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Immune cell dysfunction within the tumor microenvironment (TME) undermines the control of cancer progression. Established tumors contain phenotypically distinct, tumor-specific natural killer (NK) cells; however, the temporal dynamics, mechanistic underpinning and functional significance of the NK cell compartment remains incompletely understood. Here, we use photo-labeling, combined with longitudinal transcriptomic and cellular analyses, to interrogate the fate of intratumoral NK cells. We reveal that NK cells rapidly lose effector functions and adopt a distinct phenotypic state with features associated with tissue residency. NK cell depletion from established tumors did not alter tumor growth, indicating that intratumoral NK cells cease to actively contribute to anti-tumor responses. IL-15 administration prevented loss of function and improved tumor control, generating intratumoral NK cells with both tissue-residency characteristics and enhanced effector function. Collectively, our data reveals the fate of NK cells after recruitment into tumors and provides insight into how their function may be revived. Natural killer (NK) cells control tumor growth through direct cytotoxicity and recruitment of other leukocytes. Here, using photoconversion-based labeling to track the fate of NK cells in vivo, the authors demonstrate that loss of NK cell function occurs very rapidly following their entry into tumors, but can be reversed by IL-15 administration.

Tumour dendritic cells (DCs) internalise antigen and upregulate CCR7, which directs their migration to tumour-draining lymph nodes (dLN). CCR7 expression is coupled to an activation programme enriched in regulatory molecule expression, including PD-L1. However, the spatio-temporal dynamics of CCR7 + DCs in anti-tumour immune responses remain unclear. Here, we use photoconvertible mice to precisely track DC migration. We report that CCR7 + DCs are the dominant DC population that migrate to the dLN, but a subset remains tumour-resident despite CCR7 expression. These tumour-retained CCR7 + DCs are phenotypically and transcriptionally distinct from their dLN counterparts and heterogeneous. Moreover, they progressively downregulate the expression of antigen presentation and pro-inflammatory transcripts with more prolonged tumour dwell-time. Tumour-residing CCR7 + DCs co-localise with PD-1 + CD8 + T cells in human and murine solid tumours, and following anti-PD-L1 treatment, upregulate stimulatory molecules including OX40L, thereby augmenting anti-tumour cytolytic activity. Altogether, these data uncover previously unappreciated heterogeneity in CCR7 + DCs that may underpin a variable capacity to support intratumoural cytotoxic T cells. Recognition of tumour antigen induces dendritic cell activation and migration to the lymph node. Here, the authors use photoconvertible mice to demonstrate that some activated dendritic cells are retained in tumours and gradually lose function, but their ability to support local anti-tumour responses can be augmented by anti-PD-L1 blockade.

Summary The clinical success of immune checkpoint blockade in some patients has transformed treatment approaches in cancer and offers the hope of durable curative responses. Building from studies of chronic infection, the composition of tumour infiltrating lymphocytes and in particular, the spectrum of exhausted CD8 T cells has now been characterized in detail, profiling the phenotype, function, transcriptional regulation and even the epigenetic changes. However, what remains less clear is how intratumoural immune cells interface with populations in the periphery, both in terms of sustaining the response in cancer, but also in establishing systemic memory responses that can provide long-term protection. Here we will succinctly review the current understanding of the anti-tumour response, consider the tissue microenvironments that support key cellular subsets and the extent to which cellular migration between these sites impacts the response. Graphical Abstract Graphical Abstract

Tumour dendritic cells (DCs) internalise antigen and upregulate CCR7, which directs their migration to tumour-draining lymph nodes (dLN). CCR7 expression is coupled to a maturation programme enriched in regulatory molecule expression, including PD-L1, termed mRegDC. However, the spatio- temporal dynamics and role of mRegDCs in anti-tumour immune responses remain unclear. Using photoconvertible mice to precisely track DC migration, we found that mRegDCs were the dominant DC population arriving in the dLN, but a subset remained tumour-resident despite CCR7 expression. These tumour-retained mRegDCs were phenotypically and transcriptionally distinct from their dLN counterparts and were heterogeneous. Specifically, they demonstrated a progressive reduction in the expression of antigen presentation and pro-inflammatory transcripts with more prolonged tumour dwell-time. Tumour mRegDCs spatially co-localised with PD-1+CD8+ T cells in human and murine solid tumours. Following anti-PD-L1 treatment, tumour-residing mRegDCs adopted a state enriched in lymphocyte stimulatory molecules, including OX40L, which was capable of augmenting anti- tumour cytolytic activity. Altogether, these data uncover previously unappreciated heterogeneity in mRegDCs that may underpin a variable capacity to support intratumoural cytotoxic T cells, and provide insights into their role in cancer immunotherapy.

