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Immunotherapy has emerged as a promising treatment paradigm for many malignancies and is transforming the drug development landscape. Although immunotherapeutic agents have demonstrated clinical efficacy, they are associated with variable clinical responses, and substantial gaps remain in our understanding of their mechanisms of action and specific biomarkers of response. Currently, the number of preclinical models that faithfully recapitulate interactions between the human immune system and tumours and enable evaluation of human-specific immunotherapies in vivo is limited. Humanized mice, a term that refers to immunodeficient mice co-engrafted with human tumours and immune components, provide several advantages for immuno-oncology research. In this Review, we discuss the benefits and challenges of the currently available humanized mice, including specific interactions between engrafted human tumours and immune components, the development and survival of human innate immune populations in these mice, and approaches to study mice engrafted with matched patient tumours and immune cells. We highlight the latest advances in the generation of humanized mouse models, with the aim of providing a guide for their application to immuno-oncology studies with potential for clinical translation.Preclinical models that faithfully recapitulate interactions between the human immune system and tumours are necessary to evaluate human-specific immunotherapies in vivo; however, their number is currently limited. The authors of this Review discuss the currently available humanized mouse models, which are immunodeficient mice co-engrafted with human tumours and immune components, with a focus on their applicability in translational research.

The role of neutrophils in solid tumor metastasis remains largely controversial. In preclinical models of solid tumors, both pro-metastatic and anti-metastatic effects of neutrophils have been reported. In this study, using mouse models of breast cancer, we demonstrate that the metastasis-modulating effects of neutrophils are dictated by the status of host natural killer (NK) cells. In NK cell-deficient mice, granulocyte colony-stimulating factor-expanded neutrophils show an inhibitory effect on the metastatic colonization of breast tumor cells in the lung. In contrast, in NK cell-competent mice, neutrophils facilitate metastatic colonization in the same tumor models. In an ex vivo neutrophil-NK cell-tumor cell tri-cell co-culture system, neutrophils are shown to potentially suppress the tumoricidal activity of NK cells, while neutrophils themselves are tumoricidal. Intriguingly, these two modulatory effects by neutrophils are both mediated by reactive oxygen species. Collectively, the absence or presence of NK cells, governs the net tumor-modulatory effects of neutrophils. The role of neutrophils in the regulation of tumour growth and metastasis remains controversial. Here, the authors demonstrate that neutrophils, by exerting inhibitory effects on cytotoxic NK cells, show a net pro-metastatic effect in immune-competent mice, while they are tumoricidal and anti-metastatic in NK cell-deficient hosts.

Key Points There is a growing need for animal models to carry out in vivo studies of human biological systems without putting individuals at risk. Severely immunodeficient mice engrafted with human cells and tissues, known as 'humanized' mice, facilitate progress in studies of human haematopoiesis, immunity, gene therapy, infectious diseases, cancer and regenerative medicine. Advances in the generation of humanized mice have depended on a systematic progression of genetic modifications in immunodeficient mouse hosts and on improvements in engraftment techniques. Mice homozygous for the severe combined immunodeficiency ( scid ) gene mutation or for targeted mutations at the recombination-activating gene 1 ( Rag1 ) or Rag2 loci, accompanied by a targeted mutation at the interleukin-2 receptor γ-chain ( Il2rg ) locus, support greatly increased engraftment and function of human haematopoietic stem cells (HSCs) and peripheral-blood mononuclear cells (PBMCs) compared with previous immunodeficient mouse models. The development of immunodeficient mice that are humanized by engraftment of human lymphoid tissues, HSCs and PBMCs provides an opportunity to carry out translational research on human immunity and autoimmune diseases. These models are also being used to study the biology of human pathogens responsible for AIDS and several other infectious diseases. Humanized mice are being increasingly used as hosts for human malignant cells in studies of carcinogenesis, tumour metastasis and cancer therapy. The phenotypic and functional characterization of human tumour stem cells is also being advanced through the study of humanized mice. The potential for new advances in our understanding of human immunology and other areas of human biology that is supported by studies in humanized mice remains promising. Additional genetic and technological modifications will accelerate progress towards the development of a functional human immune system in mice. The development of humanized mice over the past few decades has enabled the examination of human haematopoiesis, immunity to infectious diseases, cancer and autoantibodies in mice. But are these mice the key to translational research or is more work required? The culmination of decades of research on humanized mice is leading to advances in our understanding of human haematopoiesis, innate and adaptive immunity, autoimmunity, infectious diseases, cancer biology and regenerative medicine. In this Review, we discuss the development of these new generations of humanized mice, how they will facilitate translational research in several biomedical disciplines and approaches to overcome the remaining limitations of these models.

