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1.
Neuro Oncol ; 26(5): 826-839, 2024 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-38237157

RESUMEN

BACKGROUND: Glioblastomas (GBMs) are central nervous system tumors that resist standard-of-care interventions and even immune checkpoint blockade. Myeloid cells in the tumor microenvironment can contribute to GBM progression; therefore, emerging immunotherapeutic approaches include reprogramming these cells to achieve desirable antitumor activity. Triggering receptor expressed on myeloid cells 2 (TREM2) is a myeloid signaling regulator that has been implicated in a variety of cancers and neurological diseases with contrasting functions, but its role in GBM immunopathology and progression is still under investigation. METHODS: Our reverse translational investigations leveraged single-cell RNA sequencing and cytometry of human gliomas to characterize TREM2 expression across myeloid subpopulations. Using 2 distinct murine glioma models, we examined the role of Trem2 on tumor progression and immune modulation of myeloid cells. Furthermore, we designed a method of tracking phagocytosis of glioma cells in vivo and employed in vitro assays to mechanistically understand the influence of TREM2 signaling on tumor uptake. RESULTS: We discovered that TREM2 expression does not correlate with immunosuppressive pathways, but rather showed strong a positive association with the canonical phagocytosis markers lysozyme (LYZ) and macrophage scavenger receptor (CD163) in gliomas. While Trem2 deficiency was found to be dispensable for gliomagenesis, Trem2+ myeloid cells display enhanced tumor uptake compared to Trem2- cells. Mechanistically, we demonstrate that TREM2 mediates phagocytosis via Syk signaling. CONCLUSIONS: These results indicate that TREM2 is not associated with immunosuppression in gliomas. Instead, TREM2 is an important regulator of phagocytosis that may be exploited as a potential therapeutic strategy for brain tumors.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Glicoproteínas de Membrana , Fagocitosis , Receptores Inmunológicos , Animales , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/genética , Glioblastoma/metabolismo , Glioblastoma/patología , Glioblastoma/genética , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Ratones , Humanos , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Microambiente Tumoral , Células Mieloides/metabolismo , Ratones Endogámicos C57BL , Células Tumorales Cultivadas , Transducción de Señal
2.
Neuro Oncol ; 2024 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-39126294

RESUMEN

BACKGROUND: Human gliomas are classified using isocitrate dehydrogenase (IDH) status as a prognosticator; however, the influence of genetic differences and treatment effects on ensuing immunity remains unclear. METHODS: In this study, we used sequential single-cell transcriptomics on 144,678 and spectral cytometry on over two million immune cells encompassing 48 human gliomas to decipher their immune landscape. RESULTS: We identified 22 distinct immune cell types that contribute to glioma immunity. Specifically, brain-resident microglia (MG) were reduced with a concomitant increase in CD8+ T lymphocytes during glioma recurrence independent of IDH status. In contrast, IDH-wild-type-associated patterns, such as an abundance of antigen-presenting cell-like MG and cytotoxic CD8+ T cells, were observed. Beyond elucidating the differences in IDH, relapse, and treatment-associated immunity, we discovered novel inflammatory MG subpopulations expressing granulysin, a cytotoxic peptide, which is otherwise expressed in lymphocytes only. Furthermore, we provide a robust genomic framework for defining macrophage polarization beyond M1/M2 paradigm and reference signatures of glioma-specific tumor immune microenvironment (termed Glio-TIME-36) for deconvoluting transcriptomic datasets. CONCLUSIONS: This study provides advanced optics of the human pan-glioma immune contexture as a valuable guide for translational and clinical applications.

3.
bioRxiv ; 2023 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-37066184

RESUMEN

Glioblastomas (GBMs) are tumors of the central nervous system that remain recalcitrant to both standard of care chemo-radiation and immunotherapies. Emerging approaches to treat GBMs include depletion or re-education of innate immune cells including microglia (MG) and macrophages (MACs). Here we show myeloid cell restricted expression of triggering receptor expressed on myeloid cells 2 (TREM2) across low- and high-grade human gliomas. TREM2 expression did not correlate with immunosuppressive pathways, but rather showed strong positive association with phagocytosis markers such as lysozyme (LYZ) and CD163 in gliomas. In line with these observations in patient tumors, Trem2-/- mice did not exhibit improved survival compared to wildtype (WT) mice when implanted with mouse glioma cell lines, unlike observations previously seen in peripheral tumor models. Gene expression profiling revealed pathways related to inflammation, adaptive immunity, and autophagy that were significantly downregulated in tumors from Trem2-/- mice compared to WT tumors. Using ZsGreen-expressing CT-2A orthotopic implants, we found higher tumor antigen engulfment in Trem2+ MACs, MG, and dendritic cells. Our data uncover TREM2 as an important immunomodulator in gliomas and inducing TREM2 mediated phagocytosis can be a potential immunotherapeutic strategy for brain tumors.

