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1.
Immunity ; 44(6): 1255-69, 2016 06 21.
Artículo en Inglés | MEDLINE | ID: mdl-27332730

RESUMEN

Inhibition of immune regulatory checkpoints, such as CTLA-4 and the PD-1-PD-L1 axis, is at the forefront of immunotherapy for cancers of various histological types. However, such immunotherapies fail to control neoplasia in a significant proportion of patients. Here, we review how a range of cancer-cell-autonomous cues, tumor-microenvironmental factors, and host-related influences might account for the heterogeneous responses and failures often encountered during therapies using immune-checkpoint blockade. Furthermore, we describe the emerging evidence of how the strong interrelationship between the immune system and the host microbiota can determine responses to cancer therapies, and we introduce a concept by which prior or concomitant modulation of the gut microbiome could optimize therapeutic outcomes upon immune-checkpoint blockade.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Receptores Coestimuladores e Inhibidores de Linfocitos T/inmunología , Resistencia a Antineoplásicos , Inmunoterapia/métodos , Neoplasias/terapia , Animales , Receptores Coestimuladores e Inhibidores de Linfocitos T/antagonistas & inhibidores , Humanos , Terapia Molecular Dirigida , Neoplasias/inmunología , Escape del Tumor , Microambiente Tumoral
2.
Immunol Rev ; 280(1): 194-206, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-29027231

RESUMEN

Cancer therapies can temporarily reduce tumor burdens by inducing malignant cell death. However, cancer cure is still far from realization because tumors often gain resistance to current treatment and eventually relapse. Accumulating evidence suggests that successful cancer interventions require anti-tumor immunity. Therapy-induced cell stress responses ultimately result in one or more cell death modalities, including apoptosis, autophagy, necroptosis, and pyroptosis. These irreversible dying processes are accompanied by active or passive release of cell death-associated molecular patterns (CDAMPs), which can be sensed by corresponding pattern recognition receptors (PRR) on tumor-infiltrating immune cells. This crosstalk with the immune system can reawaken immune surveillance in the tumor microenvironment (TME). This review focuses on immune-modulatory properties of anti-cancer regimens and CDAMP-mediated communications between cell stress responses and the immune contexture of TME. In addition, we describe how immunogenic cell death can elicit strong and durable anti-tumor immune responses.


Asunto(s)
Vacunas contra el Cáncer/inmunología , Inmunidad , Neoplasias/inmunología , Animales , Antígenos de Neoplasias/inmunología , Autofagia , Muerte Celular , Daño del ADN/inmunología , Humanos , Vigilancia Inmunológica , Receptores de Reconocimiento de Patrones/metabolismo , Microambiente Tumoral
3.
Immunol Rev ; 280(1): 165-174, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-29027230

RESUMEN

Cancer cells are subjected to constant selection by the immune system, meaning that tumors that become clinically manifest have managed to subvert or hide from immunosurveillance. Immune control can be facilitated by induction of autophagy, as well as by polyploidization of cancer cells. While autophagy causes the release of ATP, a chemotactic signal for myeloid cells, polyploidization can trigger endoplasmic reticulum stress with consequent exposure of the "eat-me" signal calreticulin on the cell surface, thereby facilitating the transfer of tumor antigens into dendritic cells. Hence, both autophagy and polyploidization cause the emission of adjuvant signals that ultimately elicit immune control by CD8+ T lymphocytes. We investigated the possibility that autophagy and polyploidization might also affect the antigenicity of cancer cells by altering the immunopeptidome. Mass spectrometry led to the identification of peptides that were presented on major histocompatibility complex (MHC) class I molecules in an autophagy-dependent fashion or that were specifically exposed on the surface of polyploid cells, yet lost upon passage of such cells through immunocompetent (but not immunodeficient) mice. However, the preferential recognition of autophagy-competent and polyploid cells by the innate and cellular immune systems did not correlate with the preferential recognition of such peptides in vivo. Moreover, vaccination with such peptides was unable to elicit tumor growth-inhibitory responses in vivo. We conclude that autophagy and polyploidy increase the immunogenicity of cancer cells mostly by affecting their adjuvanticity rather than their antigenicity.


