RESUMO
Hematopoietic stem cell transplantation can deliver therapeutic proteins to the central nervous system (CNS) through transplant-derived microglia-like cells. However, current conditioning approaches result in low and slow engraftment of transplanted cells in the CNS. Here we optimized a brain conditioning regimen that leads to rapid, robust, and persistent microglia replacement without adverse effects on neurobehavior or hematopoiesis. This regimen combines busulfan myeloablation and six days of Colony-stimulating factor 1 receptor inhibitor PLX3397. Single-cell analyses revealed unappreciated heterogeneity of microglia-like cells with most cells expressing genes characteristic of homeostatic microglia, brain-border-associated macrophages, and unique markers. Cytokine analysis in the CNS showed transient inductions of myeloproliferative and chemoattractant cytokines that help repopulate the microglia niche. Bone marrow transplant of progranulin-deficient mice conditioned with busulfan and PLX3397 restored progranulin in the brain and eyes and normalized brain lipofuscin storage, proteostasis, and lipid metabolism. This study advances our understanding of CNS repopulation by hematopoietic-derived cells and demonstrates its therapeutic potential for treating progranulin-dependent neurodegeneration.
Assuntos
Bussulfano , Microglia , Progranulinas , Animais , Microglia/metabolismo , Microglia/efeitos dos fármacos , Progranulinas/metabolismo , Progranulinas/genética , Camundongos , Bussulfano/farmacologia , Transplante de Células-Tronco Hematopoéticas , Aminopiridinas/farmacologia , Encéfalo/metabolismo , Pirróis/farmacologia , Camundongos Endogâmicos C57BL , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/citologia , Transplante de Medula Óssea , Masculino , Sistema Nervoso Central/metabolismo , Camundongos Knockout , Condicionamento Pré-Transplante/métodos , Análise de Célula Única , Citocinas/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidoresRESUMO
The growth of omic data presents evolving challenges in data manipulation, analysis, and integration. Addressing these challenges, Bioconductor1 provides an extensive community-driven biological data analysis platform. Meanwhile, tidy R programming2 offers a revolutionary standard for data organisation and manipulation. Here, we present the tidyomics software ecosystem, bridging Bioconductor to the tidy R paradigm. This ecosystem aims to streamline omic analysis, ease learning, and encourage cross-disciplinary collaborations. We demonstrate the effectiveness of tidyomics by analysing 7.5 million peripheral blood mononuclear cells from the Human Cell Atlas3, spanning six data frameworks and ten analysis tools.
RESUMO
The growth of omic data presents evolving challenges in data manipulation, analysis and integration. Addressing these challenges, Bioconductor provides an extensive community-driven biological data analysis platform. Meanwhile, tidy R programming offers a revolutionary data organization and manipulation standard. Here we present the tidyomics software ecosystem, bridging Bioconductor to the tidy R paradigm. This ecosystem aims to streamline omic analysis, ease learning and encourage cross-disciplinary collaborations. We demonstrate the effectiveness of tidyomics by analyzing 7.5 million peripheral blood mononuclear cells from the Human Cell Atlas, spanning six data frameworks and ten analysis tools.
Assuntos
Software , Humanos , Biologia Computacional/métodos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/citologia , Genômica/métodos , Análise de DadosRESUMO
Chimeric antigen receptor (CAR) T cell therapy is a promising treatment for pediatric patients with relapsed or refractory B cell acute lymphoblastic leukemia (R/R B ALL). Cytokine release syndrome (CRS) is a common toxicity after CAR T cell therapy and fever is often the first symptom. Differentiating CRS from infection after CAR T cell therapy can be challenging. Plasma microbial cell free DNA (mcfDNA) is a novel diagnostic tool which allows for qualitative and quantitative assessment of over 1000 organisms. This pilot study sought to characterize mcfDNA results in pediatric patients with R/R B ALL in the first 2 months after CAR T cell therapy.
