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Innate Lymphoid Cells (ILCs) are the innate counterpart of adaptive lymphoid T cells. They are key players in the regulation of tissues homeostasis and early inflammatory host responses. ILCs are divided into three groups, and further subdivided into five subsets, that are characterised by distinct transcription factors, surface markers and their cytokine expression profiles. Group 1 ILCs, including natural killer (NK) cells and non-NK cell ILC1s, express T-bet and produce IFN-γ. Group 2 ILCs depend on GATA3 and produce IL-4, IL-5 and IL-13. Group 3 ILCs, composed of ILC3s and Lymphoid Tissue Inducer (LTi) cells, express RORγt and produce IL-17 and IL-22. Even though, the phenotype of each subset is well defined, environmental signals can trigger the interconversion of phenotypes and the plasticity of ILCs, in both mice and humans. Several extrinsic and intrinsic drivers of ILC plasticity have been described. However, the changes in cellular metabolism that underlie ILC plasticity remain largely unexplored. Given that metabolic changes critically affect fate and effector function of several immune cell types, we, here, review recent findings on ILC metabolism and discuss the implications for ILC plasticity.

Productive angiogenesis, a prerequisite for tumour growth, depends on the balanced release of angiogenic and angiostatic factors by different cell types within hypoxic tumours. Natural killer (NK) cells kill cancer cells and infiltrate hypoxic tumour areas. Cellular adaptation to low oxygen is mediated by Hypoxia-inducible factors (HIFs). We found that deletion of HIF-1α in NK cells inhibited tumour growth despite impaired tumour cell killing. Tumours developing in these conditions were characterised by a high-density network of immature vessels, severe haemorrhage, increased hypoxia, and facilitated metastasis due to non-productive angiogenesis. Loss of HIF-1α in NK cells increased the bioavailability of the major angiogenic cytokine vascular endothelial growth factor (VEGF) by decreasing the infiltration of NK cells that express angiostatic soluble VEGFR-1. In summary, this identifies the hypoxic response in NK cells as an inhibitor of VEGF-driven angiogenesis, yet, this promotes tumour growth by allowing the formation of functionally improved vessels. Tumour hypoxia influences both the immune responses and angiogenesis. Here, the authors show that HIF-1α deletion in NK cells impairs NK cytotoxic activity but inhibit tumour growth by decreasing the infiltration of NK cells that express angiostatic soluble VEGFR-1, thus resulting in non-functional angiogenesis.

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.

The fibrogenic response in tissue-resident fibroblasts is determined by the balance between activation and repression signals from the tissue microenvironment. While the molecular pathways by which transforming growth factor-1 (TGF-β1) activates pro-fibrogenic mechanisms have been extensively studied and are recognized critical during fibrosis development, the factors regulating TGF-β1 signaling are poorly understood. Here we show that macrophage hypoxia signaling suppresses excessive fibrosis in a heart via oncostatin-m (OSM) secretion. During cardiac remodeling, Ly6C hi monocytes/macrophages accumulate in hypoxic areas through a hypoxia-inducible factor (HIF)-1α dependent manner and suppresses cardiac fibroblast activation. As an underlying molecular mechanism, we identify OSM, part of the interleukin 6 cytokine family, as a HIF-1α target gene, which directly inhibits the TGF-β1 mediated activation of cardiac fibroblasts through extracellular signal-regulated kinase 1/2-dependent phosphorylation of the SMAD linker region. These results demonstrate that macrophage hypoxia signaling regulates fibroblast activation through OSM secretion in vivo. Fibrosis is a hallmark of several cardiac pathologies and its underlying mechanisms are still poorly defined. Here the authors show that macrophage hypoxia signaling following transverse aortic constriction in mice suppresses the activation of cardiac fibroblasts by secreting oncostatin M.