4.
Nat Med ; 29(6): 1550-1562, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37248301

RESUMEN

Tumor-infiltrating T cells offer a promising avenue for cancer treatment, yet their states remain to be fully characterized. Here we present a single-cell atlas of T cells from 308,048 transcriptomes across 16 cancer types, uncovering previously undescribed T cell states and heterogeneous subpopulations of follicular helper, regulatory and proliferative T cells. We identified a unique stress response state, TSTR, characterized by heat shock gene expression. TSTR cells are detectable in situ in the tumor microenvironment across various cancer types, mostly within lymphocyte aggregates or potential tertiary lymphoid structures in tumor beds or surrounding tumor edges. T cell states/compositions correlated with genomic, pathological and clinical features in 375 patients from 23 cohorts, including 171 patients who received immune checkpoint blockade therapy. We also found significantly upregulated heat shock gene expression in intratumoral CD4/CD8+ cells following immune checkpoint blockade treatment, particularly in nonresponsive tumors, suggesting a potential role of TSTR cells in immunotherapy resistance. Our well-annotated T cell reference maps, web portal and automatic alignment/annotation tool could provide valuable resources for T cell therapy optimization and biomarker discovery.


Asunto(s)
Linfocitos T CD8-positivos , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Linfocitos Infiltrantes de Tumor , Neoplasias/genética , Neoplasias/terapia , Neoplasias/metabolismo , Inmunoterapia , Microambiente Tumoral
5.
JCI Insight ; 7(9)2022 05 09.
Artículo en Inglés | MEDLINE | ID: mdl-35316217

RESUMEN

BACKGROUNDImmune cell profiling of primary and metastatic CNS tumors has been focused on the tumor, not the tumor microenvironment (TME), or has been analyzed via biopsies.METHODSEn bloc resections of gliomas (n = 10) and lung metastases (n = 10) were analyzed via tissue segmentation and high-dimension Opal 7-color multiplex imaging. Single-cell RNA analyses were used to infer immune cell functionality.RESULTSWithin gliomas, T cells were localized in the infiltrating edge and perivascular space of tumors, while residing mostly in the stroma of metastatic tumors. CD163+ macrophages were evident throughout the TME of metastatic tumors, whereas in gliomas, CD68+, CD11c+CD68+, and CD11c+CD68+CD163+ cell subtypes were commonly observed. In lung metastases, T cells interacted with CD163+ macrophages as dyads and clusters at the brain-tumor interface and within the tumor itself and as clusters within the necrotic core. In contrast, gliomas typically lacked dyad and cluster interactions, except for T cell CD68+ cell dyads within the tumor. Analysis of transcriptomic data in glioblastomas revealed that innate immune cells expressed both proinflammatory and immunosuppressive gene signatures.CONCLUSIONOur results show that immunosuppressive macrophages are abundant within the TME and that the immune cell interactome between cancer lineages is distinct. Further, these data provide information for evaluating the role of different immune cell populations in brain tumor growth and therapeutic responses.FUNDINGThis study was supported by the NIH (NS120547), a Developmental research project award (P50CA221747), ReMission Alliance, institutional funding from Northwestern University and the Lurie Comprehensive Cancer Center, and gifts from the Mosky family and Perry McKay. Performed in the Flow Cytometry & Cellular Imaging Core Facility at MD Anderson Cancer Center, this study received support in part from the NIH (CA016672) and the National Cancer Institute (NCI) Research Specialist award 1 (R50 CA243707). Additional support was provided by CCSG Bioinformatics Shared Resource 5 (P30 CA046592), a gift from Agilent Technologies, a Research Scholar Grant from the American Cancer Society (RSG-16-005-01), a Precision Health Investigator Award from University of Michigan (U-M) Precision Health, the NCI (R37-CA214955), startup institutional research funds from U-M, and a Biomedical Informatics & Data Science Training Grant (T32GM141746).


