RESUMEN

Glioblastomas (GBM) are the most common primary malignant brain tumors, comprising 2% of all cancers in adults. Their location and cellular and molecular heterogeneity, along with their highly infiltrative nature, make their treatment challenging. Recently, our research group reported promising results from a prospective phase II clinical trial involving allogeneic vaccination with dendritic cells (DCs). To date, six out of the thirty-seven reported cases remain alive without tumor recurrence. In this study, we focused on the characterization of infiltrating immune cells observed at the time of surgical resection. An analytical model employing a neural network-based predictive algorithm was used to ascertain the potential prognostic implications of immunological variables on patients' overall survival. Counterintuitively, immune phenotyping of tumor-associated macrophages (TAMs) has revealed the extracellular marker PD-L1 to be a positive predictor of overall survival. In contrast, the elevated expression of CD86 within this cellular subset emerged as a negative prognostic indicator. Fundamentally, the neural network algorithm outlined here allows a prediction of the responsiveness of patients undergoing dendritic cell vaccination in terms of overall survival based on clinical parameters and the profile of infiltrated TAMs observed at the time of tumor excision.

Asunto(s)

Neoplasias Encefálicas , Células Dendríticas , Glioblastoma , Inmunoterapia , Humanos , Células Dendríticas/inmunología , Glioblastoma/terapia , Glioblastoma/inmunología , Glioblastoma/mortalidad , Glioblastoma/patología , Inmunoterapia/métodos , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Masculino , Femenino , Persona de Mediana Edad , Antígeno B7-H1/metabolismo , Pronóstico , Adulto , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismo , Anciano , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo

RESUMEN

Immunotherapy has brought hope to the fight against glioblastoma, but its efficacy remains unclear. We present the case of CST, a 25-year-old female patient with a large right-hemisphere glioblastoma treated with a dendritic-tumor cell fusion vaccine. CST showed a near-complete tumor response, with a marked improvement in her functional status and simultaneous increases in tumor-specific CD8+ and CD4+ T cells. Two months before recurrence, the frequency of tumor-specific T cells decreased, while that of IL-17 and CD4+ T cells increased. CST passed away 15 months after enrollment. In this illustrative case, the tumor-specific CD4+ T-cell numbers and phenotype behaved as treatment efficacy biomarkers, highlighting the key role of the latter in glioblastoma immunotherapy.

Asunto(s)

Vacunas contra el Cáncer , Glioblastoma , Linfocitos T CD4-Positivos , Vacunas contra el Cáncer/uso terapéutico , Citocinas , Células Dendríticas , Femenino , Glioblastoma/patología , Humanos

RESUMEN

To elucidate the role of leptin in acute systemic inflammation, we investigated how its infusion at low, physiologically relevant doses affects the responses to bacterial lipopolysaccharide (LPS) in rats subjected to 24 h of food deprivation. Leptin was infused subcutaneously (0-20 µg·kg-1·h-1) or intracerebroventricularly (0-1 µg·kg-1·h-1). Using hypothermia and hypotension as biomarkers of systemic inflammation, we identified the phase extending from 90 to 240 min post-LPS as the most susceptible to modulation by leptin. In this phase, leptin suppressed the rise in plasma TNF-α and accelerated the recoveries from hypothermia and hypotension. Suppression of TNF-α was not accompanied by changes in other cytokines or prostaglandins. Leptin suppressed TNF-α when infused peripherally but not when infused into the brain. Importantly, the leptin dose that suppressed TNF-α corresponded to the lowest dose that limited food consumption; this dose elevated plasma leptin within the physiological range (to 5.9 ng/ml). We then conducted in vitro experiments to investigate whether an action of leptin on macrophages could parallel our in vivo observations. The results revealed that, when sensitized by food deprivation, LPS-stimulated peritoneal macrophages can be inhibited by leptin at concentrations that are lower than those reported to promote cytokine release. It is concluded that physiological levels of leptin do not exert a proinflammatory effect but rather an anti-inflammatory effect involving selective suppression of TNF-α via an action outside the brain. The mechanism of this effect might involve a previously unrecognized, suppressive action of leptin on macrophage subpopulations sensitized by food deprivation, but future studies are warranted.