During skin injury, immune response and repair mechanisms have to be coordinated for rapid skin regeneration and the prevention of microbial infections. Natural Killer (NK) cells infiltrate hypoxic skin lesions and Hypoxia-inducible transcription factors (HIFs) mediate adaptation to low oxygen. We demonstrate that mice lacking the Hypoxia-inducible factor (HIF)-1α isoform in NK cells show impaired release of the cytokines Interferon (IFN)-γ and Granulocyte Macrophage - Colony Stimulating Factor (GM-CSF) as part of a blunted immune response. This accelerates skin angiogenesis and wound healing. Despite rapid wound closure, bactericidal activity and the ability to restrict systemic bacterial infection are impaired. Conversely, forced activation of the HIF pathway supports cytokine release and NK cell-mediated antibacterial defence including direct killing of bacteria by NK cells despite delayed wound closure. Our results identify, HIF-1α in NK cells as a nexus that balances antimicrobial defence versus global repair in the skin. During wound healing and infection in the skin there is a hypoxic environment involving HIF-1α and NK cells. Here the authors show that NK cells through HIF-1α provide a cross-regulatory balance to provide an adequate antimicrobial defence that can inhibit subsequent wound healing.

A hallmark feature of pancreatic ductal adenocarcinoma (PDAC) is massive intratumoral fibrosis, designated as desmoplasia. Desmoplasia is characterized by the expansion of cancer-associated fibroblasts (CAFs) and a massive increase in extracellular matrix (ECM). During fibrogenesis, distinct genes become reactivated specifically in fibroblasts, e.g., the disintegrin metalloprotease, ADAM12 . Previous studies have shown that immunotherapeutic ablation of ADAM12 + cells reduces fibrosis in various organs. In preclinical mouse models of PDAC, we observe ADAM12 expression in CAFs as well as in tumor cells but not in healthy mouse pancreas. Therefore, we tested prophylactic and therapeutic vaccination against ADAM12 in murine PDAC and observed delayed tumor growth along with a reduction in CAFs and tumor desmoplasia. This is furthermore associated with vascular normalization and alleviated tumor hypoxia. The ADAM12 vaccine induces a redistribution of CD8 + T cells within the tumor and cytotoxic responses against ADAM12 + cells. In summary, vaccination against the endogenous fibroblast target ADAM12 effectively depletes CAFs, reduces desmoplasia and delays the growth of murine PDACs. These results provide proof-of-principle for the development of vaccination-based immunotherapies to treat tumor desmoplasia. Synopsis ADAM12, a disintegrin and metalloprotease, is expressed in cancer-associated fibroblasts (CAFs) and tumor cells in pancreatic ductal adenocarcinoma (PDAC). Using both subcutaneous and orthotopic PDAC mouse models, we show that vaccination against ADAM12 depletes CAFs and delays tumor growth. ADAM12 vaccination induced a reduction of ADAM12+ CAFs, and decreased deposition of extracellular matrix (ECM). ADAM12 vaccination increased cytotoxic CD8 + T cell response and re-localization of T cells within the tumor tissue. ADAM12 vaccination induced vascular normalization with decreased tumor hypoxia. This study constitutes a proof of principle for the development of vaccination-based immunotherapies to target CAFs and tumor desmoplasia. ADAM12, a disintegrin and metalloprotease, is expressed in cancer-associated fibroblasts (CAFs) and tumor cells in pancreatic ductal adenocarcinoma (PDAC). Using both subcutaneous and orthotopic PDAC mouse models, we show that vaccination against ADAM12 depletes CAFs and delays tumor growth.

