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Despite recent advances in therapeutic treatments, multiple myeloma (MM) remains an incurable malignancy. Epigenetic factors contribute to the initiation, progression, relapse, and clonal heterogeneity in MM, but our knowledge on epigenetic mechanisms underlying MM development is far from complete. The SAGA complex serves as a coactivator in transcription and catalyzes acetylation and deubiquitylation. Analyses of data sets in the Cancer Dependency Map Project revealed that many SAGA components are selective dependencies in MM. To define SAGA-specific functions, we focused on ADA2B, the only subunit in the lysine acetyltransferase (KAT) module that specifically functions in SAGA. Integration of RNA sequencing (RNA-seq), assay for transposase-accessible chromatin with sequencing (ATAC-seq), and cleavage under targets and release using nuclease assay (CUT&RUN) results identified pathways directly regulated by ADA2B including MTORC1 signaling and oncogenic programs driven by MYC, E2F, and MM-specific MAF. We discovered that ADA2B is recruited to MAF and MYC gene targets, and that MAF shares a majority of its targets with MYC in MM cells. Furthermore, we found that the SANT domain of ADA2B is required for interaction with both GCN5 and PCAF acetyltransferases, incorporation into SAGA, and ADA2B protein stability. Our findings uncover previously unknown SAGA KAT module-dependent mechanisms controlling MM cell growth, revealing a vulnerability that might be exploited for future development of MM therapy.
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Bismuth produces different types of ordered superstructures on the InAs(100) surface, depending on the growth procedure and coverage. The (2 × 1) phase forms at completion of one Bi monolayer and consists of a uniformly oriented array of parallel lines of Bi dimers. Scanning tunneling and core level spectroscopies demonstrate its metallic character, in contrast with the semiconducting properties expected on the basis of the electron counting principle. The weak electronic coupling among neighboring lines gives rise to quasi one-dimensional Bi-derived bands with open contours at the Fermi level. Spin- and angle-resolved photoelectron spectroscopy reveals a giant Rashba splitting of these bands, in good agreement with ab initio electronic structure calculations. The very high density of the dimer lines, the metallic and quasi one-dimensional band dispersion and the Rashba-like spin texture make the Bi/InAs(100)-(2 × 1) phase an intriguing system, where novel transport regimes can be studied.
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Dysregulated transcription due to disruption in histone lysine methylation dynamics is an established contributor to tumorigenesis1,2. However, whether analogous pathologic epigenetic mechanisms act directly on the ribosome to advance oncogenesis is unclear. Here we find that trimethylation of the core ribosomal protein L40 (rpL40) at lysine 22 (rpL40K22me3) by the lysine methyltransferase SMYD5 regulates mRNA translation output to promote malignant progression of gastric adenocarcinoma (GAC) with lethal peritoneal ascites. A biochemical-proteomics strategy identifies the monoubiquitin fusion protein partner rpL40 (ref. 3) as the principal physiological substrate of SMYD5 across diverse samples. Inhibiting the SMYD5-rpL40K22me3 axis in GAC cell lines reprogrammes protein synthesis to attenuate oncogenic gene expression signatures. SMYD5 and rpL40K22me3 are upregulated in samples from patients with GAC and negatively correlate with clinical outcomes. SMYD5 ablation in vivo in familial and sporadic mouse models of malignant GAC blocks metastatic disease, including peritoneal carcinomatosis. Suppressing SMYD5 methylation of rpL40 inhibits human cancer cell and patient-derived GAC xenograft growth and renders them hypersensitive to inhibitors of PI3K and mTOR. Finally, combining SMYD5 depletion with PI3K-mTOR inhibition and chimeric antigen receptor T cell administration cures an otherwise lethal in vivo mouse model of aggressive GAC-derived peritoneal carcinomatosis. Together, our work uncovers a ribosome-based epigenetic mechanism that facilitates the evolution of malignant GAC and proposes SMYD5 targeting as part of a potential combination therapy to treat this cancer.
