RESUMEN
The impact of gut microbiota in eliciting innate and adaptive immune responses beneficial for the host in the context of effective therapies against cancer has been highlighted recently. Chemotherapeutic agents, by compromising, to some extent, the intestinal integrity, increase the gut permeability and selective translocation of Gram-positive bacteria in secondary lymphoid organs. There, anticommensal pathogenic Th17 T-cell responses are primed, facilitating the accumulation of Th1 helper T cells in tumor beds after chemotherapy as well as tumor regression. Importantly, the redox equilibrium of myeloid cells contained in the tumor microenvironment is also influenced by the intestinal microbiota. Hence, the anticancer efficacy of alkylating agents (such as cyclophosphamide) and platinum salts (oxaliplatin, cis-platin) is compromised in germ-free mice or animals treated with antibiotics. These findings represent a paradigm shift in our understanding of the mode of action of many compounds having an impact on the host-microbe mutualism.
Asunto(s)
Antineoplásicos/farmacología , Intestinos/microbiología , Microbiota/inmunología , Neoplasias/inmunología , Neoplasias/microbiología , Células Th17/inmunología , Animales , Antibacterianos/farmacología , Humanos , Mucosa Intestinal/patología , RatonesRESUMEN
Distinct cytotoxic agents currently used in the oncological armamentarium mediate their clinical benefit by influencing, directly or indirectly, the immune system in such a way that innate and adaptive immunity contributes to the tumoricidal activity. Now, we bring up evidence that both arms of anticancer immunity can be triggered through the intervention of the intestinal microbiota. Alkylating agents, such as cyclophosphamide, set up the stage for enhanced permeability of the small intestine, facilitating the translocation of selected arrays of Gram-positive bacteria against which the host mounts effector pTh17 cells and memory Th1 responses. In addition, gut commensals, through lipopolysaccharide and other bacterial components, switch the tumor microenvironment, in particular the redox equilibrium and the TNF production of intratumoral myeloid cells during therapies with platinum salts or intratumoral TLR9 agonists combined with systemic anti-IL10R Ab respectively. Consequently, antibiotics can compromise the efficacy of certain chemotherapeutic or immunomodulatory regimens.
Asunto(s)
Bacterias/inmunología , Intestinos/inmunología , Intestinos/microbiología , Microbiota/inmunología , Animales , Bacterias/metabolismo , Humanos , Inmunomodulación/inmunología , Transducción de SeñalRESUMEN
Immunogenic cell death induced by cytotoxic compounds contributes to the success of selected chemotherapies by eliciting a protective anticancer immune response, which is mediated by CD4(+) and CD8(+) T cells producing interferon-γ. In many instances, cancer progression is associated with high titers of tumor-specific antibodies, which become detectable in the serum, but whose functional relevance is elusive. Here, we explored the role of humoral immune responses in the anticancer efficacy of anthracyclines. Chemotherapy reduced the number of tumor-infiltrating B cells, and failed to promote humoral responses against immunodominant tumor antigens. Although anthracycline-based anticancer chemotherapies failed in T cell-deficient mice, they successfully reduced the growth of cancers developing in mice lacking B lymphocytes (due to the injection of a B-cell-depleting anti-CD20 antibody), immunoglobulins (Igs) or Ig receptors (Fc receptor) due to genetic manipulations. These results suggest that the humoral arm of antitumor immunity is dispensable for the immune-dependent therapeutic effect of anthracyclines against mouse sarcoma. In addition, we show here that the titers of IgA and IgG antibodies directed against an autoantigen appearing at the cell surface of tumor cells post chemotherapy (calreticulin, CRT) did not significantly increase in patients treated with anthracyclines, and that anti-CRT antibodies had no prognostic or predictive significance. Collectively, our data indicate that humoral anticancer immune responses differ from cellular responses in, thus far, that they do not contribute to the success of anthracycline-mediated anticancer therapies in human breast cancers and mouse sarcomas.
