those from spleen, induced the expression of CD49a on cocultured specific CD8⁺ T cells. Tumor-infiltrating lymphocytes from human mucosal lung cancer also expressed CD49a, which supports the relevance and possible extrapolation of these results in humans. We thus identified a link between the route of vaccination and the induction of a mucosal homing program on induced CD8⁺ T cells that controlled their trafficking. Immunization route directly affected the efficacy of the cancer vaccine to control mucosal tumors.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/administração & dosagem , Quimiotaxia de Leucócito , Neoplasias de Cabeça e Pescoço/terapia , Imunidade nas Mucosas , Neoplasias Pulmonares/terapia , Mucosa Nasal/imunologia , Vacinas contra Papillomavirus/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Administração Intranasal , Animais , Antígenos CD/metabolismo , Vacinas Anticâncer/imunologia , Proliferação de Células , Células Cultivadas , Células Dendríticas/imunologia , Feminino , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Injeções Intramusculares , Cadeias alfa de Integrinas/metabolismo , Integrina alfa1/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Linfonodos/imunologia , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Vacinas contra Papillomavirus/imunologia , Toxinas Shiga/administração & dosagem , Baço/imunologia , Carga Tumoral
5.
Cancer Res ; 73(1): 128-38, 2013 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23135914

RESUMO

Head and neck cancers positive for human papillomavirus (HPV) have a more favorable clinical outcome than HPV-negative cancers, but it is unknown why this is the case. We hypothesized that prognosis was affected by intrinsic features of HPV-infected tumor cells or differences in host immune response. In this study, we focused on a comparison of regulatory Foxp3(+) T cells and programmed death-1 (PD-1)(+) T cells in the microenvironment of tumors that were positive or negative for HPV, in two groups that were matched for various clinical and biologic parameters. HPV-positive head and neck cancers were more heavily infiltrated by regulatory T cells and PD-1(+) T cells and the levels of PD-1(+) cells were positively correlated with a favorable clinical outcome. In explaining this paradoxical result, we showed that these PD-1(+) T cells expressed activation markers and were functional after blockade of the PD-1-PD-L1 axis in vitro. Approximately 50% of PD-1(+) tumor-infiltrating T cells lacked Tim-3 expression and may indeed represent activated T cells. In mice, administration of a cancer vaccine increased PD-1 on T cells with concomitant tumor regression. In this setting, PD-1 blockade synergized with vaccine in eliciting antitumor efficacy. Our findings prompt a need to revisit the significance of PD-1-infiltrating T cells in cancer, where we suggest that PD-1 detection may reflect a previous immune response against tumors that might be reactivated by PD-1/PD-L1 blockade.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/virologia , Linfócitos do Interstício Tumoral/imunologia , Receptor de Morte Celular Programada 1/biossíntese , Linfócitos T/imunologia , Animais , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/virologia , Feminino , Citometria de Fluxo , Imunofluorescência , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/metabolismo , Prognóstico , Receptor de Morte Celular Programada 1/imunologia , Subpopulações de Linfócitos T/imunologia , Microambiente Tumoral/imunologia
6.
Oncoimmunology ; 1(3): 326-333, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22737608

RESUMO

CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) have emerged as a dominant T cell population inhibiting anti-tumor effector T cells. Initial strategies used for Treg-depletion (cyclophosphamide, anti-CD25 mAb…) also targeted activated T cells, as they share many phenotypic markers. Current, ameliorated approaches to inhibit Treg aim to either block their function or their migration to lymph nodes and the tumor microenvironment. Various drugs originally developed for other therapeutic indications (anti-angiogenic molecules, tyrosine kinase inhibitors,etc) have recently been discovered to inhibit Treg. These approaches are expected to be rapidly translated to clinical applications for therapeutic use in combination with immunomodulators.