Immune cell dysfunction within the tumor microenvironment undermines the control of cancer progression. NK cells play critical roles in limiting early tumor growth and metastatic disease, however, established cancers contain a phenotypically distinct, tumor-specific NK cell compartment. The temporal dynamics, mechanistic underpinning and functional significance of this tumor NK pool remains incompletely understood. To address this, we exploited photo-labeling, combined with longitudinal transcriptomic and cellular analyses, to interrogate the fate of NK cells after tumor entry. In multiple murine cancer models we reveal that conventional NK cells are continuously recruited into tumors, but rapidly adopt a distinct phenotypic state with features associated with tissue-residency and complete loss of effector functions (including chemokine and cytokine production and cytotoxicity), within 48-72 hrs of entering the tumor. Depletion of NK cells from established tumors did not alter tumor growth, indicating that intratumoral NK cells cease to actively contribute to anti- tumor responses. Furthermore, comparable NK populations were identified in human colorectal cancers, confirming translational relevance and raising the possibility that interventions to reactivate NK cells within tissues may boost anti-tumor immunity in established cancers. Indeed, administration of IL-15:IL-15Ra complexes prevented the loss of NK cell function and improved tumor control, generating intratumoral NK cells with both enhanced tissue-residency characteristics and effector function. Collectively, our data reveals the fate of cNK cells after recruitment into tumors and provides insight into how intratumoral NK cell functions may be revived. Conventional NK cells recruited from the circulation rapidly establish a tissue-resident phenotype defined by impaired cytotoxicity and chemokine production after tumor entry; administration of IL- 15:IL-15Rα complexes further promotes this tissue-residency programme but maintains core NK cell effector functions within the tumor.

The Scanning Habitable Environments with Raman and Luminescence for Organics and Chemicals (SHERLOC) is a robotic arm-mounted instrument on NASA’s Perseverance rover. SHERLOC has two primary boresights. The Spectroscopy boresight generates spatially resolved chemical maps using fluorescence and Raman spectroscopy coupled to microscopic images (10.1 μm/pixel). The second boresight is a Wide Angle Topographic Sensor for Operations and eNgineering (WATSON); a copy of the Mars Science Laboratory (MSL) Mars Hand Lens Imager (MAHLI) that obtains color images from microscopic scales (∼13 μm/pixel) to infinity. SHERLOC Spectroscopy focuses a 40 μs pulsed deep UV neon-copper laser (248.6 nm), to a ∼100 μm spot on a target at a working distance of ∼48 mm. Fluorescence emissions from organics, and Raman scattered photons from organics and minerals, are spectrally resolved with a single diffractive grating spectrograph with a spectral range of 250 to ∼370 nm. Because the fluorescence and Raman regions are naturally separated with deep UV excitation (<250 nm), the Raman region ∼ 800 – 4000 cm−1 (250 to 273 nm) and the fluorescence region (274 to ∼370 nm) are acquired simultaneously without time gating or additional mechanisms. SHERLOC science begins by using an Autofocus Context Imager (ACI) to obtain target focus and acquire 10.1 μm/pixel greyscale images. Chemical maps of organic and mineral signatures are acquired by the orchestration of an internal scanning mirror that moves the focused laser spot across discrete points on the target surface where spectra are captured on the spectrometer detector. ACI images and chemical maps (< 100 μm/mapping pixel) will enable the first Mars in situ view of the spatial distribution and interaction between organics, minerals, and chemicals important to the assessment of potential biogenicity (containing CHNOPS). Single robotic arm placement chemical maps can cover areas up to 7x7 mm in area and, with the < 10 min acquisition time per map, larger mosaics are possible with arm movements. This microscopic view of the organic geochemistry of a target at the Perseverance field site, when combined with the other instruments, such as Mastcam-Z, PIXL, and SuperCam, will enable unprecedented analysis of geological materials for both scientific research and determination of which samples to collect and cache for Mars sample return.