Assuntos
Ácidos Nucleicos Livres , Imunoterapia Adotiva , Humanos , Criança , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Masculino , Feminino , Ácidos Nucleicos Livres/sangue , Pré-Escolar , Adolescente , Receptores de Antígenos Quiméricos/imunologia , Recidiva , Projetos Piloto , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Resultado do Tratamento , Lactente , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/terapia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/diagnósticoRESUMO
Chimeric antigen receptor (CAR) T cells targeting CD22 (CD22-CAR) provide a therapeutic option for patients with CD22+ malignancies with progression after CD19-directed therapies. Using on-site, automated, closed-loop manufacturing, we conducted parallel Phase 1b clinical trials investigating a humanized CD22-CAR with 41BB costimulatory domain in children and adults with heavily treated, relapsed/refractory (r/r) B-ALL. Of 19 patients enrolled, 18 had successful CD22-CAR manufacturing, and 16 patients were infused. High grade (3-4) cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS) each occurred in only one patient; however, three patients experienced immune-effector-cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Twelve of 16 patients (75%) achieved CR with an overall 56% MRD-negative CR rate. Duration of response was overall limited (median 77 days), and CD22 expression was downregulated in 4/12 (33%) available samples at relapse. In summary, we demonstrate that closed-loop manufacturing of CD22-CAR T cells is feasible and is associated with a favorable safety profile and high CR rates in pediatric and adult r/r B-ALL, a cohort with limited CD22-CAR reporting.
Assuntos
Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Receptores de Antígenos Quiméricos , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico , Humanos , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Criança , Adulto , Feminino , Masculino , Adolescente , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/efeitos adversos , Adulto Jovem , Receptores de Antígenos Quiméricos/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Pré-Escolar , Pessoa de Meia-Idade , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ CAR-T cells express CD39 and CD73, which mediate proximal steps in Ado generation. Here, we sought to enhance CAR-T cell potency by knocking out CD39, CD73, or adenosine receptor 2a (A2aR) but observed only modest effects. In contrast, overexpression of Ado deaminase (ADA-OE), which metabolizes Ado to inosine (INO), induced stemness and enhanced CAR-T functionality. Similarly, CAR-T cell exposure to INO augmented function and induced features of stemness. INO induced profound metabolic reprogramming, diminishing glycolysis, increasing mitochondrial and glycolytic capacity, glutaminolysis and polyamine synthesis, and reprogrammed the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR-T cell products meeting criteria for clinical dosing. These results identify INO as a potent modulator of CAR-T cell metabolism and epigenetic stemness programming and deliver an enhanced potency platform for cell manufacturing.
Assuntos
Inosina , Linfócitos T , Humanos , Linfócitos T/metabolismoRESUMO
A t(4;11) leukemia model established from CRISPR-engineered chromosomal translocations between the KMT2A and AFF1 genes recapitulate proteomic, epigenomic, and transcriptomic features of primary patient leukemias.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B , Translocação Genética , Humanos , Edição de Genes , Proteômica , Proteína de Leucina Linfoide-Mieloide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas de Ligação a DNA/genética , Fatores de Elongação da Transcrição/genéticaRESUMO
Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of B cell malignancies, with multiple CAR T cell products approved for numerous indications by regulatory agencies worldwide. However, significant work remains to be done to enhance these treatments. In March 2023, a group of experts in CAR T cell therapy assembled at the National Institutes of Health in Bethesda, Maryland at the Insights in Pediatric CAR T Cell Immunotherapy: Recent Advances and Future Directions (INSPIRED) Symposium to identify key areas for research for the coming years. In session 4B, correlative studies to be incorporated into future clinical trials and real-world settings were discussed. Active areas of research identified included (1) optimizing CAR T cell product manufacturing; (2) ensuring adequate lymphodepletion prior to CAR T cell administration; (3) overcoming immunoregulatory cells and tumor stroma present in the tumor microenvironment, particularly in solid tumors; (4) understanding tumor intrinsic properties that lead to CAR T cell immunotherapy resistance; and (5) uncovering biomarkers predictive of treatment resistance, treatment durability, or immune-related adverse events. Here we review the results of previously published clinical trials and real-world studies to summarize what is currently known about each of these topics. We then outline priorities for future research that we believe will be important for improving our understanding of CAR T cell therapy and ultimately leading to better outcomes for patients.
