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PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tu...
Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor that is upregulated on activated T cells for the induction of immune tolerance. Tumour cells frequently overexpress the ligand for PD-1, programmed cell death ligand 1 (PD-L1), facilitating their escape from the immune system. Monoclonal antibodies that block the interaction between PD-1 and PD-L1, by binding to either the ligand or receptor, have shown notable clinical efficacy in patients with a variety of cancers, including melanoma, colorectal cancer, non-small-cell lung cancer and Hodgkin?s lymphoma. Although it is well established that PD-1?PD-L1 blockade activates T cells, little is known about the role that this pathway may have in tumour-associated macrophages (TAMs). Here we show that both mouse and human TAMs express PD-1. TAM PD-1 expression increases over time in mouse models of cancer and with increasing disease stage in primary human cancers. TAM PD-1 expression correlates negatively with phagocytic potency against tumour cells, and blockade of PD-1?PD-L1 in vivo increases macrophage phagocytosis, reduces tumour growth and lengthens the survival of mice in mouse models of cancer in a macrophage-dependent fashion. This suggests that PD-1?PD-L1 therapies may also function through a direct effect on macrophages, with substantial implications for the treatment of cancer with these agents.


Nature Journals

Lymphatic endothelial S1P promotes mitochondrial function and survival in nai...
Effective adaptive immune responses require a large repertoire of naive T cells that migrate throughout the body, rapidly identifying almost any foreign peptide. Because the production of T cells declines with age, naive T cells must be long-lived. However, it remains unclear how naive T cells survive for years while constantly travelling. The chemoattractant sphingosine 1-phosphate (S1P) guides T cell circulation among secondary lymphoid organs, including spleen, lymph nodes and Peyer?s patches, where T cells search for antigens. The concentration of S1P is higher in circulatory fluids than in lymphoid organs, and the S1P1 receptor (S1P1R) directs the exit of T cells from the spleen into blood, and from lymph nodes and Peyer?s patches into lymph. Here we show that S1P is essential not only for the circulation of naive T cells, but also for their survival. Using transgenic mouse models, we demonstrate that lymphatic endothelial cells support the survival of T cells by secreting S1P via the transporter SPNS2, that this S1P signals through S1P1R on T cells, and that the requirement for S1P1R is independent of the established role of the receptor in guiding exit from lymph nodes. S1P signalling maintains the mitochondrial content of naive T cells, providing cells with the energy to continue their constant migration. The S1P signalling pathway is being targeted therapeutically to inhibit autoreactive T cell trafficking, and these findings suggest that it may be possible simultaneously to target autoreactive or malignant cell survival.

PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tu...
Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor that is upregulated on activated T cells for the induction of immune tolerance. Tumour cells frequently overexpress the ligand for PD-1, programmed cell death ligand 1 (PD-L1), facilitating their escape from the immune system. Monoclonal antibodies that block the interaction between PD-1 and PD-L1, by binding to either the ligand or receptor, have shown notable clinical efficacy in patients with a variety of cancers, including melanoma, colorectal cancer, non-small-cell lung cancer and Hodgkin?s lymphoma. Although it is well established that PD-1?PD-L1 blockade activates T cells, little is known about the role that this pathway may have in tumour-associated macrophages (TAMs). Here we show that both mouse and human TAMs express PD-1. TAM PD-1 expression increases over time in mouse models of cancer and with increasing disease stage in primary human cancers. TAM PD-1 expression correlates negatively with phagocytic potency against tumour cells, and blockade of PD-1?PD-L1 in vivo increases macrophage phagocytosis, reduces tumour growth and lengthens the survival of mice in mouse models of cancer in a macrophage-dependent fashion. This suggests that PD-1?PD-L1 therapies may also function through a direct effect on macrophages, with substantial implications for the treatment of cancer with these agents.

Extreme hydrothermal conditions at an active plate-bounding fault
Temperature and fluid pressure conditions control rock deformation and mineralization on geological faults, and hence the distribution of earthquakes. Typical intraplate continental crust has hydrostatic fluid pressure and a near-surface thermal gradient of 31??15 degrees Celsius per kilometre. At temperatures above 300?450 degrees Celsius, usually found at depths greater than 10?15 kilometres, the intra-crystalline plasticity of quartz and feldspar relieves stress by aseismic creep and earthquakes are infrequent. Hydrothermal conditions control the stability of mineral phases and hence frictional?mechanical processes associated with earthquake rupture cycles, but there are few temperature and fluid pressure data from active plate-bounding faults. Here we report results from a borehole drilled into the upper part of the Alpine Fault, which is late in its cycle of stress accumulation and expected to rupture in a magnitude 8 earthquake in the coming decades. The borehole (depth 893 metres) revealed a pore fluid pressure gradient exceeding 9??1 per cent above hydrostatic levels and an average geothermal gradient of 125??55 degrees Celsius per kilometre within the hanging wall of the fault. These extreme hydrothermal conditions result from rapid fault movement, which transports rock and heat from depth, and topographically driven fluid movement that concentrates heat into valleys. Shear heating may occur within the fault but is not required to explain our observations. Our data and models show that highly anomalous fluid pressure and temperature gradients in the upper part of the seismogenic zone can be created by positive feedbacks between processes of fault slip, rock fracturing and alteration, and landscape development at plate-bounding faults.

