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OBJECTIVES: Glioblastoma (GBM) is the most aggressive of intracranial gliomas. Despite the maximal treatment intervention, the median survival rate is still about 14-16 months. Nuclear receptor-binding protein 1 (NRBP1) has a potential growth-promoting role on biology function of cells. In this study, we investigated whether NRBP1 promotes GBM malignant phenotypes and the potential mechanisms. METHODS: The correlation between NRBP1 and glioma grade, prognosis in TCGA/CGGA databases and our clinical data were analyzed. Next, we conducted knockout and overexpression of NRBP1 on GBM cells to verify that NRBP1 promoted cell proliferation, invasion, and migration in vitro and in vivo. Finally, we detected the impact of NRBP1 on PI3K/Akt signaling pathway and EMT. RESULTS: There was a correlation between elevated NRBP1 expression and advanced stage glioma, as well as decreased overall and disease-free survival. The suppression of proliferation, invasion, and migration of tumor cells was observed upon NRBP1 knockout, and in vitro studies also demonstrated the induction of apoptotic cell death. Whereas, its overexpression is associated with high multiplication rate, migration, invasion, and apoptotic escape. GO enrichment and KEGG analysis revealed that NRBP1 regulated differentially expressed gene clusters are involved in PI3K/Akt signaling pathway, as well as EMT mediated by this pathway. Moreover, the effects of NRBP1 knockdown and overexpression on GBM were mitigated by MK-2206 and SC79, both of which respectively function as an inhibitor and an activator of the PI3K/Akt signaling pathway. Similarly, the suppression of NRBP1 led to a decrease in tumor growth, whereas its overexpression promoted tumor growth in a mouse model. CONCLUSIONS: This study shows that NRBP1 promotes malignant phenotypes in GBM by activating PI3K/Akt pathway. Hence, it can function as both a predictive indicator and a new target for therapies in GBM treatment.
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Neoplasias Encefálicas , Movimiento Celular , Proliferación Celular , Glioblastoma , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Animales , Femenino , Humanos , Masculino , Ratones , Apoptosis , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Glioblastoma/genética , Glioblastoma/patología , Glioblastoma/metabolismo , Ratones Desnudos , Fenotipo , Fosfatidilinositol 3-Quinasas/metabolismo , Pronóstico , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Central nervous system tumor with BCOR internal tandem duplication (CNS tumor with BCOR-ITD) constitutes a molecularly distinct entity, characterized by internal tandem duplication within exon 15 of the BCOR transcriptional co-repressor gene (BCOR-ITD). The current study aimed to elucidate the clinical, pathological, and molecular attributes of CNS tumors with BCOR-ITD and explore their putative cellular origin. This study cohort comprised four pediatric cases, aged 23 months to 13 years at initial presentation. Magnetic resonance imaging revealed large, well-circumscribed intra-CNS masses localized heterogeneously throughout the CNS. Microscopically, tumors were composed of spindle to ovoid cells, exhibiting perivascular pseudorosettes and palisading necrosis, but lacking microvascular proliferation. Immunohistochemical staining showed diffuse tumor cell expression of BCOR, CD56, CD99, vimentin, and the stem cell markers PAX6, SOX2, CD133 and Nestin, alongside focal positivity for Olig-2, S100, SOX10, Syn and NeuN. Molecularly, all cases harbored BCOR-ITDs ranging from 87 to 119 base pairs in length, including one case with two distinct ITDs. Notably, the ITDs were interrupted by unique 1-3â¯bp insertions in all cases. In summary, CNS tumors with BCOR-ITD exhibit characteristic clinical, pathological, and molecular features detectable through BCOR immunohistochemistry and confirmatory molecular analyses. Their expression of stem cell markers raises the possibility of an origin from neuroepithelial stem cells rather than representing true embryonal neoplasms.