Assuntos
Neoplasias , Receptores de Antígenos Quiméricos , Estados Unidos , Humanos , Criança , Receptores de Antígenos Quiméricos/genética , Linfócitos T , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/uso terapêutico , Neoplasias/terapia , Imunoterapia Adotiva/efeitos adversos , Microambiente TumoralRESUMO
Hematopoietic stem cell transplantation (HSCT) represents a consolidated therapeutic strategy for high-risk pediatric acute lymphoblastic leukemia (ALL), offering the potential for curative treatment. This manuscript delves into the debate around the more universal application of HSCT for pediatric ALL in the modern era, considering the ubiquitous availability of suitable donors. In fact, despite significant advancements in chemotherapy, targeted therapy, and immunotherapy, a subset of pediatric patients with ALL with high-risk features or relapse continue to encounter poor prognostic outcomes. For this subgroup of patients, HSCT often remains the only potentially curative measure, leveraging the graft-versus- leukemia effect for long-term disease control. Nevertheless, the procedure's complexity and associated risks have traditionally curtailed its widespread use. However, the scenario is shifting with improvements in HLA matching, availability of alternative donor sources, less toxic conditioning regimens, and improved supportive care protocols. Concurrently, emerging therapies like CD19+ CAR T cells present new considerations for definitive therapy selection in relapsed/ refractory ALL. This article reviews critical current evidence and debates the potential of HSCT as a more universal treatment for ALL, reevaluating traditional treatment stratification in light of the constant availability of stem cell donors.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Criança , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Doadores de Tecidos , Prognóstico , Condicionamento Pré-Transplante/métodos , Doença Enxerto-Hospedeiro/etiologiaRESUMO
The advent of high-dimensional single-cell technologies has enabled detection of cellular heterogeneity and functional diversity of immune cells during health and disease conditions. Because of its multiplexing capabilities and limited compensation requirements, mass cytometry or cytometry by time of flight (CyTOF) has played a superior role in immune monitoring compared with flow cytometry. Further, it has higher throughput and lower cost compared with other single-cell techniques. Several published articles have utilized CyTOF to identify cellular phenotypes and features associated with disease outcomes. This article introduces CyTOF-based assays to profile immune cell-types, cell-states, and their applications in clinical research.
Assuntos
Citometria de Fluxo , Citometria de Fluxo/métodosRESUMO
Summary: While many algorithms for analyzing high-dimensional cytometry data have now been developed, the software implementations of these algorithms remain highly customized-this means that exploring a dataset requires users to learn unique, often poorly interoperable package syntaxes for each step of data processing. To solve this problem, we developed {tidytof}, an open-source R package for analyzing high-dimensional cytometry data using the increasingly popular 'tidy data' interface. Availability and implementation: {tidytof} is available at https://github.com/keyes-timothy/tidytof and is released under the MIT license. It is supported on Linux, MS Windows and MacOS. Additional documentation is available at the package website (https://keyes-timothy.github.io/tidytof/). Supplementary information: Supplementary data are available at Bioinformatics Advances online.
RESUMO
Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ CAR T cells mediate Ado-induced immunosuppression through CD39/73-dependent Ado production. Knockout of CD39, CD73 or A2aR had modest effects on exhausted CAR T cells, whereas overexpression of Ado deaminase (ADA), which metabolizes Ado to inosine (INO), induced stemness features and potently enhanced functionality. Similarly, and to a greater extent, exposure of CAR T cells to INO augmented CAR T cell function and induced hallmark features of T cell stemness. INO induced a profound metabolic reprogramming, diminishing glycolysis and increasing oxidative phosphorylation, glutaminolysis and polyamine synthesis, and modulated the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR T cell products meeting criteria for clinical dosing. These data identify INO as a potent modulator of T cell metabolism and epigenetic stemness programming and deliver a new enhanced potency platform for immune cell manufacturing.
RESUMO
Resistance to glucocorticoids (GC) is associated with an increased risk of relapse in B-cell progenitor acute lymphoblastic leukemia (BCP-ALL). Performing transcriptomic and single-cell proteomic studies in healthy B-cell progenitors, we herein identify coordination between the glucocorticoid receptor pathway with B-cell developmental pathways. Healthy pro-B cells most highly express the glucocorticoid receptor, and this developmental expression is conserved in primary BCP-ALL cells from patients at diagnosis and relapse. In-vitro and in vivo glucocorticoid treatment of primary BCP-ALL cells demonstrate that the interplay between B-cell development and the glucocorticoid pathways is crucial for GC resistance in leukemic cells. Gene set enrichment analysis in BCP-ALL cell lines surviving GC treatment show enrichment of B cell receptor signaling pathways. In addition, primary BCP-ALL cells surviving GC treatment in vitro and in vivo demonstrate a late pre-B cell phenotype with activation of PI3K/mTOR and CREB signaling. Dasatinib, a multi-kinase inhibitor, most effectively targets this active signaling in GC-resistant cells, and when combined with glucocorticoids, results in increased cell death in vitro and decreased leukemic burden and prolonged survival in an in vivo xenograft model. Targeting the active signaling through the addition of dasatinib may represent a therapeutic approach to overcome GC resistance in BCP-ALL.