7.
Vaccine ; 29(35): 5892-903, 2011 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-21723900

RESUMO

Different subsets of dendritic cells (DC) elicit qualitatively different immune responses. In mice, two lymphoid tissue-resident subsets, CD8α(+) and CD8α(-), have been implicated in the induction of T helper 1 (Th1) or Th2 responses, respectively. Moreover, CD8α(+) DC appear to play a major role in priming CD8(+) T lymphocyte responses to viral antigens in the course of diverse viral infections. These considerations have been less extensively explored for vaccine vectors derived from viruses. Despite inefficient ex vivo transduction of DC, vectored vaccines derived from human adenoviruses of serotype 5 (Ad5) elicit robust immune responses, predominantly of the Th1 orientation, in humans and mice. At present it is unknown whether Ad5 interacts with DC subsets in a differential manner, thereby influencing the quality of the elicited IR. To address this issue, successive steps (attachment, transgene expression, MHC class I antigen presentation and activation of antigen-specific T lymphocytes) involved in induction of immune responses by Ad5-based vectors have been examined in CD8α(+) and CD8α(-) murine DC subsets. Although in both ex vivo and in vivo experiments CD8α(+) and CD8α(-) DC subsets captured an Ad5-based vector to a similar extent, transgene expression and subsequent MHC class I display of a transgene-encoded antigen were more efficient in CD8α(+) DC. Moreover, following in vivo and ex vivo transduction with an Ad5-based vaccine, antigen-specific CD8(+) T lymphocytes were more efficiently activated by CD8α(+) DC than by CD8α(-) DC. Thus, superior antigen expression and MHC class I display in CD8α(+) DC may contribute to preferred priming of antigen-specific CD8(+) lymphocytes by Ad5-transduced CD8α(+) DC.


Assuntos
Adenovírus Humanos/genética , Apresentação de Antígeno/imunologia , Antígenos CD8/metabolismo , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Vetores Genéticos/imunologia , Vacinas/imunologia , Animais , Antígenos CD8/genética , Linhagem Celular , Células Dendríticas/citologia , Feminino , Vetores Genéticos/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/imunologia , Transdução Genética , Vacinas/genética
8.
Head Neck ; 32(7): 946-58, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20191626

RESUMO

Head and neck cancers are heavily infiltrated by immune cells, the significance of which is complex. The natural immune response against head and neck tumors, including anti-human papillomavirus (HPV) T cells, and humoral responses has been clearly documented. However, during the course of tumor progression, co-option of the immune system by tumor cells for their own advantage and increased resistance of tumor cells to immune attack also occur. Inflammation and immune subversion to support angiogenesis are key factors promoting tumor growth. Only a better understanding of this tumor-host interaction will permit a rational design of new immunotherapeutic approaches combining immunostimulation with drugs endowed with the ability to counteract immunoevasion mechanisms.


Assuntos
Transformação Celular Neoplásica/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/terapia , Imunomodulação/fisiologia , Evasão Tumoral/fisiologia , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos
9.
J Immunother ; 33(9): 991-8, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20948437

RESUMO

Sunitinib, an antiangiogenic molecule, is one of the first-line standard of care in the treatment of patients with metastatic renal cell carcinoma. However, it only benefits to a subgroup of patients and no predictive markers of sunitinib efficacy have been identified. Twenty-eight metastatic renal cell carcinomas were treated with sunitinib-based therapy and another subgroup of 7 primary renal cell cancer patients were also treated by sunitinib in a neoadjuvant trial. Measurements of CD3+CD4+CD25(hi) Foxp3+ regulatory T cells, an immunosuppressive cell population, were performed before and after each cycle of treatment in blood and tumor in a prospective study. We observed a decrease in the number of peripheral blood Foxp3+ regulatory T cells after each cycle of sunitinib-based therapy. The overall survival was significantly longer in patients showing a decrease in the number of Foxp3+ regulatory T cells after 2 or 3 cycles of treatment (P<0.05). The decrease in the number of regulatory T cells positively correlated with their number at baseline (P<0.01), but not with modification of tumor volume defined by Response Evaluation Criteria in Solid Tumors criteria. The clinical relevance of these results was also supported by an intratumoral decrease of regulatory T cells in 5 out of 7 patients treated by sunitinib in a neoadjuvant trial. Our study represents the first work reporting that the measurement of regulatory T cells may have a predictive value on antiangiogenic response. Antiangiogenic therapy also reversed immunosuppression in the tumor microenvironment which provides novel argument in human to favor its combination with immunotherapy.


Assuntos
Adenocarcinoma de Células Claras/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Renais/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Linfócitos T Reguladores/efeitos dos fármacos , Adenocarcinoma de Células Claras/imunologia , Adenocarcinoma de Células Claras/mortalidade , Adenocarcinoma de Células Claras/fisiopatologia , Adenocarcinoma de Células Claras/secundário , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Bevacizumab , Contagem de Células , Progressão da Doença , Intervalo Livre de Doença , Feminino , Seguimentos , Fatores de Transcrição Forkhead/biossíntese , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Neoplasias Renais/imunologia , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Neoplasias Renais/fisiopatologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/fisiopatologia , Neoplasias Pulmonares/secundário , Masculino , Terapia Neoadjuvante , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Sunitinibe , Análise de Sobrevida , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia
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