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Metiltransferasas , Proteínas Ribosómicas , Ribosomas , Neoplasias Gástricas , Animales , Femenino , Humanos , Ratones , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Epigénesis Genética/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , N-Metiltransferasa de Histona-Lisina/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , Lisina/metabolismo , Metilación/efectos de los fármacos , Metiltransferasas/antagonistas & inhibidores , Metiltransferasas/deficiencia , Metiltransferasas/metabolismo , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/metabolismo , Neoplasias Peritoneales/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Biosíntesis de Proteínas , Proteínas Ribosómicas/química , Proteínas Ribosómicas/metabolismo , Ribosomas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Chiral crystals and molecules were recently predicted to form an intriguing platform for unconventional orbital physics. Here, we report the observation of chirality-driven orbital textures in the bulk electronic structure of CoSi, a prototype member of the cubic B20 family of chiral crystals. Using circular dichroism in soft x-ray angle-resolved photoemission, we demonstrate the formation of a bulk orbital-angular-momentum texture and monopolelike orbital-momentum locking that depends on crystal handedness. We introduce the intrinsic chiral circular dichroism, icCD, as a differential photoemission observable and a natural probe of chiral electron states. Our findings render chiral crystals promising for spin-orbitronics applications.
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Pediatric cancers are frequently driven by genomic alterations that result in aberrant transcription factor activity. Here, we used functional genomic screens to identify multiple genes within the transcriptional coactivator Spt-Ada-Gcn5-acetyltransferase (SAGA) complex as selective dependencies for MYCN-amplified neuroblastoma, a disease of dysregulated development driven by an aberrant oncogenic transcriptional program. We characterized the DNA recruitment sites of the SAGA complex in neuroblastoma and the consequences of loss of SAGA complex lysine acetyltransferase (KAT) activity on histone acetylation and gene expression. We demonstrate that loss of SAGA complex KAT activity is associated with reduced MYCN binding on chromatin, suppression of MYC/MYCN gene expression programs, and impaired cell cycle progression. Further, we showed that the SAGA complex is pharmacologically targetable in vitro and in vivo with a KAT2A/KAT2B proteolysis targeting chimeric. Our findings expand our understanding of the histone-modifying complexes that maintain the oncogenic transcriptional state in this disease and suggest therapeutic potential for inhibitors of SAGA KAT activity in MYCN-amplified neuroblastoma.
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Regulación Neoplásica de la Expresión Génica , Proteína Proto-Oncogénica N-Myc , Neuroblastoma , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/patología , Humanos , Proteína Proto-Oncogénica N-Myc/genética , Proteína Proto-Oncogénica N-Myc/metabolismo , Línea Celular Tumoral , Histona Acetiltransferasas/metabolismo , Histona Acetiltransferasas/genética , Acetilación , Histonas/metabolismo , Animales , Amplificación de Genes , Cromatina/metabolismo , Cromatina/genética , RatonesRESUMEN
Despite recent advances in therapeutic treatments, multiple myeloma (MM) remains an incurable malignancy. Epigenetic factors contribute to the initiation, progression, relapse, and clonal heterogeneity in MM, but our knowledge on epigenetic mechanisms underlying MM development is far from complete. The SAGA complex serves as a coactivator in transcription and catalyzes acetylation and deubiquitylation. Analyses of datasets in the Cancer Dependency Map Project revealed many SAGA components are selective dependencies in MM. To define SAGA-specific functions, we focused on ADA2B, the only subunit in the lysine acetyltransferase (KAT) module that specifically functions in SAGA. Integration of RNA-seq, ATAC-seq, and CUT&RUN results identified pathways directly regulated by ADA2B include MTORC1 signaling, MYC, E2F, and MM-specific MAF oncogenic programs. We discovered that ADA2B is recruited to MAF and MYC gene targets, and that MAF shares a majority of its targets with MYC in MM cells. Furthermore, we found the SANT domain of ADA2B is required for interaction with both GCN5 and PCAF acetyltransferases, incorporation into SAGA, and ADA2B protein stability. Our findings uncover previously unknown SAGA KAT module-dependent mechanisms controlling MM cell growth, revealing a vulnerability that might be exploited for future development of MM therapy.