Asunto(s)
Adyuvantes Inmunológicos , Antígenos de Neoplasias/inmunología , Muerte Celular , Vigilancia Inmunológica , Neoplasias/inmunología , Adenosina Trifosfato/metabolismo , Animales , Estrés del Retículo Endoplásmico , Humanos , Ratones , Monitorización Inmunológica , Transducción de Señal
4.
Dermatol Surg ; 43 Suppl 3: S304-S311, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28961638

RESUMEN

BACKGROUND: IncobotulinumtoxinA is safe and effective in Caucasian adults. Its effects have been less documented in Asian adults. OBJECTIVE: To describe the efficacy and tolerability of incobotulinumtoxinA for treating glabellar frown lines (GFLs) in South Korean adults. METHODS: South Korean adults aged 18 to 65 years with moderate-to-severe GFLs received a single dose of 10 to 28 U incobotulinumtoxinA during routine clinical practice. After 30 ± 14 days, investigators assessed the efficacy using the Global Aesthetic Improvement Scale and rated tolerability using a 4-point scale. RESULTS: Six hundred seventy-three subjects were enrolled, of which 528 completed the study according to protocol. Glabellar frown lines improved in 98.7% (521/528) of subjects, with 30.8% of cases rated as "very much improved" and 47.4% as "much improved." The extent of improvement was unaffected by sex, age, and weight but was greater when the time between GFL identification and treatment was <6 months (p < .001) and when concomitant aesthetic nondrug treatments were used (p < .001). For 94% of subjects, tolerability was good or very good. All reported adverse events were transient and mild or moderate in severity. CONCLUSION: IncobotulinumtoxinA was well tolerated and effective for treating moderate-to-severe GFLs in Korean adults irrespective of age, sex, or weight.

5.
Adv Exp Med Biol ; 1036: 65-79, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29275465

RESUMEN

The host immune system is continuously exposed to dying cells and has evolved to distinguish between cell death events signaling potential threats and physiological apoptosis that should be tolerated. Tumors can use this distinction to their advantage, promoting apoptotic death of cancer cells to induce tolerance and evasion of immunosurveillance. On the other hand, stimuli that cause immunogenic death of cancer cells can induce an effective anti-tumor immune response. In this chapter we discuss different forms of cell death in the tumor microenvironment, and how these interact with host immune cells to impact tumor progression and cancer therapy. We focus on how cancer cells hijack aspects of cell death to promote tumor survival, and how anti-cancer treatments that activate immunogenic death modalities give strong and durable clinical efficacy.


Asunto(s)
Neoplasias/inmunología , Microambiente Tumoral/inmunología , Animales , Muerte Celular/inmunología , Humanos , Neoplasias/patología
6.
J Immunol ; 193(3): 1006-11, 2014 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-25049431

RESUMEN

Exosomes are nanometric membrane vesicles of late endosomal origin released by most, if not all, cell types as a means of sophisticated intercellular communication. A multitude of studies showed how exosomes can mediate and regulate immune responses against tumors. Dendritic cell-derived exosomes (Dex) have received much attention as immunotherapeutic anticancer agents since the discovery that they harbor functional MHC-peptide complexes, in addition to various other immune-stimulating components, that together facilitate immune cell-dependent tumor rejection. The therapeutic potential of Dex has been substantiated with their development and clinical testing in the treatment of cancer. This review focuses on mechanisms by which Dex interact with and influence immune cells and describes how they can be engineered to promote their immunogenic capacity as novel and dynamic anticancer agents.