Acquisition of a lipid-laden phenotype by immune cells has been defined in infectious diseases and atherosclerosis but remains largely uncharacterized in cancer. Here, in breast cancer models, we found that neutrophils are induced to accumulate neutral lipids upon interaction with resident mesenchymal cells in the premetastatic lung. Lung mesenchymal cells elicit this process through repressing the adipose triglyceride lipase (ATGL) activity in neutrophils in prostaglandin E2-dependent and -independent manners. In vivo, neutrophil-specific deletion of genes encoding ATGL or ATGL inhibitory factors altered neutrophil lipid profiles and breast tumor lung metastasis in mice. Mechanistically, lipids stored in lung neutrophils are transported to metastatic tumor cells through a macropinocytosis–lysosome pathway, endowing tumor cells with augmented survival and proliferative capacities. Pharmacological inhibition of macropinocytosis significantly reduced metastatic colonization by breast tumor cells in vivo. Collectively, our work reveals that neutrophils serve as an energy reservoir to fuel breast cancer lung metastasis. Phagocytes can acquire lipids and this modulates their function in a variety of disease states, such as atherosclerosis. Ren and colleagues demonstrate that neutrophils accumulate lipids and deliver them to tumor cells, which supports their proliferation, survival and metastasis.

Microglia are essential for maintenance of normal brain function, with dysregulation contributing to numerous neurological diseases. Protocols have been developed to derive microglia-like cells from human induced pluripotent stem cells (hiPSCs). However, primary microglia display major differences in morphology and gene expression when grown in culture, including down-regulation of signature microglial genes. Thus, in vitro differentiated microglia may not accurately represent resting primary microglia. To address this issue, we transplanted microglial precursors derived in vitro from hiPSCs into neonatal mouse brains and found that the cells acquired characteristic microglial morphology and gene expression signatures that closely resembled primary human microglia. Single-cell RNA-sequencing analysis of transplanted microglia showed similar cellular heterogeneity as primary human cells. Thus, hiPSCs-derived microglia transplanted into the neonatal mouse brain assume a phenotype and gene expression signature resembling that of resting microglia residing in the human brain, making chimeras a superior tool to study microglia in human disease.

Key Points Severely immunodeficient mice engrafted with functional human cells and tissues, known as 'humanized' mice, facilitate progress in studies of human haematopoiesis, immunity, gene therapy, infectious diseases, cancer and regenerative medicine. Mice homozygous for the severe combined immunodeficiency ( scid ) gene mutation or for targeted mutations at the recombination-activating gene 1 ( Rag1 ) or Rag2 loci, that also have a targeted mutation at the interleukin-2 receptor γ-chain ( Il2rg ) locus, support high levels of engraftment and function of human haematopoietic stem cells (HSCs) and human immune systems. Advances in humanized mice over the past few years have included approaches to decrease host innate immune responses. In addition, humanized mouse models have benefited greatly from the identification of human species-specific molecules that are crucial for the engraftment and function of human haematopoietic and immune systems and the expression of these molecules in the immunodeficient recipient. The development of humanized mice with functional human immune systems (generated by the engraftment of human lymphoid tissues, HSCs or peripheral blood mononuclear cells) provides an opportunity to carry out translational research on human immunity and autoimmune diseases, and for the study of the biology of the human pathogens responsible for AIDS and several other human-specific infectious diseases. Humanized mice are being used as hosts for primary human tumours for studies of tumour growth and metastasis and for experimental cancer therapy. The phenotypical and functional characterization of human tumour stem cells is also being advanced through the study of humanized mice. The potential for new advances in our understanding of human immunology and other areas of human biology that are supported by studies in humanized mice remains promising. Additional genetic and technological modifications continue to accelerate progress towards the development of a robust functional human immune system in humanized mice. This article provides a comprehensive overview of the recent advances in the development and use of humanized mice. The authors consider the remaining challenges and the potential for new advances in our understanding of human immunology through the use of these mice. Significant advances in our understanding of the in vivo functions of human cells and tissues and the human immune system have resulted from the development of 'humanized' mouse strains that are based on severely immunodeficient mice with mutations in the interleukin-2 receptor common γ-chain locus. These mouse strains support the engraftment of a functional human immune system and permit detailed analyses of human immune biology, development and functions. In this Review, we discuss recent advances in the development and utilization of humanized mice, the lessons learnt, the remaining challenges and the promise of using humanized mice for the in vivo study of human immunology.

