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1.
Cancer Cell ; 40(7): 720-737.e5, 2022 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-35660135

RESUMO

Aerobic exercise is associated with decreased cancer incidence and cancer-associated mortality. However, little is known about the effects of exercise on pancreatic ductal adenocarcinoma (PDA), a disease for which current therapeutic options are limited. Herein, we show that aerobic exercise reduces PDA tumor growth, by modulating systemic and intra-tumoral immunity. Mechanistically, exercise promotes immune mobilization and accumulation of tumor-infiltrating IL15Rα+ CD8 T cells, which are responsible for the tumor-protective effects. In clinical samples, an exercise-dependent increase of intra-tumoral CD8 T cells is also observed. Underscoring the translational potential of the interleukin (IL)-15/IL-15Rα axis, IL-15 super-agonist (NIZ985) treatment attenuates tumor growth, prolongs survival, and enhances sensitivity to chemotherapy. Finally, exercise or NIZ985 both sensitize pancreatic tumors to αPD-1, with improved anti-tumor and survival benefits. Collectively, our findings highlight the therapeutic potential of an exercise-oncology axis and identify IL-15 activation as a promising treatment strategy for this deadly disease.


Assuntos
Antineoplásicos , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Receptores de Interleucina-15/metabolismo , Antineoplásicos/farmacologia , Linfócitos T CD8-Positivos , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Humanos , Imunoterapia , Interleucina-15/metabolismo , Interleucina-15/farmacologia , Interleucina-15/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Microambiente Tumoral , Neoplasias Pancreáticas
2.
Br J Cancer ; 124(11): 1754-1756, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33758330

RESUMO

Immune checkpoint blockade (ICB) has demonstrated efficacy in multiple cancers, offering the potential of long-term disease control not achievable with cytotoxic or targeted therapies. However, the field has not yet achieved the crucial next steps - the expansion of the response rate and achievement of clinical efficacy in so-called "cold tumours". Mechanistic studies of tumour-type specific immunosuppressive pathways can reveal underlying biological hurdles to immunotherapy and offer new therapeutic insights. Our finding that tumour-derived IL-1ß mediates immunosuppression in pancreatic cancer has precipitated a new clinical trial.


Assuntos
Tolerância Imunológica/genética , Imunoterapia , Interleucina-1beta/fisiologia , Neoplasias Pancreáticas/terapia , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Imunoterapia/métodos , Imunoterapia/tendências , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
3.
JCI Insight ; 1(14)2016 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-27642636

RESUMO

In carcinogen-driven cancers, a high mutational burden results in neoepitopes that can be recognized immunologically. Such carcinogen-induced tumors may evade this immune response through "immunoediting," whereby tumors adapt to immune pressure and escape T cell-mediated killing. Many tumors lack a high neoepitope burden, and it remains unclear whether immunoediting occurs in such cases. Here, we evaluated T cell immunity in an autochthonous mouse model of pancreatic cancer and found a low mutational burden, absence of predicted neoepitopes derived from tumor mutations, and resistance to checkpoint immunotherapy. Spontaneous tumor progression was identical in the presence or absence of T cells. Moreover, tumors arising in T cell-depleted mice grew unchecked in immune-competent hosts. However, introduction of the neoantigen ovalbumin (OVA) led to tumor rejection and T cell memory, but this did not occur in OVA immune-tolerant mice. Thus, immunoediting does not occur in this mouse model - a likely consequence, not a cause, of absent neoepitopes. Because many human tumors also have a low missense mutational load and minimal neoepitope burden, our findings have clinical implications for the design of immunotherapy for patients with such tumors.


