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    ON THE COVER
    Broggi et al. show that lymphatic exudate is highly enriched intumor-associated factors and is therefore a promising source for biomarker discovery. The cover image represents a lymphatic vessel (green, VE-cadherin; blue, podoplanin) taking up tumor-derived extracellular vesicles (pink) after intradermal injection into the mouse ear dermis. Image credit: Léa Maillat, University of Chicago. See page 1091.

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ISSN 0022-1007
EISSN 1540-9538

People & Ideas

Stephanie Eisenbarth: Discovering the bigger picture

Found in Translation

With over 40 clinical trials underway, we are nearing the first FDA approved live microbial therapeutic. Here, we discuss the significant challenges of reliably administering live microorganisms to patients and the opportunities for drug delivery of these new complex therapeutics.

Insights

ILC3-like cells express Aire in the periphery.

Modulation of lupus-related signatures during pregnancy

Adiponectin accounts for gender disparity in HCC.

Reviews

In this review, Aiello and Kang discuss the molecular mechanisms, regulatory networks, and functional consequences of epithelial–mesenchymal transition (EMT) in the context of cancer metastasis, with a particular focus on partial EMT and cellular plasticity.

Brief Definitive Reports

The identity of peripheral Aire-expressing cells remains poorly understood. This study shows that Aire-expressing cells in peripheral lymph nodes exhibit typical ILC3 characteristics. These cells display potent APC features, suggesting a function in the control of T cell responses.

Cazaux et al. use intravital imaging to dissect anti-CD19 CAR T cell activity. This study uncovers both anatomical and functional diversity in the outcome of anti-CD19 CAR T cell interactions with tumor cells impacting engraftment, killing dynamics, and tumor immunoediting.

Abdulhay et al. report that an intronic genetic variant alters GATA1 splicing and presents as a distinct form of dyserythropoietic anemia in two unrelated patients. Functional studies demonstrate that the novel GATA1 isoform lacks observable activity and leads to a decrease in wild-type GATA1 levels in affected individuals.

García-Silva et al. show for the first time that extracellular vesicles isolated from the exudative seroma obtained from the lymphatic drainage implanted in melanoma patients after lymphadenectomy can be interrogated for melanoma markers and BRAF mutations. Profiling the BRAFV600E mutation in this biofluid is a novel approach to predict disease relapse.

Technical Advances and Resources

Mack et al. defined active chromatin landscapes of glioblastoma stem cells (GSCs) and primary tumor specimens, revealing novel transcriptional regulatory circuits and therapeutic targets. Super-enhancers identified essential transcription factors that underlie GSC identity and intertumoral diversity, potentially informing precision medicine.

Articles

Identifying cancer biomarkers is of great interest for patient prognosis and monitoring. However, tumor-associated factors are diluted in blood and challenging to detect. Broggi et al. show that lymphatic exudate, accessible at the time of lymphadenectomy, is highly enriched in tumor-associated factors and therefore a promising source for biomarker discovery.

Gender disparity in liver cancer incidence is a relevant feature of this malignancy. Manieri et al. show that testosterone-induced JNK1 activation in adipose tissue results in decreased levels of circulating adiponectin, which is responsible for higher incidence of hepatocellular carcinoma in males.

Shin et al. identify PIP4K2A as a putative tumor suppressor in glioblastoma using an in vivo RNAi screen system. PIP4K2A competes with PTEN to negatively regulate PI3K signaling via p85/p110 component degradation in vitro and in vivo, and its expression is significantly down-regulated in GBM patients.

High-avidity autoreactive B cells are typically removed by central tolerance mechanisms in the bone marrow. Greaves et al. demonstrate that B cell–intrinsic expression of active PI3Kα prevents central tolerance and effectively promotes differentiation and activation of high-avidity autoreactive B cells in the periphery.

Healthy and uncomplicated lupus pregnancies exhibit early and sustained transcriptional modulation of lupus-related pathways. This might contribute to fetal tolerance while predisposing pregnant women to certain infections. Failure to modulate these pathways is associated with lupus pregnancy complications.

Rapp et al. demonstrate that dendritic cells in the lymph node secrete CCL22 to build cell–cell contacts with CCR4-expressing regulatory T cells, leading to immune suppression. Conversely, CCL22 deficiency results in enhanced T cell immunity, shown here in the setting of vaccination, cancer, and inflammatory disease.

The increased cardiovascular risk in subclinical hypothyroidism has traditionally been attributed to the associated metabolic disorders. This paper, however, revealed that TSH can aggravate atherosclerosis by promoting macrophage inflammation in the plaque, which deepens our understanding of the significance of TSH elevation in subclinical hypothyroidism.

How self-DNA avoids unchecked activation of innate DNA sensors is poorly understood. Gratia et al. show that BLM protein, mutated in Bloom syndrome (BS), restrains interferon-stimulated gene induction and micronuclei recognition by cGAS. Consistently, BS patients exhibit an interferon signature.

CD4 T cell localization impacts function and differentiation. Beura et al. show that memory CD4+ T cells are largely resident in both lymphoid and non-lymphoid tissues, organize local recall responses, and share overlapping transcriptional and location-specific features with CD8+ TRM.

Corrections

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