RESUMEN
There have been major advances in the immunotherapy of cancer in recent years, including the development of T cell engagers - antibodies engineered to redirect T cells to recognize and kill cancer cells - for the treatment of haematological malignancies. However, the field still faces several challenges to develop agents that are consistently effective in a majority of patients and cancer types, such as optimizing drug dose, overcoming treatment resistance and improving efficacy in solid tumours. A new generation of T cell-targeted molecules was developed to tackle these issues that are potentially more effective and safer. In addition, agents designed to engage the antitumour activities of other immune cells, including natural killer cells and myeloid cells, are showing promise and have the potential to treat a broader range of cancers.
Asunto(s)
Inmunoterapia , Células Asesinas Naturales , Neoplasias , Linfocitos T , Humanos , Neoplasias/inmunología , Neoplasias/terapia , Inmunoterapia/métodos , Células Asesinas Naturales/inmunología , Linfocitos T/inmunología , Animales , Células Mieloides/inmunologíaRESUMEN
Rosacea is a common chronic inflammatory skin disease with a fluctuating course of excessive inflammation and apparent neovascularization. Microbial dysbiosis with a high density of Bacillus oleronius and increased activity of kallikrein 5, which cleaves cathelicidin antimicrobial peptide, are key pathogenic triggers in rosacea. However, how these events are linked to the disease remains unknown. Here, we show that type I IFNs produced by plasmacytoid DCs represent the pivotal link between dysbiosis, the aberrant immune response, and neovascularization. Compared with other commensal bacteria, B. oleronius is highly susceptible and preferentially killed by cathelicidin antimicrobial peptides, leading to enhanced generation of complexes with bacterial DNA. These bacterial DNA complexes but not DNA complexes derived from host cells are required for cathelicidin-induced activation of plasmacytoid DCs and type I IFN production. Moreover, kallikrein 5 cleaves cathelicidin into peptides with heightened DNA binding and type I IFN-inducing capacities. In turn, excessive type I IFN expression drives neoangiogenesis via IL-22 induction and upregulation of the IL-22 receptor on endothelial cells. These findings unravel a potentially novel pathomechanism that directly links hallmarks of rosacea to the killing of dysbiotic commensal bacteria with induction of a pathogenic type I IFN-driven and IL-22-mediated angiogenesis.
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Catelicidinas , Disbiosis , Interferón Tipo I , Microbiota , Rosácea , Piel , Humanos , Bacterias , ADN Bacteriano , Disbiosis/microbiología , Células Endoteliales/metabolismo , Inflamación/metabolismo , Inflamación/microbiología , Calicreínas , Rosácea/metabolismo , Rosácea/microbiología , Rosácea/patología , Interferón Tipo I/metabolismo , Microbiota/fisiología , Bacillus/metabolismo , Piel/metabolismo , Piel/microbiología , Piel/patología , Neovascularización Patológica/microbiologíaRESUMEN
Harnessing innate immunity is emerging as a promising therapeutic approach in cancer. We report here the design of tetraspecific molecules engaging natural killer (NK) cell-activating receptors NKp46 and CD16a, the ß-chain of the interleukin-2 receptor (IL-2R), and a tumor-associated antigen (TAA). In vitro, these tetraspecific antibody-based natural killer cell engager therapeutics (ANKETs) induce a preferential activation and proliferation of NK cells, and the binding to the targeted TAA triggers NK cell cytotoxicity and cytokine and chemokine production. In vivo, tetraspecific ANKETs induce NK cell proliferation and their accumulation at the tumor bed, as well as the control of local and disseminated tumors. Treatment of non-human primates with CD20-directed tetraspecific ANKET leads to CD20+ circulating B cell depletion, with minimal systemic cytokine release and no sign of toxicity. Tetraspecific ANKETs, thus, constitute a technological platform for harnessing NK cells as next-generation cancer immunotherapies.