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Neoplasias del Sistema Nervioso Central , Proteínas Proto-Oncogénicas , Proteínas Represoras , Humanos , Proteínas Represoras/genética , Proteínas Proto-Oncogénicas/genética , Neoplasias del Sistema Nervioso Central/patología , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/metabolismo , Niño , Adolescente , Masculino , Femenino , Lactante , Preescolar , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Secuencias Repetidas en Tándem , Duplicación de GenRESUMEN
Mitochondria (MT) participate in most metabolic activities of mammalian cells. A near-unidirectional mitochondrial transfer from T cells to cancer cells was recently observed to "metabolically empower" cancer cells while "depleting immune cells," providing new insights into tumor-T cell interaction and immune evasion. Here, we leverage single-cell RNA-seq technology and introduce MERCI, a statistical deconvolution method for tracing and quantifying mitochondrial trafficking between cancer and T cells. Through rigorous benchmarking and validation, MERCI accurately predicts the recipient cells and their relative mitochondrial compositions. Application of MERCI to human cancer samples identifies a reproducible MT transfer phenotype, with its signature genes involved in cytoskeleton remodeling, energy production, and TNF-α signaling pathways. Moreover, MT transfer is associated with increased cell cycle activity and poor clinical outcome across different cancer types. In summary, MERCI enables systematic investigation of an understudied aspect of tumor-T cell interactions that may lead to the development of therapeutic opportunities.
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ADN Mitocondrial , Neoplasias , Animales , Humanos , ADN Mitocondrial/genética , Linfocitos T/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Mamíferos/genética , Mamíferos/metabolismoRESUMEN
A better understanding of the regulatory mechanisms governing the development of memory CD8+ T cells could provide instructive insights into vaccination strategies and T cell-based immunotherapies. In this article, we showed that CD160 surface protein is required for CD8+ T cell memory formation. In the response to acute lymphocytic choriomeningitis virus infection in a mouse model, CD160 ablation resulted in the failure of the development of all three memory CD8+ T cell subsets (central, effective, and tissue-resident memory), concomitant with a skewed differentiation into short-lived effector T cells. Such memory-related defect was manifested by a diminished protection from viral rechallenge. Mechanistically, CD160 deficiency led to downregulation of 4-1BB in activated CD8+ T cells, which contributes to the impaired cell survival and decreased respiratory capacity. The nexus between CD160 and 4-1BB was substantiated by the observation that ectopic introduction of 4-1BB was able to largely complement the loss of CD160 in memory CD8+ T cell development. Collectively, our studies discovered that CD160, once thought to be a coinhibitor of T cell signaling, is an essential promoter of memory CD8+ T cell development via activation of the costimulatory molecule 4-1BB.
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OBJECTIVE: This study was designed to analyze the clinical effect of autologous fat-granule transplantation in augmentation rhinoplasty and explore methods to improve the fat retention rate. METHODS: A total of 70 enrolled patients were randomly divided into 2 groups: the platelet-rich fibrin (PRF) combined with high-density fat transplantation group (combined group) and the conventional fat-granule transplantation group (control group; n = 35 in each group). In the combined group, an appropriate amount of autologous fat was extracted and centrifuged, and the lower layer of high-density fat was taken and mixed with PRF isolated from whole blood for autotransplantation. In the control group, only fat was extracted and centrifuged for transplantation. The patients were followed up with for more than one year to observe the short- and long-term effects, complications, safety, and patient satisfaction. RESULTS: Six months after the operation, the nasal shape was stable, the contour was higher and more stereoscopic than before, the average increase of nasal height was 3.0 mm in the combined group and 2.0 mm in the control group. No complications, such as fat embolism, infection, or necrosis occurred during the 1-year follow-up. The satisfaction rate between the 2 groups has statistical significance (P < .05). CONCLUSION: Overall, PRF combined with autologous high-density fat transplantation is simple to perform, has a significantly increased fat-retention rate than the control group, and has stable long-term effects without obvious adverse reactions. A sufficient amount of fat and PRF transplantation can achieve a good orthopedic effect. Thus, this method can be widely used in clinical augmentation rhinoplasty.
