Data availability The data that support the plots within this paper and other findings of this study are available from the corresponding author upon request. The bulk and single-cell RNA-seq data are available as part of the Gene Expression Omnibus (GEO) SuperSeries GSE134691. Author contributions S.C. and A.G. designed the study, performed experiments, interpreted results and wrote the manuscript. J.Á.N.-Á. designed the study and experiments and interpreted data.

Highlights d Cardiomyocytes release subcellular particles called exophers d Cardiac exophers transport defective mitochondria for elimination d cMacs capture and eliminate exophers though Mertk

Highlights d Neutrophil aging is an intrinsically driven, bona fide circadian process d Bmal1 and CXCR2 induce neutrophil aging, whereas CXCR4 antagonizes it d Diurnal aging critically dictates how and when neutrophils migrate into tissues d Aging favors neutrophil clearance, thereby protecting the cardiovascular system

Man scripClick here to ie linked References SummaryClassically considered short-lived, purely defensive leukocytes, neutrophils are unique in their fast and moldable response to stimulation. This plastic behavior may underlie variable and even antagonistic functions during inflammation or cancer, yet the full spectrum of neutrophil properties as they enter healthy tissues remains unexplored. Using a new model to track neutrophil fates, we found short but variable lifetimes across multiple tissues. Through analysis of the receptor, transcriptional and chromatin accessibility landscapes, we identify varying neutrophil states and assign non-canonical functions, including vascular repair and hematopoietic homeostasis. Accordingly, depletion of neutrophils compromised angiogenesis during early age, genotoxic injury and viral infection, and impaired hematopoietic recovery after irradiation. Neutrophils acquired these properties in target tissues, a process that in the lungs occurred in CXCL12-rich areas and relied on CXCR4. Our results reveal that tissues co-opt neutrophils en route for elimination to induce programs that support their physiological demands. circulation (Hidalgo et al., 2019) and reduced transcriptional activity preclude genetic adaptation to tissue environments (Silvestre-Roig et al., 2016). Existing evidence has shown, however, that cancer can instruct different transcriptional profiles, resulting in functions that can either promote, or counteract, tumoral growth and metastasis (Coffelt et al., 2016). Similar heterogeneous behavior has been reported in the context of stroke,

Immune protection relies on the capacity of neutrophils to infiltrate challenged tissues. Naive tissues, in contrast, are believed to remain free of these cells and protected from their toxic cargo. Here, we show that neutrophils are endowed with the capacity to infiltrate multiple tissues in the steady-state, a process that follows tissue-specific dynamics. By focusing in two particular tissues, the intestine and the lungs, we find that neutrophils infiltrating the intestine are engulfed by resident macrophages, resulting in repression of Il23 transcription, reduced G-CSF in plasma, and reinforced activity of distant bone marrow niches. In contrast, diurnal accumulation of neutrophils within the pulmonary vasculature influenced circadian transcription in the lungs. Neutrophil-influenced transcripts in this organ were associated with carcinogenesis and migration. Consistently, we found that neutrophils dictated the diurnal patterns of lung invasion by melanoma cells. Homeostatic infiltration of tissues unveils a facet of neutrophil biology that supports organ function, but can also instigate pathological states.

The goal of successful anti-tumoural immunity is the development of long-term protective immunity to prevent relapse. Infiltration of tumours with CD8+ T cells with a resident memory (Trm) phenotype correlates with improved survival. However, the interplay of circulating CD8+ T cells and Trm cells remains poorly explored in tumour immunity. Using different vaccination strategies that fine-tune the generation of Trm cells or circulating memory T cells, here we show that, while both subsets are sufficient for anti-tumour immunity, the presence of Trm cells improves anti-tumour efficacy. Transferred central memory T cells (Tcm) generate Trm cells following viral infection or tumour challenge. Anti-PD-1 treatment promotes infiltration of transferred Tcm cells within tumours, improving anti-tumour immunity. Moreover, Batf3-dependent dendritic cells are essential for reactivation of circulating memory anti-tumour response. Our findings show the plasticity, collaboration and requirements for reactivation of memory CD8+ T cells subsets needed for optimal tumour vaccination and immunotherapy.

Macrophages are important for tissue function, and adapt phenotypically to each tissue by factors produced locally. A-Gonzalez et al. now show that phagocytosis of unwanted cells additionally contributes to imprinting macrophage heterogeneity, thus promoting tissue homeostasis.

BACKGROUND:The objective of this study was to prospectively evaluate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as an early imaging indicator of tumor histologic response to preoperative chemotherapy and as a possible prognostic factor for event-free survival (EFS) and overall survival in pediatric patients with newly diagnosed, nonmetastatic osteosarcoma who were treated on a single, multi-institutional phase 2 trial. METHODS: Three serial DCE-MRI examinations at week 0 (before treatment), week 9, and week 12 (tumor resection) were performed in 69 patients with nonmetastatic osteosarcoma to monitor the response to preoperative chemotherapy. Four DCE-MRI kinetic parameters (the influx volume transfer constant [K trans ], the efflux rate constant [k ep ], the relative extravascular extracellular space [v e ], and the relative vascular plasma space [v p ]) and the corresponding differences (DK trans , Dk ep , Dv e , and Dv p ) of averaged kinetic parameters between the outer and inner halves of tumors were calculated to assess their associations with tumor histologic response, EFS, and overall survival. RESULTS: The parameters K trans , v e , v p , and k ep decreased significantly from week 0 to week 9 and week 12. The parameters K trans , v p , and Dk ep at week 9 were significantly different between responders and nonresponders (P ¼ .046, P ¼ .021, and P ¼ .008, respectively). These 3 parameters were indicative of histologic response. The parameter Dv e at week 0 was a significant prognostic factor for both EFS (P ¼ .02) and overall survival (P ¼ .03). CONCLUSIONS: DCE-MRI was identified as a prognostic factor for EFS and overall survival before treatment on this trial and was indicative of a histologic response to neoadjuvant therapy. Further studies are needed to verify these findings with other treatment regimens and establish the potential role of DCE-MRI in the development of risk-adapted therapy for osteosarcoma.