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Neoplasias Pulmonares , Neoplasias Encefálicas/patología , Sistema Nervioso Central/metabolismo , Glioblastoma/patología , Humanos , Neoplasias Pulmonares/patología , Macrófagos/metabolismo , Factor de Transcripción STAT3/metabolismo , Microambiente Tumoral , Estados Unidos
6.
Neuro Oncol ; 22(2): 180-194, 2020 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-31679017

RESUMEN

CNS immune defenses are marshaled and dominated by brain resident macrophages and microglia, which are the innate immune sentinels and frontline host immune barriers against various pathogenic insults. These myeloid lineage cells are the predominant immune population in gliomas and can constitute up to 30-50% of the total cellular composition. Parenchymal microglial cells and recruited monocyte-derived macrophages from the periphery exhibit disease-specific phenotypic characteristics with spatial and temporal distinctions and are heterogeneous subpopulations based on their molecular signatures. A preponderance of myeloid over lymphoid lineage cells during CNS inflammation, including gliomas, is a contrasting feature of brain immunity relative to peripheral immunity. Herein we discuss glioma-associated macrophage and microglia immune biology in the context of their identity, molecular drivers of recruitment, nomenclature and functional paradoxes, therapeutic reprogramming and polarization strategies, relevant challenges, and our perspectives on therapeutic modulation.


Asunto(s)
Neoplasias Encefálicas/inmunología , Glioma/inmunología , Macrófagos/inmunología , Microglía/inmunología , Animales , Humanos
7.
Clin Cancer Res ; 26(18): 4983-4994, 2020 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-32605912

RESUMEN

PURPOSE: Patients with central nervous system (CNS) tumors are typically treated with radiotherapy, but this is not curative and results in the upregulation of phosphorylated STAT3 (p-STAT3), which drives invasion, angiogenesis, and immune suppression. Therefore, we investigated the combined effect of an inhibitor of STAT3 and whole-brain radiotherapy (WBRT) in a murine model of glioma. EXPERIMENTAL DESIGN: C57BL/6 mice underwent intracerebral implantation of GL261 glioma cells, WBRT, and treatment with WP1066, a blood-brain barrier-penetrant inhibitor of the STAT3 pathway, or the two in combination. The role of the immune system was evaluated using tumor rechallenge strategies, immune-incompetent backgrounds, immunofluorescence, immune phenotyping of tumor-infiltrating immune cells (via flow cytometry), and NanoString gene expression analysis of 770 immune-related genes from immune cells, including those directly isolated from the tumor microenvironment. RESULTS: The combination of WP1066 and WBRT resulted in long-term survivors and enhanced median survival time relative to monotherapy in the GL261 glioma model (combination vs. control P < 0.0001). Immunologic memory appeared to be induced, because mice were protected during subsequent tumor rechallenge. The therapeutic effect of the combination was completely lost in immune-incompetent animals. NanoString analysis and immunofluorescence revealed immunologic reprograming in the CNS tumor microenvironment specifically affecting dendritic cell antigen presentation and T-cell effector functions. CONCLUSIONS: This study indicates that the combination of STAT3 inhibition and WBRT enhances the therapeutic effect against gliomas in the CNS by inducing dendritic cell and T-cell interactions in the CNS tumor.


Asunto(s)
Neoplasias Encefálicas/terapia , Comunicación Celular/inmunología , Quimioradioterapia/métodos , Glioma/terapia , Factor de Transcripción STAT3/antagonistas & inhibidores , Animales , Presentación de Antígeno/efectos de los fármacos , Presentación de Antígeno/efectos de la radiación , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Comunicación Celular/efectos de los fármacos , Comunicación Celular/efectos de la radiación , Línea Celular Tumoral/ultraestructura , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/efectos de la radiación , Modelos Animales de Enfermedad , Glioma/inmunología , Glioma/patología , Humanos , Memoria Inmunológica/efectos de los fármacos , Ratones , Piridinas/administración & dosificación , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/efectos de la radiación , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de la radiación , Tirfostinos/administración & dosificación
8.
Artículo en Inglés | MEDLINE | ID: mdl-30298129