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Fermi surfaces of transition metals, which describe all thermodynamical and transport quantities of solids, often fail to be modeled by one-electron mean-field theory due to strong correlations among the valence electrons. In addition, relativistic spin-orbit coupling pronounced in heavier elements lifts the degeneracy of the energy bands and further modifies the Fermi surface. Palladium and rhodium, two 4d metals attributed to show significant spin-orbit coupling and electron correlations, are ideal for a systematic and fundamental study of the two fundamental physical phenomena and their interplay in the electronic structure. In this study, we explored the Fermi surface of the 4d noble metals palladium and rhodium obtained via high-resolution constant initial state momentum microscopy. The complete 3D-Fermi surfaces of palladium and rhodium were tomographically mapped using soft X-ray photon energies from 34 eV up to 660 eV. To fully capture the orbital angular momentum of states across the Fermi surface, the Fermi surface tomography was performed using p- and s- polarized light. Applicability and limitations of the nearly-free electron final state model in photoemission are discussed using a complex band structure model supported by experimental evidence. The significance of spin-orbit coupling and electron correlations across the Fermi surfaces will be discussed within the context of the photoemission results. State-of-the-art fully relativistic Korringa-Kohn-Rostoker (KKR) calculations within the one-step model of photoemission are used to support the experimental results.
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Although immune checkpoint inhibitors (ICIs) are established as effective cancer therapies, overcoming therapeutic resistance remains a critical challenge. Here we identify interleukin 6 (IL-6) as a correlate of poor response to atezolizumab (anti-PD-L1) in large clinical trials of advanced kidney, breast, and bladder cancers. In pre-clinical models, combined blockade of PD-L1 and the IL-6 receptor (IL6R) causes synergistic regression of large established tumors and substantially improves anti-tumor CD8+ cytotoxic T lymphocyte (CTL) responses compared with anti-PD-L1 alone. Circulating CTLs from cancer patients with high plasma IL-6 display a repressed functional profile based on single-cell RNA sequencing, and IL-6-STAT3 signaling inhibits classical cytotoxic differentiation of CTLs in vitro. In tumor-bearing mice, CTL-specific IL6R deficiency is sufficient to improve anti-PD-L1 activity. Thus, based on both clinical and experimental evidence, agents targeting IL-6 signaling are plausible partners for combination with ICIs in cancer patients.
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Antineoplásicos , Interleucina-6 , Neoplasias , Animales , Ratones , Antineoplásicos/uso terapéutico , Antígeno B7-H1/inmunología , Antígeno B7-H1/uso terapéutico , Linfocitos T CD8-positivos/metabolismo , Inmunoterapia , Interleucina-6/metabolismo , Neoplasias/inmunología , Neoplasias/terapiaRESUMEN
The discovery of topological states of matter has led to a revolution in materials research. When external or intrinsic parameters break symmetries, global properties of topological materials change drastically. A paramount example is the emergence of Weyl nodes under broken inversion symmetry. While a rich variety of non-trivial quantum phases could in principle also originate from broken time-reversal symmetry, realizing systems that combine magnetism with complex topological properties is remarkably elusive. Here, we demonstrate that giant open Fermi arcs are created at the surface of ultrathin hybrid magnets where the Fermi-surface topology is substantially modified by hybridization with a heavy-metal substrate. The interplay between magnetism and topology allows us to control the shape and the location of the Fermi arcs by tuning the magnetization direction. The hybridization points in the Fermi surface can be attributed to a non-trivial mixed topology and induce hot-spots in the Berry curvature, dominating spin and charge transport as well as magneto-electric coupling effects.
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Protein acetylation is conserved across phylogeny and has been recognized as one of the most prominent post-translational modifications since its discovery nearly 60 years ago. Histone acetylation is an active mark characteristic of open chromatin, but acetylation on specific lysine residues and histone variants occurs in different biological contexts and can confer various outcomes. The significance of acetylation events is indicated by the associations of lysine acetyltransferases, deacetylases, and acetyl-lysine readers with developmental disorders and pathologies. Recent advances have uncovered new roles of acetylation regulators in chromatin-centric events, which emphasize the complexity of these functional networks. In this review, we discuss mechanisms and dynamics of acetylation in chromatin organization and DNA-templated processes, including gene transcription and DNA repair and replication.