Asunto(s)
Células Dendríticas/citología , Células Dendríticas/inmunología , Exosomas/inmunología , Inmunoterapia/métodos , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/terapia , Animales , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/inmunología , Ensayos Clínicos como Asunto/métodos , Células Dendríticas/patología , Modelos Animales de Enfermedad , Exosomas/genética , Exosomas/patología , Humanos , Ratones , Terapia Molecular Dirigida/métodos , Neoplasias Experimentales/patología , Células Tumorales Cultivadas
7.
J Immunol ; 189(8): 4079-87, 2012 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-22972927

RESUMEN

Vaccination with Mycobacterium bovis bacillus Calmette-Guérin (BCG) remains the only prophylactic vaccine against tuberculosis, caused by Mycobacterium tuberculosis, but gives variable protection against pulmonary disease. The generation of host Th1 responses following BCG vaccination is accepted as the major mechanism of protection against M. tuberculosis infection. Early production of IL-17 in the lungs following M. tuberculosis challenge of mice previously vaccinated with M. tuberculosis peptides in adjuvant has been shown to be required for efficient Th1 cell recruitment. IL-10 regulates various processes involved in generation of Th1 and Th17 responses. Previous studies have shown IL-10 as a negative regulator of the immune response to primary M. tuberculosis infection, with Il10(-/-) mice having reduced lung bacterial loads. In this study we show that inhibition of IL-10 signaling during BCG vaccination enhances host-generated Ag-specific IFN-γ and IL-17A responses, and that this regimen gives significantly greater protection against aerogenic M. tuberculosis challenge in both susceptible and relatively resistant strains of mice. In M. tuberculosis-susceptible CBA/J mice, Ab blockade of IL-10R specifically during BCG vaccination resulted in additional protection against M. tuberculosis challenge of >1-log(10) compared with equivalent isotype-treated controls. The protection observed following BCG vaccination concurrent with anti-IL-10R mAb treatment was sustained through chronic M. tuberculosis infection and correlated with enhanced lung Th1 and Th17 responses and increased IFN-γ and IL-17A production by γδ T cells and an innate-like Thy1.2(+)CD3(-) lymphoid population. We show that IL-10 inhibits optimal BCG-elicited protection, therefore suggesting that antagonists of IL-10 may be of great benefit as adjuvants in preventive vaccination against tuberculosis.


Asunto(s)
Vacuna BCG/inmunología , Interferón gamma/biosíntesis , Interleucina-10/antagonistas & inhibidores , Interleucina-17/biosíntesis , Transducción de Señal/inmunología , Células TH1/inmunología , Células Th17/inmunología , Tuberculosis Pulmonar/inmunología , Animales , Anticuerpos Bloqueadores/administración & dosificación , Vacuna BCG/administración & dosificación , Benzamidas , Células Cultivadas , Femenino , Mesilato de Imatinib , Inmunidad Innata , Interleucina-10/metabolismo , Interleucina-10/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Noqueados , Piperazinas/administración & dosificación , Pirimidinas/administración & dosificación , Receptores de Interleucina-10/antagonistas & inhibidores , Receptores de Interleucina-10/inmunología , Receptores de Interleucina-10/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/microbiología , Células TH1/microbiología , Células Th17/metabolismo , Células Th17/microbiología , Tuberculosis Pulmonar/prevención & control
8.
PLoS One ; 19(4): e0300399, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38593128

RESUMEN

We propose a set of metrics, based upon the four flows theory of the communicative constitution of organizations, to evaluate the emergence of organization in a social network. Using an agent-based model (ABM), we validate that our metrics chart the evolution of partial organizations as the population progresses from complete dissociation to unified allegiance. Our metrics allow the evaluation of organizational strength much more efficiently than previous, context-specific methods. The simulation produces other results consistent with human society, such as stable heterogeneity of structures and organizational figureheads, further validating our results. The ABM of emergent organization incorporates only widely-observed cognitive behaviors and the recognition by agents of group membership, without any cooperation among the agents. The four flows are produced solely by agents biasing their limited communication resources in favor of allies. While reaffirming the centrality of communication patterns to organization, we thus also challenge the minimal conditions required to produce organizing behavior and complex social structures.