RESUMEN

Cell- and gene-based therapies form one of the pillars of regenerative medicine. They have the potential to transform quality of life and improve the health status of patients with genetic and cellular defects, including genetic diseases, neurodegenerative diseases and tissue malignancies, amongst others. Despite numerous challenges, in the last decade, tremendous unified efforts by research and clinical scientists in academic, translational and industry settings have resulted in tangible outcomes in the form of many marketing authorizations and approved commercial firsts, such as Glybera®, Kymriah®, YESCARTA®, Holoclar®, and Luxturna™. This report presents a succinct analysis of developments in the regenerative medicine landscape, including immuno-oncology, with a focus on the European Union and examples of clinical and commercial successes and failures. The factors that led to these exciting developments in immune-oncology are also considered. Concurrently, several key issues, spanning from the identification of unmet clinical need, associated challenges, economic evaluation to policy improvements are emphasized. Furthermore, industry insights encompassing the five-dimensional research and development framework for the focused development of medicine, pricing and reimbursement issues, technology adoption and permeation of innovative advanced therapy medicinal products in the clinical set up are reflected upon, following elaborate discussions that transpired in different thematic tracks of Tissue Engineering & Regenerative Medicine International Society European Chapter 2017 Industry Symposium.

9.
Cell Rep ; 25(11): 3099-3109.e3, 2018 12 11.
Artículo en Inglés | MEDLINE | ID: mdl-30540942

RESUMEN

Inflammation-induced disappearance of tissue-resident macrophages represents a key pathogen defense mechanism. Using a model of systemic blood-stage malaria, we studied the dynamics of tissue-resident macrophages in multiple organs to determine how they are depleted and refilled during the course of disease. We show that Plasmodium infection results in a transient loss of embryonically established resident macrophages prior to the parasitemia peak. Fate-mapping analysis reveals that inflammatory monocytes contribute to the repopulation of the emptied niches of splenic red pulp macrophages and hepatic Kupffer cells, while lung alveolar macrophages refill their niche predominantly through self-renewal. Interestingly, the local microenvironment of the spleen and liver can "imprint" the molecular characteristics of fetal-derived macrophages on newly differentiated bone marrow-derived immigrants with remarkably similar gene expression profiles and turnover kinetics. Thus, the mononuclear phagocytic system has developed distinct but effective tissue-specific strategies to replenish emptied niches to guarantee the functional integrity of the system.


Asunto(s)
Estadios del Ciclo de Vida , Macrófagos/parasitología , Malaria/parasitología , Especificidad de Órganos , Animales , Células de la Médula Ósea/patología , Feto/patología , Inflamación/patología , Cinética , Macrófagos del Hígado/patología , Hígado/patología , Activación de Macrófagos , Macrófagos/metabolismo , Macrófagos Alveolares/patología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Monocitos/patología , Células Mieloides/metabolismo , Plasmodium/crecimiento & desarrollo , Bazo/patología , Transcriptoma/genética
10.
Cell Rep ; 16(6): 1749-1761, 2016 08 09.
Artículo en Inglés | MEDLINE | ID: mdl-27477286

RESUMEN

Tissue macrophages exhibit diverse functions, ranging from the maintenance of tissue homeostasis, including clearance of senescent erythrocytes and cell debris, to modulation of inflammation and immunity. Their contribution to the control of blood-stage malaria remains unclear. Here, we show that in the absence of tissue-resident CD169(+) macrophages, Plasmodium berghei ANKA (PbA) infection results in significantly increased parasite sequestration, leading to vascular occlusion and leakage and augmented tissue deposition of the malarial pigment hemozoin. This leads to widespread tissue damage culminating in multiple organ inflammation. Thus, the capacity of CD169(+) macrophages to contain the parasite burden and its sequestration into different tissues and to limit infection-induced inflammation is crucial to mitigating Plasmodium infection and pathogenesis.


Asunto(s)
Macrófagos/parasitología , Malaria/inmunología , Plasmodium berghei/parasitología , Lectina 1 Similar a Ig de Unión al Ácido Siálico/genética , Animales , Eritrocitos/parasitología , Hemoproteínas/metabolismo , Macrófagos/patología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos
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