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Fibrina Rica en Plaquetas , Rinoplastia , Humanos , Rinoplastia/métodos , Trasplante Autólogo , NarizRESUMEN
Immune checkpoint blockade (ICB)-based immunotherapy depends on functional tumour-infiltrating lymphocytes (TILs), but essential cytokines are less understood. Here we uncover an essential role of endogenous IL-2 for ICB responsiveness and the correlation between insufficient IL-2 signalling and T-cell exhaustion as tumours progress. To determine if exogenous IL-2 in the tumour microenvironment can overcome ICB resistance, we engineered mesenchymal stem cells (MSCs) to successfully deliver IL-2 mutein dimer (SIL2-EMSC) to TILs. While MSCs have been used to suppress inflammation, SIL2-EMSCs elicit anti-tumour immunity and overcome ICB resistance without toxicity. Mechanistically, SIL2-EMSCs activate and expand pre-existing CD8+ TILs, sufficient for tumour control and induction of systemic anti-tumour effects. Furthermore, engineered MSCs create synergy of innate and adaptive immunity. The therapeutic benefits of SIL2-EMSCs were also observed in humanized mouse models. Overall, engineered MSCs rejuvenate CD8+ TILs and thus potentiate ICB and chemotherapy.
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Células Madre Mesenquimatosas , Neoplasias , Animales , Ratones , Linfocitos T CD8-positivos , Interleucina-2/genética , Interleucina-2/farmacología , Neoplasias/terapia , Microambiente TumoralRESUMEN
Objective: To introduce a new surgical method for the repair of a large inner canthus combined with tissue loss at the inner canthal angle of the eye by using a bird-beak-type z-shaped asymmetrical flap and to summarize its clinical effect. Method: A total of 56 patients with a large inner canthus were randomly selected, and a bird-beak-type z-shaped asymmetrical flap was used on the nasal side of the lower eyelid to repair and reconstruct the inner canthal folds. The inner canthal point was located according to physiological aesthetics. The short and long arms of the z-shaped asymmetrical flap were separated, replaced, fixed, and shaped to reconstruct the skin folds of the inner canthus and restore its aesthetic morphology. Results: All incisions after surgery achieved primary healing, and all 56 cases were followed up for 6-20 months (average 8.6 months). The caruncula lacrimalis was moderately exposed, the inner canthal angles possessed a natural appearance, and the results of the surgery were satisfactory. Five patients developed scar hyperplasia within one month after surgery, and arnica gel was applied topically for 3-6 months until the scar faded or disappeared, but no obvious scars were seen in the surgical area of the remaining patients. In two patients, the internal canthi were asymmetrical, but this improved after adjustment. Conclusion: Repair of a large inner canthus and tissue loss at the inner canthal angle of the eye using a bird-beak-type z-shaped asymmetrical flap is a simple operation, resulting in minimal trauma. Postoperatively, the inner canthal angle possessed a natural appearance with no obvious scarring.
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Leucoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is commonly induced by DARS2 abnormalities and accompanied by slowly progressing pyramidal and cerebellar dysfunction, as well as concomitant dorsal column dysfunction. In this study, an LBSL induced pluripotent stem cell (iPSC) line was generated from peripheral blood mononuclear cells of a female patient carrying biallelic mutations in DARS2. Pluripotency, differentiation potential, and karyotypic normality of this cell line were confirmed. This iPSC line offers a useful cellular model to investigate LBSL phenotypes, mechanisms, and therapy.