Asunto(s)
Comunicación , Organizaciones , Humanos , Simulación por Computador
9.
Microb Pathog ; 58: 2-16, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23257069

RESUMEN

Tuberculosis remains one of the most significant human diseases of the developing world, accounting for 3800 worldwide deaths per day. Although we currently have a vaccine for tuberculosis, BCG, this is insufficient at protecting from adult pulmonary tuberculosis in the parts of the world where a good vaccine is most needed. This has prompted the search for new vaccination strategies that can protect better than BCG, or can boost BCG-induced immunity. We discuss these subjects in line with what is known of the immune responses to BCG and Mycobacterium tuberculosis - the etiological agent of the disease, as well as the particular difficulties facing development of new vaccines against tuberculosis. A greater understanding of the factors constituting optimal protection against Mycobacterium tuberculosis infection, as well as which pathogenic factors facilitate active disease, will accelerate the delivery of safe vaccines able to restrict active tuberculosis and thus impede contagion.


Asunto(s)
Vacuna BCG/administración & dosificación , Vacuna BCG/inmunología , Mycobacterium bovis/inmunología , Mycobacterium tuberculosis/inmunología , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/prevención & control , Descubrimiento de Drogas/tendencias , Humanos , Vacunación/métodos
10.
Eur J Immunol ; 40(8): 2200-10, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20518032

RESUMEN

IL-10 regulates the balance of an immune response between pathogen clearance and immunopathology. We show here that Mycobacterium tuberculosis (Mtb) infection in the absence of IL-10 (IL-10(-/-) mice) results in reduced bacterial loads in the lung. This reduction was preceded by an accelerated and enhanced IFN-γ response in the lung, an increased influx of CD4(+) T cells into the lung, and enhanced production of chemokines and cytokines, including CXCL10 and IL-17, in both the lung and the serum. Neutralization of IL-17 affected neither the enhanced production of CXCL10 nor the accumulation of IFN-γ-producing T cells in the lungs, but led to reduced numbers of granulocytes in the lung and reduced bacterial loads in the spleens of Mtb-infected mice. This suggests that IL-17 may contribute to dissemination of Mtb.


Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Interferón gamma/biosíntesis , Interleucina-17/biosíntesis , Pulmón/metabolismo , Mycobacterium tuberculosis/inmunología , Tuberculosis/inmunología , Animales , Anticuerpos Bloqueadores/farmacología , Carga Bacteriana/efectos de los fármacos , Carga Bacteriana/genética , Carga Bacteriana/inmunología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/microbiología , Linfocitos T CD4-Positivos/patología , Movimiento Celular , Células Cultivadas , Quimiocina CXCL10/biosíntesis , Quimiocina CXCL10/genética , Femenino , Interferón gamma/genética , Interleucina-10/genética , Interleucina-17/genética , Interleucina-17/inmunología , Pulmón/inmunología , Pulmón/microbiología , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Mycobacterium tuberculosis/patogenicidad , Balance Th1 - Th2/efectos de los fármacos , Tuberculosis/genética
11.
Vaccine ; 39 Suppl 1: A15-A23, 2021 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-33422377

RESUMEN

Immunocompromised individuals are at high risk of severe illness and complications from influenza infection. For this reason, immunization using inactivated influenza vaccines is recommended for transplant patients, individuals receiving immunosuppressant treatments, and other persons with immunodeficiency. However, these immunocompromised populations are more likely to have lower and non-protective responses to annual vaccination with a standard influenza vaccine. Here, we review strategies aimed to improve the immunogenicity of influenza vaccines in immunocompromised populations. The different strategies employed have included adjuvanted vaccines, high-dose vaccines, booster doses, intradermal vaccination, and temporary discontinuation of immunosuppressant treatment regimens. High-dose trivalent, inactivated, split-virus influenza vaccine (IIV3-HD) is so far one of the leading strategies for improving vaccine responses in HIV patients, transplant patients, and persons receiving immunosuppressant therapies for inflammatory diseases. Several studies in these populations have shown stronger humoral responses with IIV3-HD than existing standard-dose trivalent vaccine, and comparable safety. Accordingly, some scientific societies have stated that high-dose influenza vaccine could be a preferred option for immunocompromised patients. However, larger randomized controlled studies are needed to validate relative immunogenicity and safety of IIV3-HD and other enhanced vaccines and vaccination strategies in immunocompromised individuals.


