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The cancer–natural killer cell immunity cycle
Immunotherapy with checkpoint blockade induces rapid and durable immune control of cancer in some patients and has driven a monumental shift in cancer treatment. Neoantigen-specific CD8+ T cells are at the forefront of current immunotherapy strategies, and the majority of drug discovery and clinical trials revolve around further harnessing these immune effectors. Yet the immune system contains a diverse range of antitumour effector cells, and these must function in a coordinated and synergistic manner to overcome the immune-evasion mechanisms used by tumours and achieve complete control with tumour eradication. A key antitumour effector is the natural killer (NK) cells, cytotoxic innate lymphocytes present at high frequency in the circulatory system and identified by their exquisite ability to spontaneously detect and lyse transformed or stressed cells. Emerging data show a role for intratumoural NK cells in driving immunotherapy response and, accordingly, there have been renewed efforts to further elucidate and target the pathways controlling NK cell antitumour function. In this Review, we discuss recent clinical evidence that NK cells are a key immune constituent in the protective antitumour immune response and highlight the major stages of the cancer–NK cell immunity cycle. We also perform a new analysis of publicly available transcriptomic data to provide an overview of the prognostic value of NK cell gene expression in 25 tumour types. Furthermore, we discuss how the role of NK cells evolves with tumour progression, presenting new opportunities to target NK cell function to enhance cancer immunotherapy response rates across a more diverse range of cancers.This Review discusses the key role that natural killer (NK) cells play in driving an antitumour immune response throughout the progression of cancer from its initial development to its metastatic spread and eventual treatment, defined herein as the cancer–NK cell immunity cycle.
Journal Article
Effects of sex and aging on the immune cell landscape as assessed by single-cell transcriptomic analysis
SignificanceDifferences in immune functioning stem from multiple factors, including sex and aging. However, the specific roles of these variables in immunity remain elusive. We profiled immunocytes from young and old males and females at single-cell resolution and constructed a precise atlas of blood-circulating immunocytes. T cell– and B cell–activated signals were higher in young females than males, while aging increased the sex-related differences in immunocytes, cellular composition, and inflammatory signaling. Additionally, males showed a higher accumulation of inflammatory factors during aging, whereas cell–cell communication analysis revealed different trends in gene expression between females and males with aging. These findings might aid in the understanding of the mechanisms underlying sex-based differences in immunity and disease susceptibility across the lifespan.
Sex and aging influence the human immune system, resulting in disparate responses to infection, autoimmunity, and cancer. However, the impact of sex and aging on the immune system is not yet fully elucidated. Using small conditional RNA sequencing, we found that females had a lower percentage of natural killer (NK) cells and a higher percentage of plasma cells in peripheral blood compared with males. Bioinformatics revealed that young females exhibited an overrepresentation of pathways that relate to T and B cell activation. Moreover, cell–cell communication analysis revealed evidence of increased activity of the BAFF/APRIL systems in females. Notably, aging increased the percentage of monocytes and reduced the percentage of naïve T cells in the blood and the number of differentially expressed genes between the sexes. Aged males expressed higher levels of inflammatory genes. Collectively, the results suggest that females have more plasma cells in the circulation and a stronger BAFF/APRIL system, which is consistent with a stronger adaptive immune response. In contrast, males have a higher percentage of NK cells in blood and a higher expression of certain proinflammatory genes. Overall, this work expands our knowledge of sex differences in the immune system in humans.
Journal Article
New avenues for systematically inferring cell-cell communication: through single-cell transcriptomics data
For multicellular organisms, cell-cell communication is essential to numerous biological processes. Drawing upon the latest development of single-cell RNA-sequencing (scRNA-seq), high-resolution transcriptomic data have deepened our understanding of cellular phenotype heterogeneity and composition of complex tissues, which enables systematic cell-cell communication studies at a single-cell level. We first summarize a common workflow of cell-cell communication study using scRNA-seq data, which often includes data preparation, construction of communication networks, and result validation. Two common strategies taken to uncover cell-cell communications are reviewed, e.g., physically vicinal structure-based and ligand-receptor interaction-based one. To conclude, challenges and current applications of cell-cell communication studies at a single-cell resolution are discussed in details and future perspectives are proposed.
Journal Article
The dormant cancer cell life cycle
The success of targeted therapies and immunotherapies has created optimism that cancers may be curable. However, not all patients respond, drug resistance is common and many patients relapse owing to dormant cancer cells. These rare and elusive cells can disseminate early and hide in specialized niches in distant organs before being reactivated to cause disease relapse after successful treatment of the primary tumour. Despite their importance, we are yet to leverage knowledge generated from experimental models and translate the potential of targeting dormant cancer cells to prevent disease relapse in the clinic. This is due, at least in part, to the lack of adherence to consensus definitions by researchers, limited models that faithfully recapitulate this stage of metastatic spread and an absence of interdisciplinary approaches. However, the application of new high-resolution, single-cell technologies is starting to revolutionize the field and transcend classical reductionist models of studying individual cell types or genes in isolation to provide a global view of the complex underlying cellular ecosystem and transcriptional landscape that controls dormancy. In this Perspective, we synthesize some of these recent advances to describe the hallmarks of cancer cell dormancy and how the dormant cancer cell life cycle offers opportunities to target not only the cancer but also its environment to achieve a durable cure for seemingly incurable cancers.This Perspective proposes operational definitions to define the hallmarks of cancer cell dormancy and, based on the latest evidence pertaining to the role of the microenvironment in regulating dormancy, presents key stages in the life cycle of a dormant cancer cell that could be targeted.
Journal Article
Mobile phone behavior
\"This book provides the first comprehensive introduction to the newly-emerging science of mobile phone behavior. It presents the unexpected complexity of human mobile phone behavior through four basic aspects of mobile phone usage (users, technologies, activities, and effects), and then explores four major domains of such behavior (medicine, business, education, and everyday life). Chapters open with thoughts on mobile phone usage and behavior from interviews with cell phone users, then present a series of scientific studies, synthesized knowledge, and real-life cases, concluding with complex but highly readable analyses of each aspect of mobile phone behavior. Readers should achieve two intellectual goals: gaining a usable knowledge of the complexity of mobile phone behaviour, and developing the skills to analyze the complexity of mobile phone usage - and further technological behaviors\"-- Provided by publisher.
Book
A Comprehensive Review on Factors Influences Biogenesis, Functions, Therapeutic and Clinical Implications of Exosomes
Exosomes are nanoscale-sized membrane vesicles secreted by almost all cell types into the extracellular environment upon fusion of multivesicular bodies and plasma membrane. Biogenesis of exosomes is a protein quality control mechanism, and once released, exosomes transmit signals to other cells. The applications of exosomes have increased immensely in biomedical fields owing to their cell-specific cargos that facilitate intercellular communications with neighboring cells through the transfer of biologically active compounds. The diverse constituents of exosomes reflect their cell of origin and their detection in biological fluids represents a diagnostic marker for various diseases. Exosome research is expanding rapidly due to the potential for clinical application to therapeutics and diagnosis. However, several aspects of exosome biology remain elusive. To discover the use of exosomes in the biomedical applications, we must better understand the basic molecular mechanisms underlying their biogenesis and function. In this comprehensive review, we describe factors involved in exosomes biogenesis and the role of exosomes in intercellular signaling and cell-cell communications, immune responses, cellular homeostasis, autophagy, and infectious diseases. In addition, we discuss the role of exosomes as diagnostic markers, and their therapeutic and clinical implications. Furthermore, we addressed the challenges and outstanding developments in exosome research, and discuss future perspectives.
Journal Article