Assuntos
Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Dasatinibe/farmacologia , Dasatinibe/uso terapêutico , Receptores de Glucocorticoides/genética , Apoptose , Proteômica , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Recidiva , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular TumoralRESUMO
Cancer immunotherapies have unique toxicities. Establishment of grading scales and standardized grade-based treatment algorithms for toxicity syndromes can improve the safety of these treatments, as observed for cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) in patients with B cell malignancies treated with chimeric antigen receptor (CAR) T cell therapy. We have observed a toxicity syndrome, distinct from CRS and ICANS, in patients treated with cell therapies for tumors in the central nervous system (CNS), which we term tumor inflammation-associated neurotoxicity (TIAN). Encompassing the concept of 'pseudoprogression,' but broader than inflammation-induced edema alone, TIAN is relevant not only to cellular therapies, but also to other immunotherapies for CNS tumors. To facilitate the safe administration of cell therapies for patients with CNS tumors, we define TIAN, propose a toxicity grading scale for TIAN syndrome and discuss the potential management of this entity, with the goal of standardizing both reporting and management.
Assuntos
Neoplasias , Síndromes Neurotóxicas , Humanos , Neoplasias/terapia , Imunoterapia Adotiva/efeitos adversos , Imunoterapia , Inflamação , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/terapia , Síndromes Neurotóxicas/etiologiaRESUMO
Childhood cancer is the second leading cause of death in children aged 1 to 14. Although survival rates have vastly improved over the past 40 years, cancer resistance and relapse remain a significant challenge. Advances in single-cell technologies enable dissection of tumors to unprecedented resolution. This facilitates unraveling the heterogeneity of childhood cancers to identify cell subtypes that are prone to treatment resistance. The rapid accumulation of single-cell data from different modalities necessitates the development of novel computational approaches for processing, visualizing, and analyzing single-cell data. Here, we review single-cell approaches utilized or under development in the context of childhood cancers. We review computational methods for analyzing single-cell data and discuss best practices for their application. Finally, we review the impact of several studies of childhood tumors analyzed with these approaches and future directions to implement single-cell studies into translational cancer research in pediatric oncology.
Assuntos
Neoplasias , Criança , Humanos , Neoplasias/etiologia , Neoplasias/terapia , Oncologia/métodos , ProteômicaRESUMO
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In the primary analysis of the global phase II ELIANA trial (ClinicalTrials.gov identifier: NCT02435849), tisagenlecleucel provided an overall remission rate of 81% in pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), with 59% of responders remaining relapse-free at 12 months. Here, we report an update on efficacy, safety, and patient-reported quality of life in 79 pediatric and young adult patients with R/R B-ALL following a median follow-up of 38.8 months. The overall remission rate was 82%. The median event-free survival was 24 months, and the median overall survival was not reached. Event-free survival was 44% (95% CI, 31 to 57) and overall survival was 63% (95% CI, 51 to 73) at 3 years overall (most events occur within the first 2 years). The estimated 3-year relapse-free survival with and without censoring for subsequent therapy was 52% (95% CI, 37 to 66) and 48% (95% CI, 34 to 60), respectively. No new or unexpected long-term adverse events were reported. Grade 3/4 adverse events were reported in 29% of patients > 1 year after infusion; grade 3/4 infection rate did not increase > 1 year after infusion. Patients reported improvements in quality of life up to 36 months after infusion. These findings demonstrate favorable long-term safety and suggest tisagenlecleucel as a curative treatment option for heavily pretreated pediatric and young adult patients with R/R B-ALL.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Qualidade de Vida , Criança , Humanos , Adulto Jovem , Doença Crônica , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfócitos T/uso terapêutico , RecidivaRESUMO
Clinical pathways are evidence-based tools that have been integrated into many aspects of pediatric hospital medicine and have proven effective at reducing in-hospital complications from a variety of diseases. Adaptation of similar tools for specific, high-risk patient populations in pediatric oncology has been slower, in part due to patient complexities and variations in management strategies. There are few published studies of clinical pathways for pediatric oncology patients. Pediatric patients with a new diagnosis of leukemia or lymphoma often present with one or more "oncologic emergencies" that require urgent intervention and deliberate multidisciplinary care to prevent significant consequences. Here, we present two clinical pathways that have recently been developed using a multidisciplinary approach at a single institution, intended for the care of patients who present with hyperleukocytosis or an anterior mediastinal mass. These clinical care pathways have provided a critical framework for the immediate care of these patients who are often admitted to the pediatric intensive care unit for initial management. The goal of the pathways is to facilitate multidisciplinary collaborations, expedite diagnosis, and streamline timely treatment initiation. Standardizing the care of high-risk pediatric oncology patients will ultimately decrease morbidity and mortality associated with these diseases to increase the potential for excellent outcomes.