Asunto(s)
Infecciones por VIH , Vacunas contra la Influenza , Gripe Humana , Anticuerpos Antivirales , Humanos , Huésped Inmunocomprometido , Inmunogenicidad Vacunal , Gripe Humana/prevención & control , Vacunación , Vacunas de Productos Inactivados
12.
Nat Commun ; 10(1): 2887, 2019 06 28.
Artículo en Inglés | MEDLINE | ID: mdl-31253760

RESUMEN

Understanding how immune challenges elicit different responses is critical for diagnosing and deciphering immune regulation. Using a modular strategy to interpret the complex transcriptional host response in mouse models of infection and inflammation, we show a breadth of immune responses in the lung. Lung immune signatures are dominated by either IFN-γ and IFN-inducible, IL-17-induced neutrophil- or allergy-associated gene expression. Type I IFN and IFN-γ-inducible, but not IL-17- or allergy-associated signatures, are preserved in the blood. While IL-17-associated genes identified in lung are detected in blood, the allergy signature is only detectable in blood CD4+ effector cells. Type I IFN-inducible genes are abrogated in the absence of IFN-γ signaling and decrease in the absence of IFNAR signaling, both independently contributing to the regulation of granulocyte responses and pathology during Toxoplasma gondii infection. Our framework provides an ideal tool for comparative analyses of transcriptional signatures contributing to protection or pathogenesis in disease.


Asunto(s)
Candidiasis/metabolismo , Interferón Tipo I/metabolismo , Interferón gamma/metabolismo , Melioidosis/metabolismo , Infecciones por Orthomyxoviridae/metabolismo , Infecciones por Virus Sincitial Respiratorio/metabolismo , Animales , Burkholderia pseudomallei , Candida albicans , Candidiasis/inmunología , Candidiasis/microbiología , Regulación de la Expresión Génica/inmunología , Subtipo H3N2 del Virus de la Influenza A , Interferón Tipo I/sangre , Interferón Tipo I/genética , Interferón gamma/sangre , Interferón gamma/genética , Pulmón , Melioidosis/inmunología , Ratones , Ratones Endogámicos C57BL , Infecciones por Orthomyxoviridae/genética , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/virología , Receptor de Interferón alfa y beta , Receptores de Interferón , Infecciones por Virus Sincitial Respiratorio/inmunología , Receptor de Interferón gamma
13.
Oncoimmunology ; 6(1): e1132137, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28197360

RESUMEN

Although anticancer therapy with immune checkpoint blockers has seen unprecedented success, it fails to control neoplasia in most patients and often causes immune-related adverse events (irAEs). Our recent research shows the immunostimulatory and antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species of the gut microbiota, signifying novel approaches to improve such immunotherapies.

14.
Oncoimmunology ; 6(8): e1299303, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28919986

RESUMEN

Existing clinical, anatomopathological and molecular biomarkers fail to reliably predict the prognosis of cutaneous melanoma. Biomarkers for determining which patients receive adjuvant therapies are needed. The emergence of new technologies and the discovery of new immune populations with different prognostic values allow the immune network in the tumor to be better understood. Importantly, new molecules identified and expressed by immune cells have been shown to reduce the antitumor immune efficacy of therapies, prompting researchers to develop antibodies targeting these so-called "immune checkpoints", which have now entered the oncotherapeutic armamentarium.