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Ensamble y Desensamble de Cromatina , Cromatina/metabolismo , Histonas/metabolismo , Procesamiento Proteico-Postraduccional , Acetilación , Animales , Cromatina/genética , Reparación del ADN , Replicación del ADN , Inestabilidad Genómica , Histonas/genética , Humanos , Lisina , Transcripción GenéticaRESUMEN
Non-neuronal responses in neurodegenerative disease have received increasing attention as important contributors to disease pathogenesis and progression. Here we utilize single-cell RNA sequencing to broadly profile 13 cell types in three different mouse models of Alzheimer disease (AD), capturing the effects of tau-only, amyloid-only, or combined tau-amyloid pathology. We highlight microglia, oligodendrocyte, astrocyte, and T cell responses and compare them across these models. Notably, we identify two distinct transcriptional states for oligodendrocytes emerging differentially across disease models, and we determine their spatial distribution. Furthermore, we explore the impact of Trem2 deletion in the context of combined pathology. Trem2 knockout mice exhibit severely blunted microglial responses to combined tau and amyloid pathology, but responses from non-microglial cell types (oligodendrocytes, astrocytes, and T cells) are relatively unchanged. These results delineate core transcriptional states that are engaged in response to AD pathology, and how they are influenced by a key AD risk gene, Trem2.
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Enfermedad de Alzheimer/patología , Amiloide/química , Astrocitos/patología , Glicoproteínas de Membrana/fisiología , Oligodendroglía/patología , Receptores Inmunológicos/fisiología , Linfocitos T/inmunología , Proteínas tau/metabolismo , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/metabolismo , Animales , Astrocitos/inmunología , Astrocitos/metabolismo , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Oligodendroglía/inmunología , Oligodendroglía/metabolismoRESUMEN
Usp22 overexpression is observed in several human cancers and is correlated with poor patient outcomes. The molecular basis underlying this correlation is not clear. Usp22 is the catalytic subunit of the deubiquitylation module in the SAGA histone-modifying complex, which regulates gene transcription. Our previous work demonstrated that the loss of Usp22 in mice leads to decreased expression of several components of receptor tyrosine kinase and TGFß signaling pathways. To determine whether these pathways are upregulated when Usp22 is overexpressed, we created a mouse model that expresses high levels of Usp22 in all tissues. Phenotypic characterization of these mice revealed over-branching of the mammary glands in females. Transcriptomic analyses indicate the upregulation of key pathways involved in mammary gland branching in mammary epithelial cells derived from the Usp22-overexpressing mice, including estrogen receptor, ERK/MAPK, and TGFß signaling. However, Usp22 overexpression did not lead to increased tumorigenesis in any tissue. Our findings indicate that elevated levels of Usp22 are not sufficient to induce tumors, but it may enhance signaling abnormalities associated with oncogenesis.
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The SAGA complex is an evolutionarily conserved transcriptional coactivator that regulates gene expression through its histone acetyltransferase and deubiquitylase activities, recognition of specific histone modifications, and interactions with transcription factors. Multiple lines of evidence indicate the existence of distinct variants of SAGA among organisms as well as within a species, permitting diverse functions to dynamically regulate cellular pathways. Our co-expression analysis of genes encoding human SAGA components showed enrichment in reproductive organs, brain tissues and the skeletal muscle, which corresponds to their established roles in developmental programs, emerging roles in neurodegenerative diseases, and understudied functions in specific cell types. SAGA subunits modulate growth, development and response to various stresses from yeast to plants and metazoans. In metazoans, SAGA further participates in the regulation of differentiation and maturation of both innate and adaptive immune cells, and is associated with initiation and progression of diseases including a broad range of cancers. The evolutionary conservation of SAGA highlights its indispensable role in eukaryotic life, thus deciphering the mechanisms of action of SAGA is key to understanding fundamental biological processes throughout evolution. To illuminate the diversity and conservation of this essential complex, here we discuss variations in composition, essentiality and co-expression of component genes, and its prominent functions across Fungi, Plantae and Animalia kingdoms.