Assuntos
Antígenos de Neoplasias/imunologia , Evasão da Resposta Imune , Imunoterapia , Neoplasias Pancreáticas/imunologia , Linfócitos T/imunologia , Animais , Linhagem Celular Tumoral , Epitopos/imunologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL
4.
Gastroenterology ; 149(1): 201-10, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25888329

RESUMO

BACKGROUND & AIMS: Immunotherapies that induce T-cell responses have shown efficacy against some solid malignancies in patients and mice, but these have little effect on pancreatic ductal adenocarcinoma (PDAC). We investigated whether the ability of PDAC to evade T-cell responses induced by immunotherapies results from the low level of immunogenicity of tumor cells, the tumor's immunosuppressive mechanisms, or both. METHODS: Kras(G12D/+);Trp53(R172H/+);Pdx-1-Cre (KPC) mice, which develop spontaneous PDAC, or their littermates (controls) were given subcutaneous injections of a syngeneic KPC-derived PDAC cell line. Mice were then given gemcitabine and an agonist of CD40 to induce tumor-specific immunity mediated by T cells. Some mice were also given clodronate-encapsulated liposomes to deplete macrophages. Tumor growth was monitored. Tumor and spleen tissues were collected and analyzed by histology, flow cytometry, and immunohistochemistry. RESULTS: Gemcitabine in combination with a CD40 agonist induced T-cell-dependent regression of subcutaneous PDAC in KPC and control mice. In KPC mice given gemcitabine and a CD40 agonist, CD4(+) and CD8(+) T cells infiltrated subcutaneous tumors, but only CD4(+) T cells infiltrated spontaneous pancreatic tumors (not CD8(+) T cells). In mice depleted of Ly6C(low) F4/80(+) extratumoral macrophages, the combination of gemcitabine and a CD40 agonist stimulated infiltration of spontaneous tumors by CD8(+) T cells and induced tumor regression, mediated by CD8(+) T cells. CONCLUSIONS: Ly6C(low) F4/80(+) macrophages that reside outside of the tumor microenvironment regulate infiltration of T cells into PDAC and establish a site of immune privilege. Strategies to reverse the immune privilege of PDAC, which is regulated by extratumoral macrophages, might increase the efficacy of T-cell immunotherapy for patients with PDAC.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Imunoterapia/métodos , Macrófagos/citologia , Macrófagos/imunologia , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Antimetabólitos Antineoplásicos/farmacologia , Antígenos CD40/agonistas , Linfócitos T CD8-Positivos/efeitos dos fármacos , Carcinoma Ductal Pancreático/imunologia , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Modelos Animais de Doenças , Imuno-Histoquímica , Macrófagos/efeitos dos fármacos , Camundongos , Neoplasias Pancreáticas/imunologia , Gencitabina , Neoplasias Pancreáticas
5.
Cancer Immunol Res ; 3(4): 399-411, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25678581

RESUMO

Disabling the function of immune checkpoint molecules can unlock T-cell immunity against cancer, yet despite remarkable clinical success with monoclonal antibodies (mAb) that block PD-1 or CTLA-4, resistance remains common and essentially unexplained. To date, pancreatic carcinoma is fully refractory to these antibodies. Here, using a genetically engineered mouse model of pancreatic ductal adenocarcinoma in which spontaneous immunity is minimal, we found that PD-L1 is prominent in the tumor microenvironment, a phenotype confirmed in patients; however, tumor PD-L1 was found to be independent of IFNγ in this model. Tumor T cells expressed PD-1 as prominently as T cells from chronically infected mice, but treatment with αPD-1 mAbs, with or without αCTLA-4 mAbs, failed in well-established tumors, recapitulating clinical results. Agonist αCD40 mAbs with chemotherapy induced T-cell immunity and reversed the complete resistance of pancreatic tumors to αPD-1 and αCTLA-4. The combination of αCD40/chemotherapy plus αPD-1 and/or αCTLA-4 induced regression of subcutaneous tumors, improved overall survival, and conferred curative protection from multiple tumor rechallenges, consistent with immune memory not otherwise achievable. Combinatorial treatment nearly doubled survival of mice with spontaneous pancreatic cancers, although no cures were observed. Our findings suggest that in pancreatic carcinoma, a nonimmunogenic tumor, baseline refractoriness to checkpoint inhibitors can be rescued by the priming of a T-cell response with αCD40/chemotherapy.