Asunto(s)
Antraciclinas/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Inmunidad Humoral , Animales , Antraciclinas/toxicidad , Anticuerpos/inmunología , Anticuerpos/farmacología , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Calreticulina/inmunología , Calreticulina/metabolismo , Línea Celular Tumoral , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Receptores Fc/metabolismo , Sarcoma/tratamiento farmacológico , Linfocitos T Citotóxicos/inmunologíaRESUMEN
OBJECTIVES: To report an outbreak due to an unusual strain of Enterococcus faecium containing both the vanA and vanB genes, in France, where the rate of glycopeptide-resistant enterococci (GRE) is below 1%. METHODS: Cases were patients infected or colonized with GRE on the haematology ward. Contact patients were screened by real-time PCR performed on rectal swabs. Clinical features were compared for GRE-positive and GRE-negative patients. GRE isolates were characterized by phenotypic and molecular methods including PFGE. Conjugation experiments were performed to identify van genetic support. RESULTS: After the index patient presented a bacteraemia with vanA/vanB E. faecium, 56 contact patients were screened, 7 of whom were found to be GRE positive: 6 additional cases with vanA/vanB E. faecium and 1 with GRE carrying vanA only. PFGE confirmed the clonal relationship of the seven vanA/vanB E. faecium strains, whereas the vanA isolate was distinct. Only the vanA gene could be transferred to enterococcal recipients by conjugation, and it was probably localized on a mobile genetic element. All isolates were resistant to vancomycin (MICâ>â256 mg/L) and teicoplanin (MICâ=â24-32 mg/L), but were susceptible to tigecycline (MICâ=â0.09 mg/L), linezolid (MICâ=â0.75 mg/L) and daptomycin (MICâ=â1-2 mg/L). Significant differences (Pâ<â0.001) between carriers and non-carriers of GRE were observed for the median duration of hospitalization (57 days versus 16.5 days) and of neutropenia (40 days versus 6 days), the median number of antibiotics used (5 versus 1.5) and the duration of glycopeptide treatment (14.5 days versus 0 days). CONCLUSIONS: vanA/vanB E. faecium strains, although rare, can emerge in the absence of previous outbreaks of vanA-GRE or vanB-GRE.
Asunto(s)
Proteínas Bacterianas/genética , Ligasas de Carbono-Oxígeno/genética , Enterococcus faecium/genética , Glicopéptidos/farmacología , Enfermedades Hematológicas/genética , Resistencia a la Vancomicina/genética , Brotes de Enfermedades , Enterococcus faecium/metabolismo , Francia/epidemiología , Glicopéptidos/uso terapéutico , Enfermedades Hematológicas/tratamiento farmacológico , Enfermedades Hematológicas/epidemiología , Unidades Hospitalarias , Humanos , Resistencia a la Vancomicina/efectos de los fármacosRESUMEN
Two antibacterial shampoos for the treatment of canine bacterial overgrowth syndrome (BOGS) were compared in a prospective controlled clinical trial. Forty dogs with clinical signs (pruritus, erythema and excoriations without pustules and/or collarettes) and cytological findings compatible with bacterial overgrowth were treated twice weekly with 3 per cent chlorhexidine shampoo (3 per cent CHX) or 2.5 per cent benzoyl peroxide shampoo (2.5 per cent BPO) and evaluated every two weeks for up to six weeks until cytological cure. Pruritus, erythema, greasy seborrhoea, malodour, excoriations, secondary hair loss, lichenification, hyperpigmentation and lesion extent were each scored on a 0 to 3 severity scale and combined to calculate an aggregate score. Among the 34 dogs with good compliance to treatment, reduction of cocci counts of at least 90 per cent was recorded in 11 of 18 dogs after 3 per cent CHX and nine of 16 dogs after 2.5 per cent BPO, with no significant difference between the two products (P=0.98). Lesion score was significantly reduced in both groups (63.48 (34.45)) per cent with 3 per cent CHX v 54.45 (33.61) per cent with 2.5 per cent BPO, P=0.36) and time to cytological cure was not significantly different between groups (P=0.13), at the end of the treatment. In the present study, 3 per cent CHX and 2.5 per cent BPO were similarly effective in the treatment of canine BOGS.
Asunto(s)
Antibacterianos/uso terapéutico , Peróxido de Benzoílo/uso terapéutico , Clorhexidina/uso terapéutico , Enfermedades de los Perros/tratamiento farmacológico , Enfermedades Cutáneas Bacterianas/veterinaria , Administración Tópica , Animales , Peróxido de Benzoílo/administración & dosificación , Clorhexidina/administración & dosificación , Recuento de Colonia Microbiana/veterinaria , Fármacos Dermatológicos/uso terapéutico , Perros , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Enfermedades Cutáneas Bacterianas/tratamiento farmacológico , Resultado del TratamientoRESUMEN
OBJECTIVES: Two antimicrobial shampoos for treatment of canine Malassezia dermatitis (CMD) were compared in a prospective, randomised, single-blinded, field clinical trial. METHODS: Sixty-seven dogs with pedal or generalised dermatitis associated with Malassezia overgrowth (MO) were treated with 3% chlorhexidine shampoo (3%CHX) or 2% miconazole-2% chlorhexidine shampoo (2%MIC/CHX) and evaluated for up to 6 weeks until cytological recovery. Pruritus, erythema, papules, greasy seborrhoea, scaling, malodour, excoriations, secondary hairloss, lichenification, hyperpigmentation and lesion extent were each scored on a 0-3 severity scale and combined making an aggregate score. RESULTS: Among 54 dogs with good treatment compliance, reduction of yeast counts by at least 88% was recorded in 21 of 22 dogs with 3%CHX and 30 of 32 dogs with 2%MIC/CHX. No significant difference was detected between products for yeast count reduction (P=0·592). Time to cytological recovery was not significantly different between groups (P=0·960). Lesion score was significantly reduced in both groups after treatment (72·5 ±25·7% with 3%CHX versus 78·7 ±22·3% with 2%MIC/CHX, P=0·309). Four dogs treated with chlorhexidine shampoo showed minor adverse effects. CLINICAL SIGNIFICANCE: In this study, 3%CHX was clinically as effective as 2%MIC/CHX for treatment of CMD.