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Histona Acetiltransferasas , Animales , Secuencia Conservada , Histona Acetiltransferasas/metabolismo , Humanos , Plantas , Procesamiento Proteico-Postraduccional , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Factores de Transcripción/metabolismo , Transcripción GenéticaRESUMEN
BACKGROUND: CD8+ tissue-resident memory T (TRM) cells, marked by CD103 (ITGAE) expression, are thought to actively suppress cancer progression, leading to the hypothesis that their presence in tumors may predict response to immunotherapy. METHODS: Here, we test this by combining high-dimensional single-cell modalities with bulk tumor transcriptomics from 1868 patients enrolled in lung and bladder cancer clinical trials of atezolizumab (anti-programmed cell death ligand 1 (PD-L1)). RESULTS: ITGAE was identified as the most significantly upregulated gene in inflamed tumors. Tumor CD103+ CD8+ TRM cells exhibited a complex phenotype defined by the expression of checkpoint regulators, cytotoxic proteins, and increased clonal expansion. CONCLUSIONS: Our analyses indeed demonstrate that the presence of CD103+ CD8+ TRM cells, quantified by tracking intratumoral CD103 expression, can predict treatment outcome, suggesting that patients who respond to PD-1/PD-L1 blockade are those who exhibit an ongoing antitumor T-cell response.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígenos CD/genética , Antígeno B7-H1/antagonistas & inhibidores , Biomarcadores de Tumor/genética , Linfocitos T CD8-positivos/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Cadenas alfa de Integrinas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/efectos adversos , Antígeno B7-H1/inmunología , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Bases de Datos Genéticas , Perfilación de la Expresión Génica , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Fenotipo , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Tiempo , Resultado del Tratamiento , Microambiente Tumoral , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/inmunologíaRESUMEN
Dysregulated microglia are intimately involved in neurodegeneration, including Alzheimer's disease (AD) pathogenesis, but the mechanisms controlling pathogenic microglial gene expression remain poorly understood. The transcription factor CCAAT/enhancer binding protein beta (c/EBPß) regulates pro-inflammatory genes in microglia and is upregulated in AD. We show expression of c/EBPß in microglia is regulated post-translationally by the ubiquitin ligase COP1 (also called RFWD2). In the absence of COP1, c/EBPß accumulates rapidly and drives a potent pro-inflammatory and neurodegeneration-related gene program, evidenced by increased neurotoxicity in microglia-neuronal co-cultures. Antibody blocking studies reveal that neurotoxicity is almost entirely attributable to complement. Remarkably, loss of a single allele of Cebpb prevented the pro-inflammatory phenotype. COP1-deficient microglia markedly accelerated tau-mediated neurodegeneration in a mouse model where activated microglia play a deleterious role. Thus, COP1 is an important suppressor of pathogenic c/EBPß-dependent gene expression programs in microglia.
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Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Ligasas/metabolismo , Microglía/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina/genética , Enfermedad de Alzheimer/metabolismo , Animales , Línea Celular , Técnicas de Cocultivo/métodos , Femenino , Expresión Génica/fisiología , Regulación de la Expresión Génica/fisiología , Células HEK293 , Humanos , Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismoRESUMEN
BACKGROUND: The glomerulus is a specialized capillary bed that is involved in urine production and BP control. Glomerular injury is a major cause of CKD, which is epidemic and without therapeutic options. Single-cell transcriptomics has radically improved our ability to characterize complex organs, such as the kidney. Cells of the glomerulus, however, have been largely underrepresented in previous single-cell kidney studies due to their paucity and intractability. METHODS: Single-cell RNA sequencing comprehensively characterized the types of cells in the glomerulus from healthy mice and from four different disease models (nephrotoxic serum nephritis, diabetes, doxorubicin toxicity, and CD2AP deficiency). RESULTS: All cell types in the glomerulus were identified using unsupervised clustering analysis. Novel marker genes and gene signatures of mesangial cells, vascular smooth muscle cells of the afferent and efferent arterioles, parietal epithelial cells, and three types of endothelial cells were identified. Analysis of the disease models revealed cell type-specific and injury type-specific responses in the glomerulus, including acute activation of the Hippo pathway in podocytes after nephrotoxic immune injury. Conditional deletion of YAP or TAZ resulted in more severe and prolonged proteinuria in response to injury, as well as worse glomerulosclerosis. CONCLUSIONS: Generation of comprehensive high-resolution, single-cell transcriptomic profiles of the glomerulus from healthy and injured mice provides resources to identify novel disease-related genes and pathways.
