ABSTRACT
Highlights from the Science family of journals.
ABSTRACT
Highlights from the Science family of journals.
ABSTRACT
Highlights from the Science family of journals.
ABSTRACT
Highlights from the Science family of journals.
ABSTRACT
Highlights from the Science family of journals.
ABSTRACT
Highlights from the Science family of journals.
ABSTRACT
Highlights from the Science family of journals.
ABSTRACT
Highlights from the Science family of journals.
ABSTRACT
Highlights from the Science family of journals.
ABSTRACT
Glioblastoma (GBM) is the most common malignant brain tumor in adults, responsible for approximately 225,000 deaths per year. Despite preclinical successes, most interventions have failed to extend patient survival by more than a few months. Treatment with anti-programmed cell death protein 1 (anti-PD-1) immune checkpoint blockade (ICB) monotherapy has been beneficial for malignant tumors such as melanoma and lung cancers but has yet to be effectively employed in GBM. This study aimed to determine whether supplementing anti-PD-1 ICB with engineered extended half-life IL2, a potent lymphoproliferative cytokine, could improve outcomes. This combination therapy, subsequently referred to as enhanced checkpoint blockade (ECB), delivered intraperitoneally, reliably cures approximately 50% of C57BL/6 mice bearing orthotopic GL261 gliomas and extends median survival of the treated cohort. In the CT2A model, characterized as being resistant to CBI, ECB caused a decrease in CT2A tumor volume in half of measured animals similar to what was observed in GL261-bearing mice, promoting a trending survival increase. ECB generates robust immunologic responses, features of which include secondary lymphoid organ enlargement and increased activation status of both CD4 and CD8 T cells. This immunity is durable, with long-term ECB survivors able to resist GL261 rechallenge. Through employment of depletion strategies, ECB's efficacy was shown to be independent of host MHC class I-restricted antigen presentation but reliant on CD4 T cells. These results demonstrate ECB is efficacious against the GL261 glioma model through an MHC class I-independent mechanism and supporting further investigation into IL2-supplemented ICB therapies for tumors of the central nervous system.
Subject(s)
Glioblastoma , Glioma , Mice , Animals , Interleukin-2/pharmacology , Interleukin-2/therapeutic use , Half-Life , Mice, Inbred C57BL , Glioma/pathology , Cell Line, TumorABSTRACT
Highlights from the Science family of journals.
ABSTRACT
To disseminate through the body, Zika virus (ZIKV) is thought to exploit the mobility of myeloid cells, in particular monocytes and dendritic cells. However, the timing and mechanisms underlying shuttling of the virus by immune cells remains unclear. To understand the early steps in ZIKV transit from the skin, at different time points, we spatially mapped ZIKV infection in lymph nodes (LNs), an intermediary site en route to the blood. Contrary to prevailing hypotheses, migratory immune cells are not required for the virus to reach the LNs or blood. Instead, ZIKV rapidly infects a subset of sessile CD169+ macrophages in the LNs, which release the virus to infect downstream LNs. Infection of CD169+ macrophages alone is sufficient to initiate viremia. Overall, our experiments indicate that macrophages that reside in the LNs contribute to initial ZIKV spread. These studies enhance our understanding of ZIKV dissemination and identify another anatomical site for potential antiviral intervention.
Subject(s)
Zika Virus Infection , Zika Virus , Humans , Macrophages , Monocytes/pathology , Lymph Nodes/pathologyABSTRACT
Highlights from the Science family of journals.
ABSTRACT
Highlights from the Science family of journals.
ABSTRACT
Highlights from the Science family of journals.
ABSTRACT
Highlights from the Science family of journals.
ABSTRACT
Highlights from the Science family of journals.
ABSTRACT
Cellular senescence is a plausible mediator of inflammation-related tissue dysfunction. In the aged brain, senescent cell identities and the mechanisms by which they exert adverse influence are unclear. Here we used high-dimensional molecular profiling, coupled with mechanistic experiments, to study the properties of senescent cells in the aged mouse brain. We show that senescence and inflammatory expression profiles increase with age and are brain region- and sex-specific. p16-positive myeloid cells exhibiting senescent and disease-associated activation signatures, including upregulation of chemoattractant factors, accumulate in the aged mouse brain. Senescent brain myeloid cells promote peripheral immune cell chemotaxis in vitro. Activated resident and infiltrating immune cells increase in the aged brain and are partially restored to youthful levels through p16-positive senescent cell clearance in female p16-InkAttac mice, which is associated with preservation of cognitive function. Our study reveals dynamic remodeling of the brain immune cell landscape in aging and suggests senescent cell targeting as a strategy to counter inflammatory changes and cognitive decline.
Subject(s)
Cyclin-Dependent Kinase Inhibitor p16 , Rejuvenation , Aging , Animals , Brain/metabolism , Cellular Senescence/physiology , Chemotactic Factors , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Female , Male , MiceABSTRACT
Highlights from the Science family of journals.
ABSTRACT
Highlights from the Science family of journals.