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Interleucina-2 , Neoplasias , Animales , Interleucina-2/genética , Células Asesinas Naturales , Receptores de Interleucina-2/metabolismo , Citocinas , Neoplasias/genética , Quimiocinas/metabolismoRESUMEN
OBJECTIVES: Severe COVID-19 is associated with exaggerated complement activation. We assessed the efficacy and safety of avdoralimab (an anti-C5aR1 mAb) in severe COVID-19. DESIGN: FOR COVID Elimination (FORCE) was a double-blind, placebo-controlled study. SETTING: Twelve clinical sites in France (ICU and general hospitals). PATIENTS: Patients receiving greater than or equal to 5 L oxygen/min to maintain Sp o2 greater than 93% (World Health Organization scale ≥ 5). Patients received conventional oxygen therapy or high-flow oxygen (HFO)/noninvasive ventilation (NIV) in cohort 1; HFO, NIV, or invasive mechanical ventilation (IMV) in cohort 2; and IMV in cohort 3. INTERVENTIONS: Patients were randomly assigned, in a 1:1 ratio, to receive avdoralimab or placebo. The primary outcome was clinical status on the World Health Organization ordinal scale at days 14 and 28 for cohorts 1 and 3, and the number of ventilator-free days at day 28 (VFD28) for cohort 2. MEASUREMENTS AND MAIN RESULTS: We randomized 207 patients: 99 in cohort 1, 49 in cohort 2, and 59 in cohort 3. During hospitalization, 95% of patients received glucocorticoids. Avdoralimab did not improve World Health Organization clinical scale score on days 14 and 28 (between-group difference on day 28 of -0.26 (95% CI, -1.2 to 0.7; p = 0.7) in cohort 1 and -0.28 (95% CI, -1.8 to 1.2; p = 0.6) in cohort 3). Avdoralimab did not improve VFD28 in cohort 2 (between-group difference of -6.3 (95% CI, -13.2 to 0.7; p = 0.96) or secondary outcomes in any cohort. No subgroup of interest was identified. CONCLUSIONS: In this randomized trial in hospitalized patients with severe COVID-19 pneumonia, avdoralimab did not significantly improve clinical status at days 14 and 28 (funded by Innate Pharma, ClinicalTrials.gov number, NCT04371367).
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COVID-19 , Humanos , SARS-CoV-2 , Anticuerpos Monoclonales Humanizados/uso terapéutico , Oxígeno , Resultado del TratamientoRESUMEN
Immuno-oncology is revolutionizing the treatment of cancers, by inducing the recognition and elimination of tumor cells by the immune system. Recent advances have focused on generating or unleashing tumor antigen-specific T-cell responses, leading to alternative treatment paradigms for many cancers. Despite these successes, the clinical benefit has been limited to a subset of patients and certain tumor types, highlighting the need for alternative strategies. One innovative approach is to broaden and amplify antitumoral immune responses by targeting innate immunity. Particularly, the aim has been to develop new antibody formats capable of stimulating the antitumor activity of innate immune cells, boosting not only their direct role in tumor elimination, but also their function in eliciting multicellular immune responses ultimately resulting in long-lasting tumor control by adaptive immunity. This review covers the development of a new class of synthetic molecules, natural killer cell engagers (NKCEs), which are built from fragments of monoclonal antibodies (mAbs) and are designed to harness the immune functions of NK cells in cancer. As currently shown in preclinical studies and clinical trials, NKCEs are promising candidates for the next generation of tumor immunotherapies.
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Inmunoterapia/métodos , Inmunoterapia/tendencias , Células Asesinas Naturales/inmunología , Oncología Médica/tendencias , Neoplasias/inmunología , Animales , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológicoRESUMEN
Coronavirus disease 2019 (COVID-19) is a disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in a pandemic1. The C5a complement factor and its receptor C5aR1 (also known as CD88) have a key role in the initiation and maintenance of several inflammatory responses by recruiting and activating neutrophils and monocytes1. Here we provide a longitudinal analysis of immune responses, including phenotypic analyses of immune cells and assessments of the soluble factors that are present in the blood and bronchoalveolar lavage fluid of patients at various stages of COVID-19 severity, including those who were paucisymptomatic or had pneumonia or acute respiratory distress syndrome. The levels of soluble C5a were increased in proportion to the severity of COVID-19 and high expression levels of C5aR1 receptors were found in blood and pulmonary myeloid cells, which supports a role for the C5a-C5aR1 axis in the pathophysiology of acute respiratory distress syndrome. Anti-C5aR1 therapeutic monoclonal antibodies prevented the C5a-mediated recruitment and activation of human myeloid cells, and inhibited acute lung injury in human C5aR1 knock-in mice. These results suggest that blockade of the C5a-C5aR1 axis could be used to limit the infiltration of myeloid cells in damaged organs and prevent the excessive lung inflammation and endothelialitis that are associated with acute respiratory distress syndrome in patients with COVID-19.