Abstract Objectives were to investigate the effects of supplementation with corn dried distiller’s grains plus solubles (DDGS) to late gestating beef cows on arterial blood flow to the mammary glands during late gestation and early lactation; colostrum and milk production; dystocia and immunity; and calf BW. Cows were fed a control (CON; n = 15; 5.1% CP; 36.2% ADF) diet consisting of 90% corn stover and 10% corn silage on a dry basis offered ad libitum or CON diet with supplementation of DDGS (0.30% of BW; SUP n = 12). Mammary gland blood flow was assessed on day 245 of gestation. At parturition, maternal and calving parameters were assessed; colostrum and jugular blood was sampled; and dams were weighed. Mammary gland blood flow and milk production was measured on day 44 of lactation. Calves were weighed fortnightly for 8 wk and at weaning. Colostrum production tended to be greater in SUP dams than in CON dams (837 vs. 614 ± 95 g, P = 0.10). Calves of SUP dams were heavier at birth and 24 h (0 h, 43.2 vs. 39.8 ± 1.0 kg, P = 0.02; 24 h, 44.0 vs. 40.4 ± 1.1 kg, P = 0.02). At birth and 24 h, blood pCO2 was greater in calves born to SUP dams (6.82 vs. 6.00 ± 0.41 kPa, P = 0.04). Serum IgG did not differ (P = 0.21) at 24 h. Ipsilateral mammary gland blood flow of SUP cows was greater than CON cows (2.76 vs. 1.76 ± 0.30 L/min; P = 0.03); however, when summed with contralateral, total blood flow was similar (P = 0.33). Hemodynamic measures on day 44 of lactation were similar (P ≥ 0.32). Milk production tended to be increased (13.5 vs. 10.2 ± 1.2 kg/d, P = 0.07) in SUP vs. CON cows. Despite similar BW through 56 d, calves from SUP cows were heavier (P = 0.04) at weaning (309.7 vs. 292.0 ± 6.0 kg). In conclusion, we accept our hypothesis that DDGS supplementation during gestation influenced mammary blood flow, milk production and calf weights. These findings implicate maternal nutrition’s leverage on both nutrient and passive immunity delivery to the calf early in life as well as potential advantages on long-term performance.

BackgroundExtremely low birth weight (ELBW) infants are at risk for end-organ hypoxia and ischemia. Regional tissue oxygenation of the brain and gut as monitored with near-infrared spectroscopy (NIRS) may change with postnatal age, but normal ranges are not well defined.MethodsA prospective study of ELBW preterm infants utilized NIRS monitoring to assess changes in cerebral and mesenteric saturation (Csat and Msat) over the first week after birth. This secondary study of a multicenter trial comparing hemoglobin transfusion thresholds assessed cerebral and mesenteric fractional tissue oxygen extraction (cFTOE and mFTOE) and relationships with perinatal variables.ResultsIn 124 infants, both Csat and Msat declined over the first week, with a corresponding increase in oxygen extraction. With lower gestational age, lower birth weight, and 5-min Apgar score ≤5, there was a greater increase in oxygen extraction in the brain compared to the gut. Infants managed with a lower hemoglobin transfusion threshold receiving ≥2 transfusions in the first week had the lowest Csat and highest cFTOE (p < 0.001).ConclusionBrain oxygen extraction preferentially increased in more immature and anemic preterm infants. NIRS monitoring may enhance understanding of cerebral and mesenteric oxygenation patterns and inform future protective strategies in the preterm ELBW population.ImpactSimultaneous monitoring of cerebral and mesenteric tissue saturation demonstrates the balance of oxygenation between preterm brain and gut and may inform protective strategies.Over the first week, oxygen saturation of the brain and gut declines as oxygen extraction increases.A low hemoglobin transfusion threshold is associated with lower cerebral saturation and higher cerebral oxygen extraction compared to a high hemoglobin transfusion threshold, although this did not translate into clinically relevant differences in the TOP trial primary outcome.Greater oxygen extraction by the brain compared to the gut occurs with lower gestational age, lower birth weight, and 5-min Apgar score ≤5.