Asunto(s)

Leptina/farmacología , Macrófagos/efectos de los fármacos , Animales , Citocinas/metabolismo , Fiebre/tratamiento farmacológico , Privación de Alimentos/fisiología , Inflamación/tratamiento farmacológico , Lipopolisacáridos/farmacología , Macrófagos/metabolismo , Masculino , Ratas Wistar

RESUMEN

This study introduces the respiratory exchange ratio (RER; the ratio of whole-body CO2 production to O2 consumption) as an aid to monitor metabolic acidosis during the early phase of endotoxic shock in unanesthetized, freely moving rats. Two serotypes of lipopolysaccharide (lipopolysaccharide [LPS] O55:B5 and O127:B8) were tested at shock-inducing doses (0.5-2 mg/kg). Phasic rises in RER were observed consistently across LPS serotypes and doses. The RER rise often exceeded the ceiling of the quotient for oxidative metabolism, and was mirrored by depletion of arterial bicarbonate and decreases in pH It occurred independently of ventilatory adjustments. These data indicate that the rise in RER results from a nonmetabolic CO2 load produced via an acid-induced equilibrium shift in the bicarbonate buffer. Having validated this new experimental aid, we asked whether acidosis was interconnected with the metabolic and thermal responses that accompany endotoxic shock in unanesthetized rats. Contrary to this hypothesis, however, acidosis persisted regardless of whether the ambient temperature favored or prevented downregulation of mitochondrial oxidation and regulated hypothermia. We then asked whether the substrate that fuels aerobic metabolism could be a relevant factor in LPS-induced acidosis. Food deprivation was employed to divert metabolism away from glucose oxidation and toward fatty acid oxidation. Interestingly, this intervention attenuated the RER response to LPS by 58%, without suppressing other key aspects of systemic inflammation. We conclude that acid production in unanesthetized rats with endotoxic shock results from a phasic activation of glycolysis, which occurs independently of physiological changes in mitochondrial oxidation and body temperature.

Asunto(s)

Acidosis/metabolismo , Temperatura Corporal/fisiología , Endotoxemia/metabolismo , Intercambio Gaseoso Pulmonar/fisiología , Acidosis/inducido químicamente , Acidosis/fisiopatología , Animales , Temperatura Corporal/efectos de los fármacos , Metabolismo de los Hidratos de Carbono/efectos de los fármacos , Dióxido de Carbono/metabolismo , Endotoxemia/complicaciones , Endotoxemia/fisiopatología , Ácidos Grasos/metabolismo , Glucosa/metabolismo , Lipopolisacáridos/administración & dosificación , Lipopolisacáridos/efectos adversos , Lipopolisacáridos/farmacología , Masculino , Mitocondrias/metabolismo , Mitocondrias/fisiología , Oxidación-Reducción/efectos de los fármacos , Consumo de Oxígeno/fisiología , Ratas , Ratas Wistar , Serotipificación , Choque Séptico/complicaciones , Choque Séptico/metabolismo , Choque Séptico/fisiopatología

RESUMEN

We tested the hypothesis that development of hypothermia instead of fever in endotoxic shock is consequential to hypoxia. Endotoxic shock was induced by bacterial lipopolysaccharide (LPS, 500 µg kg(-1) i.v.) in rats at an ambient temperature of 22 °C. A ß3-adrenergic agonist known to activate metabolic heat production, CL316,243, was employed to evaluate whether thermogenic capacity could be impaired by the fall in oxygen delivery (DO2) during endotoxic shock. This possibility was rejected as CL316,243 (0.15 mg kg(-1) i.v.) evoked similar rises in oxygen consumption (V̇O2) in the presence and absence of endotoxic shock. Next, to investigate whether a less severe form of circulatory hypoxia could be triggering hypothermia, the circulating volume of LPS-injected rats was expanded using 6% hetastarch with the intention of improving tissue perfusion and alleviating hypoxia. This intervention attenuated not only the fall in arterial pressure induced by LPS, but also the associated falls in V̇O2 and body temperature. These effects, however, occurred independently of hypoxia, as they were not accompanied by any detectable changes in NAD(+)/NADH ratios. Further experimentation revealed that even the earliest drops in cardiac output and DO2 during endotoxic shock did not precede the reduction in V̇O2 that brings about hypothermia. In fact, DO2 and V̇O2 fell in such a synchrony that the DO2/V̇O2 ratio remained unaffected. Only when hypothermia was prevented by exposure to a warm environment (30 °C) did an imbalance in the DO2/V̇O2 ratio become evident, and such an imbalance was associated with reductions in the renal and hypothalamic NAD(+)/NADH ratios. In conclusion, hypometabolism and hypothermia in endotoxic shock are not consequential to hypoxia but serve as a pre-emptive strategy to avoid hypoxia in this model.

Asunto(s)

Hipotermia/fisiopatología , Consumo de Oxígeno , Oxígeno/sangre , Choque Séptico/fisiopatología , Termogénesis , Animales , Gasto Cardíaco , Metabolismo Energético , Hipotermia/etiología , Hipotermia/metabolismo , Masculino , NAD/metabolismo , Ratas , Ratas Wistar , Choque Séptico/complicaciones , Choque Séptico/metabolismo