Genomic analyses identify hundreds of variants associated with age at menarch...
John Perry, Ken Ong and colleagues analyze genotype data on ?370,000 women and identify 389 independent signals that associate with age at menarche, implicating ?250 genes. Their analyses suggest causal inverse associations, independent of BMI, between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men.

Adiposity amplifies the genetic risk of fatty liver disease conferred by mult...
Jonathan Cohen, Helen Hobbs and colleagues show that adiposity significantly amplifies the effects of PNPLA3, TM6SF2, and GCKR sequence variants on nonalcoholic fatty liver disease. They find that synergy between adiposity and genotype influences the full spectrum of the disease, from steatosis to hepatic inflammation and cirrhosis.

RNA-binding proteins, the guardians of the marginal zone
RNA-binding proteins (RBPs) take control of binary cell-fate 'decisions' and cellular identity in lymphoid organs, as the RBP ZFP36L1 is shown to negatively regulate the stability of the transcription factors KLF2 and IRF8 to control the maintenance, survival and localization of marginal zone B cells.

Maintenance of the marginal-zone B cell compartment specifically requires the...
Turner and colleagues show that the RNA-binding protein ZFP36L1 regulates a post-transcriptional hub that determines the identity of marginal-zone B cells by promoting their localization and survival.

Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor pati...
Transcription factors compete for superenhancer sites and have antagonist functions. Farrar and colleagues identify regulatory competition between STAT5 and IKAROS or NF-?B in B cells and show that the ratio of STAT5 to IKAROS or to NF-?B can serve as a prognostic marker of disease severity of the leukemia B-ALL.

A role for oncostatin M in inflammatory bowel disease
A new study identifies oncostatin M (OSM) as a potential biomarker and therapeutic target for anti-tumor necrosis factor (TNF)-refractory inflammatory bowel disease (IBD), and pinpoints mucosal stromal cells as key players in OSM-mediated inflammation.

A heart?brain?kidney network controls adaptation to cardiac stress through ti...
The ability of the heart to withstand pressure overload, as occurs in heart failure, depends on a multi-organ circuit, in which sympathetic activation of the kidney leads to release of the cytokine CSF2 into the circulation, stimulating cardiac-resident macrophages that protect the heart.


Nature Reviews

Genetics: Gender-specific factors in cancer susceptibility
Two studies published in Nature Genetics have delved into the complex genetics of cancer susceptibility and have shown links of both timing of puberty onset and mosaic loss of chromosome Y (mLOY) to cancer risk.Previous genomic analyses have indicated various genetic factors associated

Genetics of coronary artery disease: discovery, biology and clinical translation
Coronary artery disease is the leading global cause of mortality. Long recognized to be heritable, recent advances have started to unravel the genetic architecture of the disease. Common variant association studies have linked approximately 60 genetic loci to coronary risk. Large-scale gene sequencing efforts and

Autism genetics: opportunities and challenges for clinical translation
Genetic studies have revealed the involvement of hundreds of gene variants in autism. Their risk effects are highly variable, and they are frequently related to other conditions besides autism. However, many different variants converge on common biological pathways. These findings indicate that aetiological heterogeneity, variable

The X chromosome in space
Extensive 3D folding is required to package a genome into the tiny nuclear space, and this packaging must be compatible with proper gene expression. Thus, in the well-hierarchized nucleus, chromosomes occupy discrete territories and adopt specific 3D organizational structures that facilitate interactions between regulatory elements

Ageing: Is fat a key to longevity?
Worms with impaired H3K4 trimethylation have an extended lifespan, which is associated with the accumulation of monounsaturated fatty acids in their intestines.

RNA decay: The anti-apoptotic function of ADAR1
An isoform of the RNA-editing protein ADAR1 is shown to be activated through nuclear export in response to cellular stress and to protect anti-apoptotic mRNAs from Staufen 1-mediated decay.

The HSP90 chaperone machinery
The heat shock protein 90 (HSP90) chaperone machinery is a key regulator of proteostasis under both physiological and stress conditions in eukaryotic cells. As HSP90 has several hundred protein substrates (or 'clients'), it is involved in many cellular processes beyond protein folding, which include DNA

Brain ageing: A youthful reminder
A study shows that systemic adminstration of plasma from human umbilical cord counteracts ageing-induced impairment of hippocampal function in mice and identifies a key protein in plasma that confers such effects.

Adult hippocampal neurogenesis and cognitive flexibility ? linking memory and...
Adult hippocampal neurogenesis has been implicated in cognitive processes, such as pattern separation, and in the behavioural effects of stress and antidepressants. Young adult-born neurons have been shown to inhibit the overall activity of the dentate gyrus by recruiting local interneurons, which may result in

The brain, sirtuins, and ageing
In mammals, recent studies have demonstrated that the brain, the hypothalamus in particular, is a key bidirectional integrator of humoral and neural information from peripheral tissues, thus influencing ageing both in the brain and at the 'systemic' level. CNS decline drives the progressive impairment of