15.
Cancer Res ; 77(15): 4146-4157, 2017 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-28536278

RESUMEN

Athough the clinical efficacy of oncolytic viruses has been demonstrated for local treatment, the ability to induce immune-mediated regression of distant metastases is still poorly documented. We report here that the engineered oncolytic vaccinia virus VVWR-TK-RR--Fcu1 can induce immunogenic cell death and generate a systemic immune response. Effects on tumor growth and survival was largely driven by CD8+ T cells, and immune cell infiltrate in the tumor could be reprogrammed toward a higher ratio of effector T cells to regulatory CD4+ T cells. The key role of type 1 IFN pathway in oncolytic virotherapy was also highlighted, as we observed a strong abscopal response in Ifnar-/- tumors. In this model, single administration of virus directly into the tumors on one flank led to regression in the contralateral flank. Moreover, these effects were further enhanced when oncolytic treatment was combined with immunogenic chemotherapy or with immune checkpoint blockade. Taken together, our results suggest how to safely improve the efficacy of local oncolytic virotherapy in patients whose tumors are characterized by dysregulated IFNα signaling. Cancer Res; 77(15); 4146-57. ©2017 AACR.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Interferón-alfa/antagonistas & inhibidores , Neoplasias Experimentales/terapia , Viroterapia Oncolítica/métodos , Animales , Antígeno B7-H1/antagonistas & inhibidores , Antígeno CTLA-4/antagonistas & inhibidores , Línea Celular Tumoral , Modelos Animales de Enfermedad , Citometría de Flujo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Virus Oncolíticos , Compuestos Organoplatinos/farmacología , Oxaliplatino , Receptor de Interferón alfa y beta/metabolismo , Virus Vaccinia
16.
Oncoimmunology ; 6(1): e1137418, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28197361

RESUMEN

Despite effective targeted therapy acting on KIT and PDGFRA tyrosine kinases, gastrointestinal stromal tumors (GIST) escape treatment by acquiring mutations conveying resistance to imatinib mesylate (IM). Following the identification of NKp30-based immunosurveillance of GIST and the off-target effects of IM on NK cell functions, we investigated the predictive value of NKp30 isoforms and NKp30 soluble ligands in blood for the clinical response to IM. The relative expression and the proportions of NKp30 isoforms markedly impacted both event-free and overall survival, in two independent cohorts of metastatic GIST. Phenotypes based on disbalanced NKp30B/NKp30C ratio (ΔBClow) and low expression levels of NKp30A were identified in one third of patients with dismal prognosis across molecular subtypes. This ΔBClow blood phenotype was associated with a pro-inflammatory and immunosuppressive tumor microenvironment. In addition, detectable levels of the NKp30 ligand sB7-H6 predicted a worse prognosis in metastatic GIST. Soluble BAG6, an alternate ligand for NKp30 was associated with low NKp30 transcription and had additional predictive value in GIST patients with high NKp30 expression. Such GIST microenvironments could be rescued by therapy based on rIFN-α and anti-TRAIL mAb which reinstated innate immunity.

17.
J Clin Invest ; 126(4): 1139-43, 2016 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-27035805

RESUMEN

Intercellular signaling via extracellular vesicles (EVs) is an underappreciated modality of cell-cell crosstalk that enables cells to convey packages of complex instructions to specific recipient cells. EVs transmit these instructions through their cargoes of multiple proteins, nucleic acids, and specialized lipids, which are derived from their cells of origin and allow for combinatorial effects upon recipient cells. This Review series brings together the recent progress in our understanding of EV signaling in physiological and pathophysiological conditions, highlighting how certain EVs, particularly exosomes, can promote or regulate infections, host immune responses, development, and various diseases - notably cancer. Given the diverse nature of EVs and their abilities to profoundly modulate host cells, this series puts particular emphasis on the clinical applications of EVs as therapeutics and as diagnostic biomarkers.


Asunto(s)
Comunicación Celular/inmunología , Micropartículas Derivadas de Células/inmunología , Exosomas/inmunología , Infecciones/inmunología , Transducción de Señal/inmunología , Animales , Biomarcadores/metabolismo , Micropartículas Derivadas de Células/metabolismo , Exosomas/metabolismo , Humanos , Infecciones/metabolismo , Infecciones/terapia
18.
Nat Rev Cancer ; 16(12): 759-773, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27687979