Assuntos
Antígeno B7-H1/imunologia , Antígeno CTLA-4/imunologia , Carcinoma Ductal Pancreático/terapia , Neoplasias Pancreáticas/terapia , Subpopulações de Linfócitos T/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígenos CD40/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Carcinoma Ductal Pancreático/imunologia , Linhagem Celular Tumoral , Terapia Combinada , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Engenharia Genética/métodos , Humanos , Tolerância Imunológica/efeitos dos fármacos , Tolerância Imunológica/imunologia , Imunidade Celular , Interferon gama/imunologia , Ativação Linfocitária/imunologia , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/imunologia , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Gencitabina , Neoplasias Pancreáticas
6.
J Clin Invest ; 124(6): 2626-39, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24789911

RESUMO

Myeloid-derived suppressor cells (MDSCs) dampen the immune response thorough inhibition of T cell activation and proliferation and often are expanded in pathological conditions. Here, we studied the fate of MDSCs in cancer. Unexpectedly, MDSCs had lower viability and a shorter half-life in tumor-bearing mice compared with neutrophils and monocytes. The reduction of MDSC viability was due to increased apoptosis, which was mediated by increased expression of TNF-related apoptosis-induced ligand receptors (TRAIL-Rs) in these cells. Targeting TRAIL-Rs in naive mice did not affect myeloid cell populations, but it dramatically reduced the presence of MDSCs and improved immune responses in tumor-bearing mice. Treatment of myeloid cells with proinflammatory cytokines did not affect TRAIL-R expression; however, induction of ER stress in myeloid cells recapitulated changes in TRAIL-R expression observed in tumor-bearing hosts. The ER stress response was detected in MDSCs isolated from cancer patients and tumor-bearing mice, but not in control neutrophils or monocytes, and blockade of ER stress abrogated tumor-associated changes in TRAIL-Rs. Together, these data indicate that MDSC pathophysiology is linked to ER stress, which shortens the lifespan of these cells in the periphery and promotes expansion in BM. Furthermore, TRAIL-Rs can be considered as potential targets for selectively inhibiting MDSCs.


Assuntos
Estresse do Retículo Endoplasmático , Células Mieloides/imunologia , Células Mieloides/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Animais , Apoptose/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Modelos Biológicos , Células Mieloides/patologia
7.
Cancer Immunol Immunother ; 62(5): 949-54, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23589109

RESUMO

Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive and lethal cancer which is poorly responsive to standard therapies. Although the PDA tumor microenvironment is considered especially immunosuppressive, recent data mostly from genetically engineered and other mouse models of the disease suggest that novel immunotherapeutic approaches hold promise. Here, we describe both laboratory and clinical efforts to target the CD40 pathway for immunotherapy in PDA. Findings suggest that CD40 agonists can mediate both T-cell-dependent and T-cell-independent immune mechanisms of tumor regression in mice and patients. T-cell-independent mechanisms are associated with macrophage activation and the destruction of PDA tumor stroma, supporting the concept that immune modulation of the tumor microenvironment represents a useful approach in cancer immunotherapy.


Assuntos
Antígenos CD40/metabolismo , Imunoterapia/métodos , Neoplasias Pancreáticas/diagnóstico , Animais , Anticorpos/química , Engenharia Genética/métodos , Humanos , Imunossupressores/uso terapêutico , Ativação de Macrófagos , Macrófagos/citologia , Camundongos , Modelos Biológicos , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/terapia , Linfócitos T/citologia , Linfócitos T/imunologia , Microambiente Tumoral
8.
Retrovirology ; 6: 18, 2009 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-19220914