Asunto(s)
Antifúngicos/uso terapéutico , Dermatomicosis/veterinaria , Enfermedades de los Perros/tratamiento farmacológico , Malassezia/efectos de los fármacos , Animales , Antifúngicos/efectos adversos , Clorhexidina/efectos adversos , Clorhexidina/uso terapéutico , Recuento de Colonia Microbiana/veterinaria , Dermatomicosis/tratamiento farmacológico , Dermatomicosis/patología , Enfermedades de los Perros/patología , Perros , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada/veterinaria , Femenino , Malassezia/crecimiento & desarrollo , Masculino , Miconazol/efectos adversos , Miconazol/uso terapéutico , Estudios Prospectivos , Resultado del TratamientoRESUMEN
On the basis of experimental models and some human data, we can assume that tumor outgrowth results from the balance between immunosurveillance (the extrinsic tumor suppressor mechanisms) and immunosubversion dictated by transformed cells and/or the corrupted surrounding microenvironment. Cancer immunosurveillance relies mainly upon conventional lymphocytes exerting either lytic or secretory functions, whereas immunosubversion results from the activity of regulatory T or suppressor myeloid cells and soluble mediators. Although specific tools to target or ablate dendritic cells (DCs) became only recently available, accumulating evidence points to the critical role of the specialized DC system in dictating most of the conventional and regulatory functions of tumor-specific T lymphocytes. Although DC can be harnessed to silence tumor development, tumors in turn can exploit DC to evade immunity. Indeed, DCs harbor defects in their differentiation and stimulatory functions in cancer-bearing hosts and can actively promote T-cell tolerance to self-tumor antigens. In this review, we will focus on the dual role of DC during tumor progression and discuss pharmacoimmunological strategies to harness DC against cancer.
Asunto(s)
Células Dendríticas/fisiología , Neoplasias/inmunología , Traslado Adoptivo/métodos , Animales , Citoprotección/inmunología , Células Dendríticas/trasplante , Quimioterapia/tendencias , Humanos , Vigilancia Inmunológica/fisiología , Neoplasias/etiología , Neoplasias/patología , Neoplasias/terapia , Escape del Tumor/inmunología , Escape del Tumor/fisiologíaRESUMEN
Exosomes are nanometer particles (50-100 nm) secreted by most living cells. The first description of exosomes was made in 1987 by Rose Johnstone, who described a vesicle formation during the maturation process of reticulocytes. At this time it has been suggested that exosome release could represent a major route for the externalization of obsolete membrane proteins. A renewed vision of exosome function was raised when Graça Raposo demonstrated in 1996 that exosomes derived from B cells could have immunogenic capacities. Since then, exosomes have been described in numerous cell types IN VITRO, including hematopoietic and nonhematopoietic cells. The physiological relevance of exosomes IN VIVO still remains unclear. Studies have demonstrated that exosomes can play a role in the physiology of originating cells (i.e., reticulocyte-derived exosomes). Furthermore, exosomes can act on intercellular communication by allowing exchange of proteins, lipids, and also mRNA between cells. Finally, exosomes have been shown to modulate the immune system (i.e., dendritic cells, B cells, and tumor cells). In the present review, we have focused on the potential therapeutic role of exosomes as a cell free vaccine in cancer.
Asunto(s)
Vacunas contra el Cáncer/inmunología , Vesículas Citoplasmáticas/inmunología , Neoplasias/terapia , Vacunas de Subunidad/inmunología , Animales , Vesículas Citoplasmáticas/química , Células Dendríticas/química , Células Dendríticas/citología , Humanos , Neoplasias/inmunologíaRESUMEN
Macrophages play a central role in inflammation and host defence against microorganisms, but they also participate actively in the resolution of inflammation after alternative activation. However, it is not known whether the resolution of inflammation requires alternative activation of new resting monocytes/macrophages or if proinflammatory activated macrophages have the capacity to switch their activation towards anti-inflammation. In order to answer this question, we first characterized differential human macrophage activation phenotypes. We found that CD163 and CD206 exhibited mutually exclusive induction patterns after stimulation by a panel of anti-inflammatory molecules, whereas CCL18 showed a third, overlapping, pattern. Hence, alternative activation is not a single process, but provides a variety of different cell populations. The capacity of macrophages to switch from one activation state to another was then assessed by determining the reversibility of CD163 and CD206 expression and of CCL18 and CCL3 production. We found that every activation state was rapidly and fully reversible, suggesting that a given cell may participate sequentially in both the induction and the resolution of inflammation. These findings may provide new insight into the inflammatory process as well as new fields of investigation for immunotherapy in the fields of chronic inflammatory diseases and cancer.