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COVID-19/complicaciones , COVID-19/inmunología , Complemento C5a/inmunología , Inflamación/complicaciones , Inflamación/inmunología , Receptor de Anafilatoxina C5a/inmunología , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/inmunología , Lesión Pulmonar Aguda/prevención & control , Animales , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/inmunología , Antígeno CD11b/inmunología , Antígeno CD11b/metabolismo , COVID-19/sangre , COVID-19/patología , Complemento C5a/antagonistas & inhibidores , Complemento C5a/biosíntesis , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/prevención & control , Modelos Animales de Enfermedad , Femenino , Humanos , Inflamación/tratamiento farmacológico , Inflamación/patología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Ratones , Ratones Endogámicos C57BL , Células Mieloides/efectos de los fármacos , Células Mieloides/inmunología , Células Mieloides/patología , Receptor de Anafilatoxina C5a/antagonistas & inhibidores , Receptor de Anafilatoxina C5a/sangre , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/inmunología , Síndrome de Dificultad Respiratoria/prevención & control , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidadAsunto(s)
Betacoronavirus/patogenicidad , Infecciones por Coronavirus/inmunología , Terapia Molecular Dirigida/métodos , Neumonía Viral/inmunología , Neumonía/inmunología , Síndrome Respiratorio Agudo Grave/inmunología , Antivirales/uso terapéutico , Apirasa/antagonistas & inhibidores , Apirasa/genética , Apirasa/inmunología , Linfocitos B/inmunología , Linfocitos B/patología , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Antígeno B7-H1/inmunología , Betacoronavirus/inmunología , COVID-19 , Estudios de Casos y Controles , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/virología , Expresión Génica/efectos de los fármacos , Humanos , Factores Inmunológicos/uso terapéutico , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/patología , Subfamília C de Receptores Similares a Lectina de Células NK/antagonistas & inhibidores , Subfamília C de Receptores Similares a Lectina de Células NK/genética , Subfamília C de Receptores Similares a Lectina de Células NK/inmunología , Pandemias , Neumonía/tratamiento farmacológico , Neumonía/genética , Neumonía/virología , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/genética , Neumonía Viral/virología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , SARS-CoV-2 , Síndrome Respiratorio Agudo Grave/tratamiento farmacológico , Síndrome Respiratorio Agudo Grave/genética , Síndrome Respiratorio Agudo Grave/virología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/patologíaRESUMEN
Skin wounds heal by coordinated induction of inflammation and tissue repair, but the initiating events are poorly defined. Here we uncover a fundamental role of commensal skin microbiota in this process and show that it is mediated by the recruitment and the activation of type I interferon (IFN)-producing plasmacytoid DC (pDC). Commensal bacteria colonizing skin wounds trigger activation of neutrophils to express the chemokine CXCL10, which recruits pDC and acts as an antimicrobial protein to kill exposed microbiota, leading to the formation of CXCL10-bacterial DNA complexes. These complexes and not complexes with host-derived DNA activate pDC to produce type I IFNs, which accelerate wound closure by triggering skin inflammation and early T cell-independent wound repair responses, mediated by macrophages and fibroblasts that produce major growth factors required for healing. These findings identify a key function of commensal microbiota in driving a central innate wound healing response of the skin.
Asunto(s)
Células Dendríticas/inmunología , Fibroblastos/inmunología , Macrófagos/inmunología , Microbiota/inmunología , Neutrófilos/inmunología , Piel/inmunología , Animales , Células Cultivadas , Quimiocina CXCL10/metabolismo , Humanos , Inmunidad Innata , Inflamación , Interferón Tipo I/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Piel/patología , Simbiosis , Cicatrización de HeridasRESUMEN
Innate lymphoid cells (ILCs) are detected in multiple tumor types, but their contribution to tumor immunity remains unclear. Moral et al. show that a subset of tumor ILCs (TILCs) may participate in an organ-specific immune response and can be unleashed by PD-1 blockers to sustain tumor-specific T cell responses.