Glioma growth and progression are characterized by abundant development of blood vessels that are highly aberrant and poorly functional, with detrimental consequences for drug delivery efficacy. The mechanisms driving this vessel dysmorphia during tumor progression are poorly understood. Using longitudinal intravital imaging in a mouse glioma model, we identify that dynamic sprouting and functional morphogenesis of a highly branched vessel network characterize the initial tumor growth, dramatically changing to vessel expansion, leakage, and loss of branching complexity in the later stages. This vascular phenotype transition was accompanied by recruitment of predominantly pro‐inflammatory M1‐like macrophages in the early stages, followed by in situ repolarization to M2‐like macrophages, which produced VEGF‐A and relocate to perivascular areas. A similar enrichment and perivascular accumulation of M2 versus M1 macrophages correlated with vessel dilation and malignancy in human glioma samples of different WHO malignancy grade. Targeting macrophages using anti‐CSF1 treatment restored normal blood vessel patterning and function. Combination treatment with chemotherapy showed survival benefit, suggesting that targeting macrophages as the key driver of blood vessel dysmorphia in glioma progression presents opportunities to improve efficacy of chemotherapeutic agents. We propose that vessel dysfunction is not simply a general feature of tumor vessel formation, but rather an emergent property resulting from a dynamic and functional reorganization of the tumor stroma and its angiogenic influences. Synopsis Dynamic multi‐photon imaging and genetic labeling and targeting in an orthotopic tumor model reveals that progressive changes in stromal cells are the leading cause of vascular dysmorphia in glioma. Initial tumour growth is accompanied by functional vessel patterning. Progressive blood vessel dysmorphia coincides with bone‐marrow derived macrophage recruitment. M2‐polarized macrophages accumulate around tumour blood vessels in glioma progression in mouse and with increasing WHO grades in humans. Depleting macrophages or their VEGF production restore blood vessel caliber and function. Macrophages depletion enhances efficacy of chemotherapeutic agents. Graphical Abstract Dynamic multi‐photon imaging and genetic labeling and targeting in an orthotopic tumor model reveals that progressive changes in stromal cells are the leading cause of vascular dysmorphia in glioma.

Hypoxia is a hallmark of inflamed, infected or damaged tissue, and the adaptation to inadequate tissue oxygenation is regulated by hypoxia-inducible factors (HIFs). HIFs are key mediators of the cellular response to hypoxia, but they are also associated with pathological stress such as inflammation, bacteriological infection or cancer. In addition, HIFs are central regulators of many innate and adaptive immunological functions, including migration, antigen presentation, production of cytokines and antimicrobial peptides, phagocytosis as well as cellular metabolic reprogramming. A characteristic feature of immune cells is their ability to infiltrate and operate in tissues with low level of nutrients and oxygen. The objective of this article is to discuss the role of HIFs in the function of innate and adaptive immune cells in hypoxia, with a focus on how hypoxia modulates immunometabolism.

Chemotherapy remains a mainstay of cancer treatment but its use is often limited by the development of adverse reactions. Severe loss of body weight (cachexia) is a frequent cause of death in cancer patients and is exacerbated by chemotherapy. We show that genetic inactivation of vascular endothelial growth factor (VEGF)-A in myeloid cells prevents chemotherapy-induced cachexia by inhibiting skeletal muscle loss and the lipolysis of white adipose tissue. It also improves clearance of senescent tumour cells by natural killer cells and inhibits tumour regrowth after chemotherapy. The effects depend on the chemoattractant chemerin, which is released by the tumour endothelium in response to chemotherapy. The findings define chemerin as a critical mediator of the immune response, as well as an important inhibitor of cancer cachexia. Targeting myeloid cell-derived VEGF signalling should impede the lipolysis and weight loss that is frequently associated with chemotherapy, thereby substantially improving the therapeutic outcome. Chemerin is an adipokine often downregulated in tumours. Here the authors show that chemotherapy induces chemerin production by endothelial cells, leading to cachexia, and that VEGF ablation in myeloid cells prevents cachexia in a chemerin-dependent manner, and improves chemotherapeutic effects.

Tissue injury initiates a complex series of events that act to restore structure and physiological homeostasis. Infiltration of inflammatory cells and vascular remodeling are both keystones of this process. However, the role of inflammation and angiogenesis in general and, more specifically, the significance of inflammatory cell-derived VEGF in this context are unclear. To determine the role of inflammatory cell-derived VEGF in a clinically relevant and chronically inflamed injury, pulmonary fibrosis, we deleted the VEGF-A gene in myeloid cells. In a model of pulmonary fibrosis in mice, deletion of VEGF in myeloid cells resulted in significantly reduced formation of blood vessels; however, it causes aggravated fibrotic tissue damage. This was accompanied by a pronounced decrease in epithelial cell survival and a striking increase in myofibroblast invasion. The drastic increase in fibrosis following loss of myeloid VEGF in the damaged lungs was also marked by increased levels of hypoxia-inducible factor (HIF) expression and Wnt/β-catenin signaling. This demonstrates that the process of angiogenesis, driven by myeloid cell-derived VEGF, is essential for the prevention of fibrotic damage.