BackgroundThis systematic review assessed the minimum requirements necessary to create an enabling environment for sustained hand hygiene practices: quantity of water and soap, and number, spacing, location, and design of hand hygiene facilities.MethodsWe searched PubMed, Web of Science, EMBASE, CINAHL, Global Health, Cochrane Library, Global Index Medicus, Scopus, PAIS Index, WHO IRIS, UN Digital Library and World Bank eLibrary, and consulted experts. Eligible studies were published through 29 March 2023, observational, in non-healthcare community settings, and reported on at least one of the five categories: (1) quantity of water, (2) quantity of soap, (3) location of hand hygiene materials, (4) number of users or spacing of facilities and (5) considerations for equitable access. Two reviewers independently extracted data from each study and assessed risk of bias using the Mixed Method Appraisal Tool.ResultsThis review identified 37 studies that met inclusion criteria from 27 countries, representing 4 of the 6 WHO regions (Africa, South-East Asia, the Americas and Europe). Household settings were the most represented (59% of studies), followed by institutional or school settings (41%) and public establishments (27%). Of the 37 studies, 12 (32%) assessed the relationship between a material requirement and hand hygiene practices. Despite extensive global research on hand hygiene, we found a lack of evidence linking material requirements with handwashing practices in community settings.ConclusionsThis review was limited to observational studies, and more data could be derived from experimental studies. Important evidence gaps include the quantity of water and soap needed, the influence of facility location and design on hand hygiene practice, and material needs providing equitable access. Further research is needed to strengthen the evidence base for hand hygiene recommendations and supplement the expert opinion on which many recommendations are currently based.PROSPERO registration numberCRD42023429145.

IntroductionThis systematic review sought to understand barriers and enablers to hand hygiene in community settings.MethodsEligible studies addressed hand hygiene in a community setting, included a qualitative component, and were published in English between 1 January 1980 and 29 March 2023. Studies were excluded if in healthcare settings or were animal research. We searched PubMed, Web of Science, EMBASE, CINAHL, Global Health, Cochrane Library, Global Index Medicus, Scopus, Public Affairs Information Service Index, WHO Institutional Repository for Information Sharing, UN Digital Library and World Bank eLibrary, manually searched relevant systematic reviews’ reference lists, and consulted experts. We used MaxQDA software to code papers, using the COM-B (Capability, Opportunity, Motivation and Behaviour) framework to classify barriers and enablers. We used thematic analysis to describe each COM-B subtheme identified, GRADE-CERQual to assess confidence in evidence for thematic findings and the Mixed Method Appraisal Tool (MMAT) to assess risk of study bias.Results80 studies were included; most took place in Africa (31; 39%), South-East Asia (31; 39%) and domestic settings (54; 68%). The mean MMAT score was 4.86 (good quality). Barriers and/or enablers were reported across all COM-B constructs and subconstructs. The most reported barriers aligned with Physical Opportunity (eg, soap availability), Reflective Motivation (eg, hand hygiene not prioritised) and Automatic Motivation (eg, no habit). In contrast, the most reported enablers aligned with Automatic Motivation (ie, habit) and Reflective Motivation (ie, perception of health risk).ConclusionFindings confirm that a lack of necessary resources for hand hygiene hinders practice, even when people are motivated. Results may explain why hand hygiene increases when there are acute health risks (eg, COVID-19), but decreases when risks are perceived to fade. The qualitative methodology used among the studies may have revealed a broader array of barriers and enablers than what might have been found by quantitative, researcher-driven studies, but representativeness may be limited. Evidence was also limited on alcohol-based hand rubs. Findings can inform the design of future hand hygiene initiatives.PROSPERO registration numberCRD42023429145.