Asunto(s)
Linfocitos , Neoplasias , Humanos , Inmunidad Innata , Receptor de Muerte Celular Programada 1 , Linfocitos TRESUMEN
An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
New therapies that promote antitumour immunity have been recently developed. Most of these immunomodulatory approaches have focused on enhancing T-cell responses, either by targeting inhibitory pathways with immune checkpoint inhibitors, or by targeting activating pathways, as with chimeric antigen receptor T cells or bispecific antibodies. Although these therapies have led to unprecedented successes, only a minority of patients with cancer benefit from these treatments, highlighting the need to identify new cells and molecules that could be exploited in the next generation of immunotherapy. Given the crucial role of innate immune responses in immunity, harnessing these responses opens up new possibilities for long-lasting, multilayered tumour control.
Asunto(s)
Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/inmunología , Inmunoterapia/métodos , Inmunoterapia/tendencias , Neoplasias/inmunología , Neoplasias/terapia , Animales , Humanos , Neoplasias/tratamiento farmacológico , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunologíaRESUMEN
Lupus erythematosus (LE) patients develop autoantibodies that form circulating immune complexes (ICs) with extracellular self-nucleic acids. These ICs are deposited into peripheral tissues, where they trigger detrimental organ inflammation. Recent evidence suggests that ICs contain LL37-DNA complexes derived from neutrophil extracellular traps (NETs) and that LE patients develop pathogenic autoantibodies against these structures, including Abs to LL37. However, the mechanism that leads to the generation of these Abs is unknown. In this study, we show that NETs directly trigger Ab production by human memory B cells. This occurs via LL37-DNA complexes present in NETs, which have the unique ability to gain access to endosomal compartments of B cells and to trigger TLR9 activation. In LE patients, NET-derived LL37-DNA complexes trigger polyclonal B cell activation via TLR9, but also specifically expand self-reactive memory B cells producing anti-LL37 Abs in an Ag-dependent manner. These findings suggest a unique link between neutrophils and B cells in which NETs trigger a concerted activation of TLR9 and BCR leading to anti-NET autoantibody production in lupus.
Asunto(s)
Linfocitos B/inmunología , Lupus Eritematoso Sistémico/inmunología , Activación de Linfocitos/inmunología , Neutrófilos/inmunología , Péptidos Catiónicos Antimicrobianos/inmunología , Autoanticuerpos/inmunología , ADN/inmunología , Trampas Extracelulares/inmunología , Humanos , Memoria Inmunológica/inmunología , Receptor Toll-Like 9/inmunología , CatelicidinasRESUMEN
Although anti-tumor necrosis factor (TNF) agents are highly effective in the treatment of psoriasis, 2-5% of treated patients develop psoriasis-like skin lesions called paradoxical psoriasis. The pathogenesis of this side effect and its distinction from classical psoriasis remain unknown. Here we show that skin lesions from patients with paradoxical psoriasis are characterized by a selective overexpression of type I interferons, dermal accumulation of plasmacytoid dendritic cells (pDC), and reduced T-cell numbers, when compared to classical psoriasis. Anti-TNF treatment prolongs type I interferon production by pDCs through inhibition of their maturation. The resulting type I interferon overexpression is responsible for the skin phenotype of paradoxical psoriasis, which, unlike classical psoriasis, is independent of T cells. These findings indicate that paradoxical psoriasis represents an ongoing overactive innate inflammatory process, driven by pDC-derived type I interferon that does not lead to T-cell autoimmunity.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Autoinmunidad/inmunología , Interferón Tipo I/inmunología , Psoriasis/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Adalimumab/efectos adversos , Adalimumab/inmunología , Adalimumab/uso terapéutico , Adolescente , Adulto , Anciano , Animales , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Autoinmunidad/efectos de los fármacos , Células Cultivadas , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/metabolismo , Citocinas/genética , Citocinas/inmunología , Citocinas/metabolismo , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Femenino , Humanos , Infliximab/efectos adversos , Infliximab/inmunología , Infliximab/uso terapéutico , Interferón Tipo I/genética , Interferón Tipo I/metabolismo , Masculino , Ratones Endogámicos BALB C , Persona de Mediana Edad , Psoriasis/inducido químicamente , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismo , Adulto JovenRESUMEN
By screening a drug library comprising FDA approved compounds, we discovered a potent interaction between the antifungal agent haloprogin and the experimental organometallic drug RAPTA-T, to synergistically induce cancer cell killing. The combination of these two small molecules, even at low doses, elicited an improved therapeutic response on tumor growth over either agent alone or the current treatment used in the clinic in the highly aggressive syngeneic B16F10 melanoma tumor model, where classical cytotoxic chemotherapeutic agents show little efficacy. The combination with the repurposed chemodrug haloprogin provides the basis for a new powerful treatment option for cutaneous melanoma. Importantly, because synergistic induction of tumor cell death is achieved with low individual drug doses, and cellular targets for RAPTA-T are different from those of classical chemotherapeutic drugs, a therapeutic strategy based on this approach could avoid toxicities and potentially resistance mechanisms, and could even inhibit metastatic progression.