RESUMEN

Fundamental cancer research and the development of efficacious antineoplastic treatments both rely on experimental systems in which the relationship between malignant cells and immune cells can be studied. Mouse models of transplantable, carcinogen-induced or genetically engineered malignancies - each with their specific advantages and difficulties - have laid the foundations of oncoimmunology. These models have guided the immunosurveillance theory that postulates that evasion from immune control is an essential feature of cancer, the concept that the long-term effects of conventional cancer treatments mostly rely on the reinstatement of anticancer immune responses and the preclinical development of immunotherapies, including currently approved immune checkpoint blockers. Specific aspects of pharmacological development, as well as attempts to personalize cancer treatments using patient-derived xenografts, require the development of mouse models in which murine genes and cells are replaced with their human equivalents. Such 'humanized' mouse models are being progressively refined to characterize the leukocyte subpopulations that belong to the innate and acquired arms of the immune system as they infiltrate human cancers that are subjected to experimental therapies. We surmise that the ever-advancing refinement of murine preclinical models will accelerate the pace of therapeutic optimization in patients.


Asunto(s)
Modelos Animales de Enfermedad , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Alternativas a las Pruebas en Animales , Animales , Carcinógenos/toxicidad , Xenoinjertos , Humanos , Sistema Inmunológico/fisiopatología , Ratones , Ratones Transgénicos , Neoplasias/inducido químicamente
19.
J Mol Med (Berl) ; 94(5): 497-508, 2016 05.
Artículo en Inglés | MEDLINE | ID: mdl-26931513

RESUMEN

In the past decade, the focus of tumor biology research has been switching from the functional dissection of oncogenes and tumor suppressor genes to investigation of the cross-talk between tumor cells and their microenvironment. Tumorigenesis requires the organized assembly of cancer cells with non-malignant cells and non-cellular stroma, resembling an abnormal organogenesis. This process can be modulated by local cellular stress responses, such as senescence, ER stress and autophagy, and inflammatory and immunosuppressive cells and effector molecules within the tumor microenvironment (TME). Various cellular stress responses and cell death modalities are triggered in response to chemotherapies, radiotherapies, and targeted therapies (including immunotherapies). The exposure of immunostimulatory factors could (re)awaken anti-tumor immunity. Unexpectedly, the gut microbial flora is becoming recognized as an important external modulator of the TME. We will discuss in detail the TME changes that take place after certain cancer therapies, highlighting the importance of cellular stress responses, tumor-infiltrating immune cells, and microbiota-derived factors.


Asunto(s)
Neoplasias/patología , Neoplasias/terapia , Microambiente Tumoral , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Muerte Celular/inmunología , Muerte Celular/efectos de la radiación , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/inmunología , Transformación Celular Neoplásica/metabolismo , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Progresión de la Enfermedad , Humanos , Sistema Inmunológico/citología , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Inmunomodulación/efectos de los fármacos , Inmunomodulación/efectos de la radiación , Inflamación/complicaciones , Inflamación/etiología , Inflamación/metabolismo , Neoplasias/etiología , Neoplasias/metabolismo , Radioterapia/efectos adversos , Radioterapia/métodos , Estrés Fisiológico/efectos de los fármacos , Estrés Fisiológico/efectos de la radiación , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de la radiación
20.
J Clin Invest ; 126(4): 1224-32, 2016 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-27035813

RESUMEN

DC-derived exosomes (Dex) are nanometer-sized membrane vesicles that are secreted by the sentinel antigen-presenting cells of the immune system: DCs. Like DCs, the molecular composition of Dex includes surface expression of functional MHC-peptide complexes, costimulatory molecules, and other components that interact with immune cells. Dex have the potential to facilitate immune cell-dependent tumor rejection and have distinct advantages over cell-based immunotherapies involving DCs. Accordingly, Dex-based phase I and II clinical trials have been conducted in advanced malignancies, showing the feasibility and safety of the approach, as well as the propensity of these nanovesicles to mediate T and NK cell-based immune responses in patients. This Review will evaluate the interactions of Dex with immune cells, their clinical progress, and the future of Dex immunotherapy for cancer.


Asunto(s)
Células Dendríticas/inmunología , Exosomas/inmunología , Inmunidad Celular , Inmunoterapia/métodos , Neoplasias/terapia , Animales , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Células Dendríticas/patología , Exosomas/patología , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/patología , Neoplasias/inmunología , Neoplasias/patología , Linfocitos T/inmunología , Linfocitos T/patología
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