RESUMO

BACKGROUND: RNA interference is a gene regulatory mechanism that employs small RNA molecules such as microRNA. Previous work has shown that HIV-1 produces TAR viral microRNA. Here we describe the effects of the HIV-1 TAR derived microRNA on cellular gene expression. RESULTS: Using a variation of standard techniques we have cloned and sequenced both the 5' and 3' arms of the TAR miRNA. We show that expression of the TAR microRNA protects infected cells from apoptosis and acts by down-regulating cellular genes involved in apoptosis. Specifically, the microRNA down-regulates ERCC1 and IER3, protecting the cell from apoptosis. Comparison to our cloned sequence reveals possible target sites for the TAR miRNA as well. CONCLUSION: The TAR microRNA is expressed in all stages of the viral life cycle, can be detected in latently infected cells, and represents a mechanism wherein the virus extends the life of the infected cell for the purpose of increasing viral replication.


Assuntos
Apoptose/fisiologia , Regulação da Expressão Gênica , Repetição Terminal Longa de HIV/fisiologia , HIV-1/metabolismo , MicroRNAs/metabolismo , Sequência de Bases , Caspase 3/metabolismo , Linhagem Celular , Proteínas de Ligação a DNA/metabolismo , Endonucleases/metabolismo , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Células HeLa , Interações Hospedeiro-Patógeno , Humanos , MicroRNAs/química , Ribonuclease III/metabolismo , Alinhamento de Sequência , Células U937
9.
BMC Mol Biol ; 8: 63, 2007 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-17663774

RESUMO

BACKGROUND: RNA interference (RNAi) is a regulatory mechanism conserved in higher eukaryotes. The RNAi pathway generates small interfering RNA (siRNA) or micro RNA (miRNA) from either long double stranded stretches of RNA or RNA hairpins, respectively. The siRNA or miRNA then guides an effector complex to a homologous sequence of mRNA and regulates suppression of gene expression through one of several mechanisms. The suppression of gene expression through these mechanisms serves to regulate endogenous gene expression and protect the cell from foreign nucleic acids. There is growing evidence that many viruses have developed in the context of RNAi and express either a suppressor of RNAi or their own viral miRNA. RESULTS: In this study we investigated the possibility that the HIV-1 TAR element, a hairpin structure of ~50 nucleotides found at the 5' end of the HIV viral mRNA, is recognized by the RNAi machinery and processed to yield a viral miRNA. We show that the protein Dicer, the enzyme responsible for cleaving miRNA and siRNA from longer RNA sequences, is expressed in CD4+ T-cells. Interestingly, the level of expression of Dicer in monocytes is sub-optimal, suggesting a possible role for RNAi in maintaining latency in T-cells. Using a biotin labeled TAR element we demonstrate that Dicer binds to this structure. We show that recombinant Dicer is capable of cleaving the TAR element in vitro and that TAR derived miRNA is present in HIV-1 infected cell lines and primary T-cell blasts. Finally, we show that a TAR derived miRNA is capable of regulating viral gene expression and may be involved in repressing gene expression through transcriptional silencing. CONCLUSION: HIV-1 TAR element is processed by the Dicer enzyme to create a viral miRNA. This viral miRNA is detectable in infected cells and appears to contribute to viral latency.


Assuntos
RNA Helicases DEAD-box/metabolismo , Endorribonucleases/metabolismo , Repetição Terminal Longa de HIV/genética , HIV-1/genética , MicroRNAs/metabolismo , Western Blotting , Antígenos CD4/metabolismo , Linhagem Celular , Células Cultivadas , Montagem e Desmontagem da Cromatina , Imunoprecipitação da Cromatina , RNA Helicases DEAD-box/genética , Endorribonucleases/genética , Regulação Viral da Expressão Gênica , HIV-1/crescimento & desenvolvimento , HIV-1/metabolismo , Humanos , Células Jurkat , Luciferases/genética , Luciferases/metabolismo , MicroRNAs/genética , Mutação , Ligação Proteica , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , RNA Viral/genética , RNA Viral/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Ribonuclease III , Linfócitos T/metabolismo , Linfócitos T/virologia , Células U937
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