Asunto(s)
Antifúngicos/uso terapéutico , Reposicionamiento de Medicamentos/métodos , Melanoma/tratamiento farmacológico , Compuestos Organometálicos/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Antifúngicos/química , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Supervivencia Celular/efectos de los fármacos , Sinergismo Farmacológico , Femenino , Citometría de Flujo , Ratones , Ratones Endogámicos C57BL , Compuestos Organometálicos/química , Éteres Fenílicos/uso terapéutico , Melanoma Cutáneo MalignoRESUMEN
The endoplasmic reticulum kinase inositol-requiring enzyme 1 (IRE1) and its downstream target X-box-binding protein 1 (XBP1) drive B-cell differentiation toward plasma cells and have been shown to contribute to multiple myeloma development; yet, little is known of the role of this pathway in diffuse large B-cell lymphoma (DLBCL). Here, we show that in the germinal center B-cell-like (GCB) DLBCL subtype, IRE1 expression is reduced to a level that prevents XBP1 activation. Gene expression profiles indicated that, in GCB DLBCL cancer samples, expression of IRE1 messenger RNA was inversely correlated with the levels and activity of the epigenetic repressor, histone methyltransferase enhancer of zeste homolog 2 (EZH2). Correspondingly, in GCB-derived cell lines, the IRE1 promoter carried increased levels of the repressive epigenetic mark histone 3 lysine 27 trimethylation. Pharmacological inhibition of EZH2 erased those marks and restored IRE1 expression and function in vitro and in vivo. Moreover, reconstitution of the IRE1-signaling pathway, by expression of the XBP1-active form, compromised GCB DLBCL tumor growth in a mouse xenograft cancer model. These findings indicate that IRE1-XBP1 downregulation distinguishes GCB DLBCL from other DLBCL subtypes and contributes to tumor growth.
Asunto(s)
Linfocitos B/inmunología , Endorribonucleasas/genética , Regulación Neoplásica de la Expresión Génica , Centro Germinal/inmunología , Linfoma de Células B Grandes Difuso/inmunología , Proteínas Serina-Treonina Quinasas/genética , ARN Mensajero/genética , Proteína 1 de Unión a la X-Box/genética , Animales , Linfocitos B/patología , Diferenciación Celular , Línea Celular Tumoral , Proliferación Celular , Endorribonucleasas/antagonistas & inhibidores , Endorribonucleasas/inmunología , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/inmunología , Epigénesis Genética , Centro Germinal/patología , Histonas/genética , Histonas/inmunología , Humanos , Indazoles/farmacología , Leupeptinas/farmacología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/terapia , Ratones , Ratones de la Cepa 129 , Células Plasmáticas/inmunología , Células Plasmáticas/patología , Regiones Promotoras Genéticas , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/inmunología , Piridonas/farmacología , ARN Mensajero/antagonistas & inhibidores , ARN Mensajero/inmunología , Transducción de Señal , Proteína 1 de Unión a la X-Box/antagonistas & inhibidores , Proteína 1 de Unión a la X-Box/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
IMPORTANCE: Treatment of pityriasis rubra pilaris (PRP) is solely based on its resemblance to psoriasis rather than any knowledge of its pathomechanism. Insight into pathogenic mediators of inflammation is essential for targeted and valid treatment options that could replace previous serendipitous therapeutic approaches in refractory PRP. OBJECTIVE: To determine whether blockade of the interleukin 23-helper T cell 17 (IL-23-TH17) pathway with ustekinumab represents an efficacious and, based on its proinflammatory cytokine profile, targeted treatment option in PRP. DESIGN, SETTING, AND