RESUMO
PURPOSE: In many cancers, nivolumab in combination with ipilimumab improves response rates compared with either agent alone, but the combination has not been evaluated in childhood cancer. We conducted a phase I/II trial of nivolumab plus ipilimumab in children and young adults with recurrent/refractory solid tumors. PATIENTS AND METHODS: ADVL1412, Part C assessed safety of nivolumab plus ipilimumab at two dose levels (DL): DL1 1 mg/kg of each drug and DL2 3 mg/kg nivolumab plus 1 mg/kg ipilimumab. Part D evaluated response at the recommended phase II dose (RP2D) in Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma. Part E tested DL3 (1 mg/kg nivolumab plus 3 mg/kg ipilimumab) in Ewing sarcoma and rhabdomyosarcoma. Tumor response was measured using RECIST v1.1. Pharmacokinetics and PD-L1 expression on archival tissues were assessed. RESULTS: Fifty-five eligible patients enrolled. Based on safety, tolerability, and similar drug exposure to the same doses administered in adults, DL2 was defined as the pediatric RP2D. Among 41 patients treated at the RP2D, 2 patients experienced dose-limiting toxicities during cycle 1, and 4 patients experienced toxicities beyond that period. Two patients had clinically significant sustained partial responses (1 rhabdomyosarcoma, 1 Ewing sarcoma) and 4 had stable disease. Among 8 patients treated at DL3, 3 dose-limiting toxicities (DLT) occurred, all immune-related adverse events; no objective responses were observed. CONCLUSIONS: The RP2D of nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) is well tolerated in children and young adults with solid tumors and shows some clinical activity. Increased dose of ipilimumab (3 mg/kg) plus nivolumab (1 mg/kg) was associated with increased toxicity without clinical benefit.
Assuntos
Rabdomiossarcoma , Sarcoma de Ewing , Humanos , Adulto Jovem , Criança , Ipilimumab , Nivolumabe , Sarcoma de Ewing/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Rabdomiossarcoma/tratamento farmacológicoRESUMO
The role of immune checkpoint inhibitors (ICIs) in the treatment of pediatric cancers continues to evolve. Such therapies function by augmenting existing antitumor T-cell responses that have been rendered ineffective by inhibitory pathways. Although ICIs have proven highly effective for adult cancers, initial phase I/II clinical trials using single-agent ICIs against unselected pediatric cancers have been overall disappointing. With the exception of pediatric classic Hodgkin lymphoma, responses to ICIs have been infrequent, likely stemming from an inherent difference in the immunogenicity of childhood cancers, which, on average, have far fewer neoantigens than adult cancers. Recently, however, hope has reemerged that certain subsets of children with cancer may benefit from ICI therapies. In preliminary studies, patients with both pediatric hypermutated and SMARCB1-deficient cancers have had impressive responses to ICI therapies, likely as a result of underlying biologies that enhance neoantigen expression and tumoral inflammation. Dedicated trials are ongoing to fully evaluate the efficacy of ICIs for patients with these subsets of pediatric cancer.
Assuntos
Doença de Hodgkin , Pediatria , Criança , Humanos , Inibidores de Checkpoint Imunológico , Fatores Imunológicos , ImunoterapiaRESUMO
The increasing use of mass cytometry for analyzing clinical samples offers the possibility to perform comparative analyses across public datasets. However, challenges in batch normalization and data integration limit the comparison of datasets not intended to be analyzed together. Here, we present a data integration strategy, CytofIn, using generalized anchors to integrate mass cytometry datasets from the public domain. We show that low-variance controls, such as healthy samples and stable channels, are inherently homogeneous, robust against stimulation, and can serve as generalized anchors for batch correction. Single-cell quantification comparing mass cytometry data from 989 leukemia files pre- and post normalization with CytofIn demonstrates effective batch correction while recapitulating the gold-standard bead normalization. CytofIn integration of public cancer datasets enabled the comparison of immune features across histologies and treatments. We demonstrate the ability to integrate public datasets without necessitating identical control samples or bead standards for fast and robust analysis using CytofIn.