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1.
NPJ Biofilms Microbiomes ; 9(1): 59, 2023 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-37612266

RESUMO

Immune responses can have opposing effects in colorectal cancer (CRC), the balance of which may determine whether a cancer regresses, progresses, or potentially metastasizes. These effects are evident in CRC consensus molecular subtypes (CMS) where both CMS1 and CMS4 contain immune infiltrates yet have opposing prognoses. The microbiome has previously been associated with CRC and immune response in CRC but has largely been ignored in the CRC subtype discussion. We used CMS subtyping on surgical resections from patients and aimed to determine the contributions of the microbiome to the pleiotropic effects evident in immune-infiltrated subtypes. We integrated host gene-expression and meta-transcriptomic data to determine the link between immune characteristics and microbiome contributions in these subtypes and identified lipopolysaccharide (LPS) binding as a potential functional mechanism. We identified candidate bacteria with LPS properties that could affect immune response, and tested the effects of their LPS on cytokine production of peripheral blood mononuclear cells (PBMCs). We focused on Fusobacterium periodonticum and Bacteroides fragilis in CMS1, and Porphyromonas asaccharolytica in CMS4. Treatment of PBMCs with LPS isolated from these bacteria showed that F. periodonticum stimulates cytokine production in PBMCs while both B. fragilis and P. asaccharolytica had an inhibitory effect. Furthermore, LPS from the latter two species can inhibit the immunogenic properties of F. periodonticum LPS when co-incubated with PBMCs. We propose that different microbes in the CRC tumor microenvironment can alter the local immune activity, with important implications for prognosis and treatment response.


Assuntos
Neoplasias Colorretais , Lipopolissacarídeos , Humanos , Leucócitos Mononucleares , Microambiente Tumoral , Bactérias/genética , Citocinas , Imunidade
2.
Nat Commun ; 12(1): 2626, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976179

RESUMO

By conferring systemic protection and durable benefits, cancer immunotherapies are emerging as long-term solutions for cancer treatment. One such approach that is currently undergoing clinical testing is a therapeutic anti-cancer vaccine that uses two different viruses expressing the same tumor antigen to prime and boost anti-tumor immunity. By providing the additional advantage of directly killing cancer cells, oncolytic viruses (OVs) constitute ideal platforms for such treatment strategy. However, given that the targeted tumor antigen is encoded into the viral genomes, its production requires robust infection and therefore, the vaccination efficiency partially depends on the unpredictable and highly variable intrinsic sensitivity of each tumor to OV infection. In this study, we demonstrate that anti-cancer vaccination using OVs (Adenovirus (Ad), Maraba virus (MRB), Vesicular stomatitis virus (VSV) and Vaccinia virus (VV)) co-administered with antigenic peptides is as efficient as antigen-engineered OVs and does not depend on viral replication. Our strategy is particularly attractive for personalized anti-cancer vaccines targeting patient-specific mutations. We suggest that the use of OVs as adjuvant platforms for therapeutic anti-cancer vaccination warrants testing for cancer treatment.


Assuntos
Antígenos de Neoplasias/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Neoplasias/imunologia , Vírus Oncolíticos/genética , Poli I-C/administração & dosagem , Poli I-C/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/genética , Vacinas de Subunidades Antigênicas/imunologia , Vaccinia virus , Vírus da Estomatite Vesicular Indiana , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Br J Oral Maxillofac Surg ; 54(2): 230-1, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26747014

RESUMO

The effective communication of risk, which is central to the process of consent, can be difficult, and can be hard for patients to understand. We introduce the potential utility of the micromort, a unit of risk defined as a one-in-a-million chance of sudden death, which allows clinicians to compare the risks of an intervention with those of different activities, making them easier to understand.

4.
J Control Release ; 220(Pt A): 210-221, 2015 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-26482080

RESUMO

Due to cancer's genetic complexity, significant advances in the treatment of metastatic disease will require sophisticated, multi-pronged therapeutic approaches. Here we demonstrate the utility of a Drosophila melanogaster cell platform for the production and in vivo delivery of multi-gene biotherapeutic systems. We show that cultured Drosophila S2 cell carriers can stably propagate oncolytic viral therapeutics that are highly cytotoxic for mammalian cancer cells without adverse effects on insect cell viability or gene expression. Drosophila cell carriers administered systemically to immunocompetent animals trafficked to tumors to deliver multiple biotherapeutics with little apparent off-target tissue homing or toxicity, resulting in a therapeutic effect. Cells of this Dipteran invertebrate provide a genetically tractable platform supporting the integration of complex, multi-gene biotherapies while avoiding many of the barriers to systemic administration of mammalian cell carriers. These transporters have immense therapeutic potential as they can be modified to express large banks of biotherapeutics with complementary activities that enhance anti-tumor activity.


Assuntos
Drosophila melanogaster/genética , Terapia Genética/métodos , Neoplasias Pulmonares/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Animais , Chlorocebus aethiops , Drosophila melanogaster/citologia , Drosophila melanogaster/imunologia , Drosophila melanogaster/virologia , Feminino , Regulação Neoplásica da Expressão Gênica , Regulação Viral da Expressão Gênica , Células HT29 , Células HeLa , Humanos , Imunocompetência , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/virologia , Células MCF-7 , Camundongos Endogâmicos BALB C , Vírus Oncolíticos/imunologia , Vírus Oncolíticos/patogenicidade , Fatores de Tempo , Transfecção , Carga Tumoral , Células Vero , Ensaios Antitumorais Modelo de Xenoenxerto
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