PARTICIPANTS: In this case report, a patient with PRP received outpatient treatment at a university hospital department of dermatology with ustekinumab according to the dosing regimen approved for psoriasis. Lesional skin biopsy samples were taken from this patient and 2 others with refractory PRP. Messenger RNA (mRNA) expression of proinflammatory innate and T-cell-derived cytokines were measured and compared with skin samples from patients with psoriasis and healthy donors. From 1 patient, lesional skin samples were taken before ustekinumab treatment and 4 and 28 weeks after treatment initiation. Follow-up was completed after 6 months. INTERVENTION: Subcutaneous ustekinumab, 45 mg, at weeks 0 and 4 and quarterly thereafter. MAIN OUTCOMES AND MEASURES: The primary outcome was to determine the changes in expression of proinflammatory innate and T-cell-derived cytokines during ustekinumab therapy. The secondary objective was to evaluate the clinical and histopathologic phenotype in relation to the mRNA expression profile of proinflammatory cytokines. RESULTS: In lesional PRP skin samples from a single patient, upregulated expression levels were found for most proinflammatory innate cytokines, including tumor necrosis factor (TNF), IL-6, IL-12, IL-23, and IL-1ß. Among adaptive T-cell cytokines, an increase of TH1 cytokines and, in particular, TH17 cytokines IL-17A, IL-17F, and IL-22 was seen in PRP. The patient with PRP who received ustekinumab showed regression of skin lesions after 2 weeks and almost complete resolution after 1 month. Clinical and histopathologic improvement paralleled the expression levels of TH17 cytokines but not of interferon-γ and TNF, which lagged behind the amelioration. CONCLUSIONS AND RELEVANCE: In this case report, a role of the IL-23-TH17-axis in PRP was identified, suggesting a shared pathogenic inflammatory pathway with psoriasis, despite evident clinical and histopathologic differences. In addition, this report provides a rationale for targeting the IL-23-TH17-pathway as a treatment option for refractory PRP.
Asunto(s)
Fármacos Dermatológicos/uso terapéutico , Interleucina-23/genética , Pitiriasis Rubra Pilaris/tratamiento farmacológico , Células Th17/metabolismo , Ustekinumab/uso terapéutico , Adulto , Biopsia , Citocinas/genética , Fármacos Dermatológicos/farmacología , Estudios de Seguimiento , Humanos , Masculino , Pitiriasis Rubra Pilaris/genética , Pitiriasis Rubra Pilaris/patología , Psoriasis/patología , ARN Mensajero/metabolismo , Factores de Tiempo , Resultado del Tratamiento , Regulación hacia Arriba , Ustekinumab/farmacologíaRESUMEN
Activation of the elongation factor 2 kinase (eEF2K) leads to the phosphorylation and inhibition of the elongation factor eEF2, reducing mRNA translation rates. Emerging evidence indicates that the regulation of factors involved in protein synthesis may be critical for controlling diverse biological processes including cancer progression. Here we show that inhibitors of the HIV aspartyl protease (HIV-PIs), nelfinavir in particular, trigger a robust activation of eEF2K leading to the phosphorylation of eEF2. Beyond its anti-viral effects, nelfinavir has antitumoral activity and promotes cell death. We show that nelfinavir-resistant cells specifically evade eEF2 inhibition. Decreased cell viability induced by nelfinavir is impaired in cells lacking eEF2K. Moreover, nelfinavir-mediated anti-tumoral activity is severely compromised in eEF2K-deficient engrafted tumors in vivo Our findings imply that exacerbated activation of eEF2K is detrimental for tumor survival and describe a mechanism explaining the anti-tumoral properties of HIV-PIs.