Sphingolipids, lipids with a common sphingoid base (also termed long chain base) backbone, play essential cellular structural and signaling functions. Alterations of sphingolipid levels have been implicated in many diseases, including neurodegenerative disorders. However, it remains largely unclear whether sphingolipid changes in these diseases are pathological events or homeostatic responses. Furthermore, how changes in sphingolipid homeostasis shape the progression of aging and neurodegeneration remains to be clarified. We identified two mouse strains, flincher (fln) and toppler (to), with spontaneous recessive mutations that cause cerebellar ataxia and Purkinje cell degeneration. Positional cloning demonstrated that these mutations reside in the Lass1 gene. Lass1 encodes (dihydro)ceramide synthase 1 (CerS1), which is highly expressed in neurons. Both fln and to mutations caused complete loss of CerS1 catalytic activity, which resulted in a reduction in sphingolipid biosynthesis in the brain and dramatic changes in steady-state levels of sphingolipids and sphingoid bases. In addition to Purkinje cell death, deficiency of CerS1 function also induced accumulation of lipofuscin with ubiquitylated proteins in many brain regions. Our results demonstrate clearly that ceramide biosynthesis deficiency can cause neurodegeneration and suggest a novel mechanism of lipofuscin formation, a common phenomenon that occurs during normal aging and in some neurodegenerative diseases.

Immunodeficient mice engrafted with human cells and tissues have provided an exciting alternative to in vitro studies with human tissues and nonhuman primates for the study of human immunobiology. A major breakthrough in the early 2000s was the introduction of a targeted mutation in the interleukin 2 (IL-2) receptor common gamma chain (IL2rgn null ) into mice that were already deficient in T and B cells. Among other immune defects, natural killer (NK) cells are disrupted in these mice, permitting efficient engraftment with human hematopoietic cells that generate a functional human immune system. These humanized mouse models are becoming increasingly important for preclinical studies of human immunity, hematopoiesis, tissue regeneration, cancer, and infectious diseases. In particular, humanized mice have enabled studies of the pathogenesis of human-specific pathogens, including human immunodeficiency virus type 1, Epstein Barr virus, and Salmonella typhi. However, there are a number of limitations in the currently available humanized mouse models. Investigators are continuing to identify molecular mechanisms underlying the remaining defects in the engrafted human immune system and are generating \"next generation\" models to overcome these final deficiencies. This article provides an overview of some of the emerging models of humanized mice, their use in the study of infectious diseases, and some of the remaining limitations that are currently being addressed.

With the increase in knowledge resulting from the sequencing of the human genome, the genetic basis for the underlying differences in individuals, their diseases, and how they respond to therapies is starting to be understood. This has formed the foundation for the era of precision medicine in many human diseases that is beginning to be implemented in the clinic, particularly in cancer. However, preclinical testing of therapeutic approaches based on individual biology will need to be validated in animal models prior to translation into patients. Although animal models, particularly murine models, have provided significant information on the basic biology underlying immune responses in various diseases and the response to therapy, murine and human immune systems differ markedly. These fundamental differences may be the underlying reason why many of the positive therapeutic responses observed in mice have not translated directly into the clinic. There is a critical need for preclinical animal models in which human immune responses can be investigated. For this, many investigators are using humanized mice, i.e., immunodeficient mice engrafted with functional human cells, tissues, and immune systems. We will briefly review the history of humanized mice, the remaining limitations, approaches to overcome them and how humanized mouse models are being used as a preclinical bridge in precision medicine for evaluation of human therapies prior to their implementation in the clinic.

Dendritic cells can capture and transfer retroviruses in vitro across synaptic cell-cell contacts to uninfected cells, a process called trans-infection. Whether trans-infection contributes to retroviral spread in vivo remains unknown. Here, we visualize how retroviruses disseminate in secondary lymphoid tissues of living mice. We demonstrate that murine leukemia virus (MLV) and human immunodeficiency virus (HIV) are first captured by sinus-lining macrophages. CD169/Siglec-1, an I-type lectin that recognizes gangliosides, captures the virus. MLV-laden macrophages then form long-lived synaptic contacts to trans-infect B-1 cells. Infected B-1 cells subsequently migrate into the lymph node to spread the infection through virological synapses. Robust infection in lymph nodes and spleen requires CD169, suggesting that a combination of fluid-based movement followed by CD169-dependent trans-infection can contribute to viral spread.