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Enfermedades Renales/etiología , Glomérulos Renales/patología , Animales , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Glomérulos Renales/metabolismo , Células Mesangiales/patología , Ratones , Ratones Endogámicos C57BL , Podocitos/patologíaRESUMEN
Although elevated plasma interleukin-8 (pIL-8) has been associated with poor outcome to immune checkpoint blockade 1, this has not been comprehensively evaluated in large randomized studies. Here we analyzed circulating pIL-8 and IL8 gene expression in peripheral blood mononuclear cells and tumors of patients treated with atezolizumab (anti-PD-L1 monoclonal antibody) from multiple randomized trials representing 1,445 patients with metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma. High levels of IL-8 in plasma, peripheral blood mononuclear cells and tumors were associated with decreased efficacy of atezolizumab in patients with mUC and metastatic renal cell carcinoma, even in tumors that were classically CD8+ T cell inflamed. Low baseline pIL-8 in patients with mUC was associated with increased response to atezolizumab and chemotherapy. Patients with mUC who experienced on-treatment decreases in pIL-8 exhibited improved overall survival when treated with atezolizumab but not with chemotherapy. Single-cell RNA sequencing of the immune compartment showed that IL8 is primarily expressed in circulating and intratumoral myeloid cells and that high IL8 expression is associated with downregulation of the antigen-presentation machinery. Therapies that can reverse the impacts of IL-8-mediated myeloid inflammation will be essential for improving outcomes of patients treated with immune checkpoint inhibitors.
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Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Interleucina-8/metabolismo , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígeno B7-H1/inmunología , Biomarcadores Farmacológicos/sangre , Biomarcadores Farmacológicos/metabolismo , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Transicionales/diagnóstico , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/metabolismo , Carcinoma de Células Transicionales/mortalidad , Resistencia a Antineoplásicos , Femenino , Humanos , Interleucina-8/sangre , Neoplasias Renales/diagnóstico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/metabolismo , Neoplasias Renales/mortalidad , Masculino , Neoplasias/metabolismo , Neoplasias/mortalidad , Pronóstico , Análisis de Supervivencia , Insuficiencia del Tratamiento , Neoplasias Urológicas/diagnóstico , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/metabolismo , Neoplasias Urológicas/mortalidadRESUMEN
Despite the resounding clinical success in cancer treatment of antibodies that block the interaction of PD1 with its ligand PDL11, the mechanisms involved remain unknown. A major limitation to understanding the origin and fate of T cells in tumour immunity is the lack of quantitative information on the distribution of individual clonotypes of T cells in patients with cancer. Here, by performing deep single-cell sequencing of RNA and T cell receptors in patients with different types of cancer, we survey the profiles of various populations of T cells and T cell receptors in tumours, normal adjacent tissue, and peripheral blood. We find clear evidence of clonotypic expansion of effector-like T cells not only within the tumour but also in normal adjacent tissue. Patients with gene signatures of such clonotypic expansion respond best to anti-PDL1 therapy. Notably, expanded clonotypes found in the tumour and normal adjacent tissue can also typically be detected in peripheral blood, which suggests a convenient approach to patient identification. Analyses of our data together with several external datasets suggest that intratumoural T cells, especially in responsive patients, are replenished with fresh, non-exhausted replacement cells from sites outside the tumour, suggesting continued activity of the cancer immunity cycle in these patients, the acceleration of which may be associated with clinical response.