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Quinasa del Factor 2 de Elongación/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Línea Celular , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Resistencia a Medicamentos/genética , Quinasa del Factor 2 de Elongación/genética , Femenino , Expresión Génica , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Ratones Noqueados , Complejos Multiproteicos/metabolismo , Nelfinavir/química , Nelfinavir/farmacología , Neoplasias/genética , Factor 2 de Elongación Peptídica/metabolismo , Fosforilación , Biosíntesis de Proteínas , Serina-Treonina Quinasas TOR/metabolismo , Carga TumoralRESUMEN
BACKGROUND: Data on patients affected by chronic mucocutaneous candidiasis underscore the preponderant role of IL-17 receptor A (IL-17RA) in preserving mucocutaneous immunity. Little is known about the role of adenosine deaminase (ADA) 2 in regulation of immune responses, although recent reports linked ADA2 deficiency with inflammation and vasculitis. OBJECTIVE: We sought to investigate the mechanisms of chronic inflammation and vasculitis in a child lacking IL-17RA and ADA2 to identify therapeutic targets. METHODS: We report a family with 2 siblings who have had recurrent mucocutaneous infections with Candida albicans and Staphylococcus aureus and chronic inflammatory disease and vasculitis since early childhood, which were refractory to classical treatments. Array-based comparative genomic hybridization analysis showed that both siblings are homozygous for a 770-kb deletion on chr22q11.1 encompassing both IL17RA and cat eye critical region 1 (CECR1). Immunologic studies were carried out by means of flow cytometry, ELISA, and RIA. RESULTS: As expected, in the affected child we found a lack of IL-17RA expression, which implies a severe malfunction in the IL-17 signaling pathway, conferring susceptibility to recurrent mucocutaneous infections. Surprisingly, we detected an in vitro and in vivo upregulation of proinflammatory cytokines, notably IL-1ß and TNF-α, which is consistent with the persistent systemic inflammation. CONCLUSIONS: This work emphasizes the utility of whole-genome analyses combined with immunologic investigation in patients with unresolved immunodeficiency. This approach is likely to provide an insight into immunologic pathways and mechanisms of disease. It also provides molecular evidence for more targeted therapies. In addition, our report further corroborates a potential role of ADA2 in modulating immunity and inflammation.
Asunto(s)
Adenosina Desaminasa/deficiencia , Adenosina Desaminasa/genética , Candidiasis Mucocutánea Crónica/genética , Inflamación/genética , Péptidos y Proteínas de Señalización Intercelular/deficiencia , Péptidos y Proteínas de Señalización Intercelular/genética , Receptores de Interleucina-17/deficiencia , Receptores de Interleucina-17/genética , Vasculitis/genética , Adenosina Desaminasa/inmunología , Adolescente , Candidiasis Mucocutánea Crónica/complicaciones , Candidiasis Mucocutánea Crónica/inmunología , Niño , Preescolar , Enfermedad Crónica , Hibridación Genómica Comparativa , Resultado Fatal , Femenino , Humanos , Inflamación/complicaciones , Inflamación/inmunología , Péptidos y Proteínas de Señalización Intercelular/inmunología , Receptores de Interleucina-17/inmunología , Eliminación de Secuencia , Hermanos , Vasculitis/complicaciones , Vasculitis/inmunologíaRESUMEN
Spontaneous CD8 T-cell responses occur in growing tumors but are usually poorly effective. Understanding the molecular and cellular mechanisms that drive these responses is of major interest as they could be exploited to generate a more efficacious antitumor immunity. As such, stimulator of IFN genes (STING), an adaptor molecule involved in cytosolic DNA sensing, is required for the induction of antitumor CD8 T responses in mouse models of cancer. Here, we find that enforced activation of STING by intratumoral injection of cyclic dinucleotide GMP-AMP (cGAMP), potently enhanced antitumor CD8 T responses leading to growth control of injected and contralateral tumors in mouse models of melanoma and colon cancer. The ability of cGAMP to trigger antitumor immunity was further enhanced by the blockade of both PD1 and CTLA4. The STING-dependent antitumor immunity, either induced spontaneously in growing tumors or induced by intratumoral cGAMP injection was dependent on type I IFNs produced in the tumor microenvironment. In response to cGAMP injection, both in the mouse melanoma model and an ex vivo model of cultured human melanoma explants, the principal source of type I IFN was not dendritic cells, but instead endothelial cells. Similarly, endothelial cells but not dendritic cells were found to be the principal source of spontaneously induced type I IFNs in growing tumors. These data identify an unexpected role of the tumor vasculature in the initiation of CD8 T-cell antitumor immunity and demonstrate that tumor endothelial cells can be targeted for immunotherapy of melanoma.