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Aspartato-ARNt Ligasa , Células Madre Pluripotentes Inducidas , Leucoencefalopatías , Aspartato-ARNt Ligasa/genética , Aspartato-ARNt Ligasa/metabolismo , Tronco Encefálico/metabolismo , Femenino , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Ácido Láctico/metabolismo , Leucocitos Mononucleares/metabolismo , Leucoencefalopatías/genética , Mutación , Médula Espinal/metabolismoRESUMEN
Mutations in STK11/LKB1 in non-small cell lung cancer (NSCLC) are associated with poor patient responses to immune checkpoint blockade (ICB), and introduction of a Stk11/Lkb1 (L) mutation into murine lung adenocarcinomas driven by mutant Kras and Trp53 loss (KP) resulted in an ICB refractory syngeneic KPL tumor. Mechanistically this occurred because KPL mutant NSCLCs lacked TCF1-expressing CD8 T cells, a phenotype recapitulated in human STK11/LKB1 mutant NSCLCs. Systemic inhibition of Axl results in increased type I interferon secretion from dendritic cells that expanded tumor-associated TCF1+PD-1+CD8 T cells, restoring therapeutic response to PD-1 ICB in KPL tumors. This was observed in syngeneic immunocompetent mouse models and in humanized mice bearing STK11/LKB1 mutant NSCLC human tumor xenografts. NSCLC-affected individuals with identified STK11/LKB1 mutations receiving bemcentinib and pembrolizumab demonstrated objective clinical response to combination therapy. We conclude that AXL is a critical targetable driver of immune suppression in STK11/LKB1 mutant NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Quinasas de la Proteína-Quinasa Activada por el AMP , Animales , Linfocitos T CD8-positivos/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Ratones , Receptor de Muerte Celular Programada 1/genética , Proteínas Serina-Treonina Quinasas/genética , Tirosina Quinasa del Receptor AxlRESUMEN
PD-1 signaling on T cells is the major pathway that limits T cell immunity, but the efficacy of anti-PD-1 therapy has been limited to a small proportion of patients with advanced cancers. We fortuitously observed that anti-PD-1 therapy depends on IL-2 signaling, which raises the possibility that a lack of IL-2 limits anti-PD-1-induced effector T cell expansion. To selectively deliver IL-2 to PD-1+CD8+ tumor-infiltrating lymphocytes (TILs), we engineered a low-affinity IL-2 paired with anti-PD-1 (PD-1-laIL-2), which reduced affinity to peripheral Treg cells but enhanced avidity to PD-1+CD8+ TILs. PD-1-laIL-2 exerted better tumor control and lower toxicity than single or mixed treatments. Mechanistically, PD-1-laIL-2 could effectively expand dysfunctional and tumor-specific CD8+ T cells. Furthermore, we discovered that presumably dysfunctional PD-1+TIM3+ TILs are the dominant tumor-specific T cells responding to PD-1-laIL-2. Collectively, these results highlight that PD-1-laIL-2 can target and reactivate tumor-specific TILs for tumor regression as a unique strategy with stronger efficacy and lower toxicity.
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Linfocitos T CD8-positivos/inmunología , Inmunidad Celular/efectos de los fármacos , Interleucina-2/farmacología , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias Experimentales/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Animales , Inmunidad Celular/genética , Interleucina-2/genética , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Neoplasias Experimentales/genética , Neoplasias Experimentales/terapia , Receptor de Muerte Celular Programada 1/genéticaRESUMEN
It remains poorly defined whether any human miRNAs play protective roles during HIV infection. Here, focusing on a unique cohort of HIV-infected former blood donors, we identified miR-31 (hsa-miR-31) by comparative miRNA profiling as the only miRNA inversely correlating with disease progression. We further validated this association in two prospective cohort studies. Despite conservation during evolution, hsa-miR-31, unlike its mouse counterpart (mmu-miR-31), was downregulated in human T cell upon activation. Our ex vivo studies showed that inhibiting miR-31 in naïve CD4+ T cells promoted a transcriptional profile with activation signature. Consistent with this skewing effect, miR-31 inhibition led to remarkably increased susceptibility to HIV infection. The suppressive nature of miR-31 in CD4+ T cell activation was pinpointed to its ability to decrease T-bet, the key molecule governing IFN-γ production and activation of CD4+ T cells, by directly targeting the upstream STAT1 transcriptional factor for downregulation, thus blunting Th1 response. Our results implicated miR-31 as a useful biomarker for tracking HIV disease progression and, by demonstrating its importance in tuning the activation of CD4+ T cells, suggested that miR-31 may play critical roles in other physiological contexts where the CD4+ T cell homeostasis needs to be deliberately controlled.
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Infecciones por VIH/genética , Infecciones por VIH/inmunología , MicroARNs/inmunología , Linfocitos T/inmunología , Adulto , Biomarcadores , Progresión de la Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Células HEK293 , Homeostasis , Humanos , Interferón gamma/inmunología , Masculino , Persona de Mediana Edad , Factor de Transcripción STAT1/inmunología , Proteínas de Dominio T Box/inmunologíaRESUMEN
Blockade of CD47, the "do not eat me" signal, has limited effects in solid tumors despite its potent antitumor effects in hematopoietic malignancies. Taking advantage of the high expression of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) on Treg cells and abundant Fc receptor-expressing active phagocytes inside the tumor microenvironment (TME), we designed and tested a heterodimer combining an anti-CTLA-4 antibody, which targets Treg cells, with the CD47 ligand, signal regulatory protein α (SIRPα), to selectively block CD47 on intratumoral Treg cells. We hypothesized that heterodimer treatment would increase antibody-dependent cellular phagocytosis of the targeted Treg cells. We found that anti-CTLA-4×SIRPα preferentially depleted ICOShigh immunosuppressive Treg cells in the TME and enhanced immunity against solid tumors, including MC38 and CT26 murine colon cancers. Mechanistically, we found that CD47 expression on Treg cells limited anti-CTLA-4-mediated depletion and Fc on the heterodimer-enhanced depletion. Furthermore, anti-human CTLA-4×SIRPα depleted tumor Treg cells and exhibits less toxicity than anti-human CTLA-4 in a humanized mouse model. Collectively, these results demonstrate that simultaneously modulating both "eat me" and do not eat me signals induces Treg cell depletion inside the TME and may be an effective strategy for treating solid tumors.
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Antígeno CD47 , Neoplasias , Animales , Antígeno CTLA-4 , Ratones , Neoplasias/tratamiento farmacológico , Linfocitos T Reguladores , Microambiente TumoralRESUMEN
Desmoplastic myxoid tumor (DMT), SMARCB1 mutant is a recently proposed new entity that mainly occurs in the pineal region and has epigenetic features similar to those of atypical teratoid/rhabdoid tumors (AT/RT)-MYC and poorly differentiated chordomas. Herein, we present a new case of a 33-year-old man with headaches, dizziness, nausea, vomiting, and blurred vision, who was initially found to have a suspicious germinoma on imaging. After surgical removal of the lesion, the postoperative pathological diagnosis was DMT, SMARCB1 mutant. To the best of our knowledge, this is the first case reported in China. Our findings also extend the range of the immunohistochemical phenotype of this rare tumor.
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Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Mutación/genética , Glándula Pineal/diagnóstico por imagen , Proteína SMARCB1/genética , Adulto , Neoplasias Encefálicas/cirugía , Humanos , Masculino , Glándula Pineal/cirugía , Tumor Rabdoide/diagnóstico por imagen , Tumor Rabdoide/genética , Tumor Rabdoide/cirugía , Teratoma/diagnóstico por imagen , Teratoma/genética , Teratoma/cirugíaRESUMEN
Increased neoantigens in hypermutated cancers with DNA mismatch repair deficiency (dMMR) are proposed as the major contributor to the high objective response rate in anti-PD-1 therapy. However, the mechanism of drug resistance is not fully understood. Using tumor models defective in the MMR gene Mlh1 (dMLH1), we show that dMLH1 tumor cells accumulate cytosolic DNA and produce IFN-ß in a cGAS-STING-dependent manner, which renders dMLH1 tumors slowly progressive and highly sensitive to checkpoint blockade. In neoantigen-fixed models, dMLH1 tumors potently induce T cell priming and lose resistance to checkpoint therapy independent of tumor mutational burden. Accordingly, loss of STING or cGAS in tumor cells decreases tumor infiltration of T cells and endows resistance to checkpoint blockade. Clinically, downregulation of cGAS/STING in human dMMR cancers correlates with poor prognosis. We conclude that DNA sensing within tumor cells is essential for dMMR-triggered anti-tumor immunity. This study provides new mechanisms and biomarkers for anti-dMMR-cancer immunotherapy.
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Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Proteínas de la Membrana/genética , Homólogo 1 de la Proteína MutL/deficiencia , Neoplasias/genética , Nucleotidiltransferasas/genética , Animales , Línea Celular Tumoral , Reparación de la Incompatibilidad de ADN , Regulación hacia Abajo , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Interferón beta/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Trasplante de Neoplasias , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Nucleotidiltransferasas/metabolismo , Pronóstico , Transducción de Señal/efectos de los fármacosRESUMEN
Recently, immune checkpoint blockade (ICB), especially anti-programmed death 1 (anti-PD-1) and anti-programmed death-ligand 1 (anti-PD-L1) therapy, has become an increasingly appealing therapeutic strategy for cancer patients. However, only a small portion of patients responds to anti-PD treatment. Therefore, treatment strategies are urgently needed to reverse the ICB-resistant tumor microenvironment (TME). It has become clear that the TME has diminished innate sensing that is critical to activate adaptive immunity. In addition, tumor cells upregulate various immunosuppressive factors to diminish the immune response and resist immunotherapy. In this review, we briefly update the current small molecular drugs that could synergize with immunotherapy, especially anti-PD therapy. We will discuss the modes of action by those drugs including inducing innate sensing and limiting immunosuppressive factors in the TME.
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Antígeno B7-H1/genética , Neoplasias/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Factores Inmunológicos/uso terapéutico , Inmunoterapia , Neoplasias/inmunología , Neoplasias/patología , Neovascularización Patológica/inmunología , Neovascularización Patológica/patología , Transducción de Señal/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunologíaRESUMEN
BACKGROUND: Signal regulatory protein α (SIRPα) is a myeloid-lineage inhibitory receptor that restricts innate immunity through engagement of its cell surface ligand CD47. Blockade of the CD47-SIRPα interaction synergizes with tumor-specific antibodies and T-cell checkpoint inhibitors by promoting myeloid-mediated antitumor functions leading to the induction of adaptive immunity. Inhibition of the CD47-SIRPα interaction has focused predominantly on targeting CD47, which is expressed ubiquitously and contributes to the accelerated blood clearance of anti-CD47 therapeutics. Targeting SIRPα, which is myeloid-restricted, may provide a differential pharmacokinetic, safety, and efficacy profile; however, SIRPα polymorphisms and lack of pan-allelic and species cross-reactive agents have limited the clinical translation of antibodies against SIRPα. Here, we report the development of humanized AB21 (hAB21), a pan-allelic anti-SIRPα antibody that binds human, cynomolgus monkey, and mouse SIRPα alleles with high affinity and blocks the interaction with CD47. METHODS: Human macrophages derived from donors with various SIRPα v1 and v2 allelic status were used to assess the ability of hAB21 to enhance phagocytosis. HAB21_IgG subclasses were evaluated for targeted depletion of peripheral blood mononuclear cells, phagocytosis and in vivo efficacy in xenograft models. Combination therapy with anti-PD1/anti-PD-L1 in several syngeneic models was performed. Immunophenotyping of tissues from MC38 tumor-bearing mice treated with AB21 and anti-PD-1 was evaluated. PK, PD and tolerability of hAB21 were evaluated in cynomolgus monkeys. RESULTS: SIRPα blockade with hAB21 promoted macrophage-mediated antibody-dependent phagocytosis of tumor cells in vitro and improved responses to rituximab in the Raji human tumor xenograft mouse model. Combined with PD-1/PD-L1 blockade, AB21 improved response rates by facilitating monocyte activation, dendritic cell activation, and T cell effector functions resulting in long term, durable antitumor immunity. In cynomolgus monkeys, hAB21 has a half-life of 5.3 days at 10 mg/kg and complete target occupancy with no hematological toxicity or adverse findings at doses up to 30 mg/kg. CONCLUSIONS: The in vitro and in vivo antitumor activity of hAB21 broadly recapitulates that of CD47 targeted therapies despite differences in ligand expression, binding partners, and function, validating the CD47-SIRPα axis as a fundamental myeloid checkpoint pathway and its blockade as promising therapeutic intervention for treatment of human malignancies.
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Inmunidad Adaptativa , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno CD47/inmunología , Neoplasias/terapia , Receptores Inmunológicos/antagonistas & inhibidores , Animales , Antígenos de Diferenciación/inmunología , Antineoplásicos Inmunológicos/farmacología , Línea Celular Tumoral , Femenino , Humanos , Inmunoterapia , Macaca fascicularis , Macrófagos/inmunología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Neoplasias/inmunología , Fagocitosis , Receptores Inmunológicos/inmunologíaRESUMEN
Effectively activating macrophages against cancer is promising but challenging. In particular, cancer cells express CD47, a 'don't eat me' signal that interacts with signal regulatory protein alpha (SIRPα) on macrophages to prevent phagocytosis. Also, cancer cells secrete stimulating factors, which polarize tumor-associated macrophages from an antitumor M1 phenotype to a tumorigenic M2 phenotype. Here, we report that hybrid cell membrane nanovesicles (known as hNVs) displaying SIRPα variants with significantly increased affinity to CD47 and containing M2-to-M1 repolarization signals can disable both mechanisms. The hNVs block CD47-SIRPα signaling axis while promoting M2-to-M1 repolarization within tumor microenvironment, significantly preventing both local recurrence and distant metastasis in malignant melanoma models. Furthermore, by loading a stimulator of interferon genes (STING) agonist, hNVs lead to potent tumor inhibition in a poorly immunogenic triple negative breast cancer model. hNVs are safe, stable, drug loadable, and suitable for genetic editing. These properties, combined with the capabilities inherited from source cells, make hNVs an attractive immunotherapy.
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Micropartículas Derivadas de Células/inmunología , Inmunoterapia/métodos , Macrófagos/inmunología , Melanoma/terapia , Recurrencia Local de Neoplasia/prevención & control , Neoplasias de la Mama Triple Negativas/terapia , Animales , Antígeno CD47/metabolismo , Línea Celular Tumoral/trasplante , Modelos Animales de Enfermedad , Femenino , Células HEK293 , Humanos , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Melanoma/inmunología , Melanoma/secundario , Proteínas de la Membrana/agonistas , Proteínas de la Membrana/inmunología , Ratones , Nanopartículas/administración & dosificación , Recurrencia Local de Neoplasia/inmunología , Nucleótidos Cíclicos/administración & dosificación , Receptores Inmunológicos/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Neoplasias de la Mama Triple Negativas/inmunología , Escape del Tumor/efectos de los fármacos , Escape del Tumor/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
The understanding of protective immunity during HIV infection remains elusive. Here we showed that CD160 defines a polyfunctional and proliferative CD8+ T cell subset with a protective role during chronic HIV-1 infection. CD160+ CD8+ T cells derived from HIV+ patients correlated with slow progressions both in a cross-sectional study and in a 60-month longitudinal cohort, displaying enhanced cytotoxicity and proliferative capacity in response to HIV Gag stimulation; triggering CD160 promoted their functionalities through MEK-ERK and PI3K-AKT pathways. These observations were corroborated by studying chronic lymphocytic choriomeningitis virus (LCMV) infection in mice. The genetic ablation of CD160 severely impaired LCMV-specific CD8+ T cell functionalities and thereby resulted in loss of virus control. Interestingly, transcriptional profiling showed multiple costimulatory and survival pathways likely to be involved in CD160+ T cell development. Our data demonstrated that CD160 acts as a costimulatory molecule positively regulating CD8+ T cells during chronic viral infections, thus representing a potential target for immune intervention.