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NK cell and ILC heterogeneity in colorectal cancer. New perspectives from high dimensional data

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NK cell and ILC heterogeneity in colorectal cancer. New perspectives from high dimensional data

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Innate lymphoid cells (ILCs) and tissue-resident natural killer (NK) cells ensure immunity at environmental interfaces and help maintain barrier integrity of the intestinal tract. This wide range of innate lymphocytes is able to provide fast and potent inflammatory responses that, when deregulated, have been associated with pathogenesis of inflammatory bowel disease (IBD) and colorectal cancer (CRC). While the presence of tumor-infiltrating NK cells is generally associated with a favorable outcome in CRC patients, emerging evidence reveals distinct roles for ILCs in regulating CRC pathogenesis and progression. Advances in next generation sequencing technology, and in particular of single-cell RNA-seq approaches, along with multidimensional flow cytometry analysis, have helped to deconvolute the complexity and heterogeneity of the ILC system both in homeostatic and pathological contexts. In this review, we discuss the protective and detrimental roles of NK cells and ILCs in the pathogenesis of CRC, focusing on the phenotypic and transcriptional modifications these cells undergo during CRC development and progression.

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... During the invasion of tumor cells into surrounding tissues, it was bound to cause a significant increase in the level of inflammatory response and oxidative stress response in the above regional tissues [18,19]. In the digestive tract, the patient's mucosa was correspondingly damaged, and the ability to absorb nutrients was significantly reduced [20]. The body's vitamin D level was significantly deficient, and the risk of diffuse muscle pain in the waist, pelvis, and lower limbs was significantly increased [21]. ...
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... Comprehensive transcriptomic and high-dimensional flow cytometry studies have revealed a high degree of phenotypic complexity among innate lymphocytes in CRC [22][23][24][25][113][114][115][116]. Thus, together with NK cells, ieILC1-like cells represent the most abundant tumor-infiltrating innate lymphoid subset in CRC patients [114]. ...
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... However, NK cells can also be resident in tissues displaying highly variable expression patterns. Thus a clear distinction between tissue-resident NK cells and ILCs, especially ILC1, can be challenging [19,20]. ...
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Innate lymphoid cells (ILC) are a recently identified group of innate lymphocytes. ILC are subdivided into cytotoxic ILC (i.e., conventional natural killer (NK) cells) and helper ILC. Helper ILC are tissue-resident cells that have been involved in various physiological and pathological processes of organs and tissues. While their roles during inflammation are well studied, their contribution to tumor immunity is not well known. Here, we will provide an overview of the various helper ILC subsets, their development and function and discuss their potential roles during tumorigenesis and for anti-tumor immunity at border surface with the environment.
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Innate lymphoid cells (ILC) play critical roles in regulating immunity, inflammation, and tissue homeostasis in mice. However, limited access to non-diseased human tissues has hindered efforts to profile anatomically-distinct ILCs in humans. Through flow cytometric and transcriptional analyses of lymphoid, mucosal, and metabolic tissues from previously healthy human organ donors, here we have provided a map of human ILC heterogeneity across multiple anatomical sites. In contrast to mice, human ILCs are less strictly compartmentalized and tissue localization selectively impacts ILC distribution in a subset-dependent manner. Tissue-specific distinctions are particularly apparent for ILC1 populations, whose distribution was markedly altered in obesity or aging. Furthermore, the degree of ILC1 population heterogeneity differed substantially in lymphoid versus mucosal sites. Together, these analyses comprise a comprehensive characterization of the spatial and temporal dynamics regulating the anatomical distribution, subset heterogeneity, and functional potential of ILCs in non-diseased human tissues. Innate lymphoid cells (ILC) critically regulate tissue immunity and homeostasis in mice, but limited access to healthy human tissues has hindered efforts to profile anatomically-distinct ILCs in humans. Yudanin and colleagues provide a comprehensive map of the spatial and temporal dynamics regulating the anatomical distribution, subset heterogeneity, and functional potential of ILCs in non-diseased human tissues.
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The immune system employs an array of effector cells to ensure tissue homeostasis and protection against pathogens. Lymphocytes belonging to both the adaptive and innate branches share several functions, comprising the ability to directly kill stressed or transformed cells, and to provide helper responses through specific production of cytokines. These properties are regulated by distinct sets of soluble molecules, receptors, and intracellular factors, which altogether tune the functional output of effector lymphocytes and their final activation state. In contrast to adaptive T cells, innate lymphoid cells (ILCs) do not require antigen receptors and are characterized for their ability to provide rapid immune responses. While the factors underlying functional diversification and the main principles leading to ILC activation have been dissected, our understanding of the mechanisms underlying termination of ILC effector functions is still in its infancy. Herein, we discuss the recent findings describing how ILC responses are turned off in the context of inflammation and cancer.
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Natural killer (NK) cells develop from common progenitors but diverge into distinct subsets, which differ in cytokine production, cytotoxicity, homing, and memory traits. Given their promise in adoptive cell therapies for cancer, a deeper understanding of regulatory modules controlling clinically beneficial NK phenotypes is of high priority. We report integrated “-omics” analysis of human NK subsets, which revealed super-enhancers associated with gene cohorts that may coordinate NK functions and localization. A transcription factor-based regulatory scheme also emerged, which is evolutionarily conserved and shared by innate and adaptive lymphocytes. For both NK and T lineages, a TCF1-LEF1-MYC axis dominated the regulatory landscape of long-lived, proliferative subsets that traffic to lymph nodes. In contrast, effector populations circulating between blood and peripheral tissues shared a PRDM1-dominant landscape. This resource defines transcriptional modules, regulated by feedback loops, which may be leveraged to enhance phenotypes for NK cell-based therapies.
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Group 2 innate lymphoid cells (ILC2s) are the most well defined group of ILCs. ILC2 development is controlled by the GATA‐3 transcription factor and these cells produce archetypal type 2 cytokines, such as IL‐5 and IL‐13. These cytokines mediate parasite expulsion and tissue repair, but also contribute to type 2 inflammatory diseases, including allergy, asthma and chronic rhinosinusitis with nasal polyps. In response to tightly regulated local environmental cues ILCs can generate characteristics of other subtypes, a process known as plasticity. Recent advances in the ILC2 field has led to the discovery that ILC2s can promptly shift to functional IFN‐γ‐producing ILC1s or IL‐17‐producing ILC3s, depending on the cytokines and chemokines produced by antigen presenting cells or epithelial cells. Due to yet unknown triggers, this complex network of signals may become dysregulated. In this review, we will discuss general ILC characteristic, ILC2 development, plasticity, memory function, and implications in disease.
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Group 2 innate lymphoid cells (ILC2s) play critical roles in the induction of type 2 inflammation, response to parasite infection, metabolic homeostasis, and tissue repair. These multifunctional roles of ILC2s are tightly controlled by complex regulatory systems in the local microenvironment, the disruption of which may cause various health problems. This review summarizes up‐to‐date knowledge regarding positive and negative regulators for ILC2s based on their function and signaling pathways, including activating cytokines (IL‐33, IL‐25; MAPK, NF‐κB pathways), co‐stimulatory cytokines (IL‐2, IL‐7, IL‐9, TSLP; STAT5, IL‐4; STAT6, TNF superfamily; MAPK, NF‐κB pathways), suppressive cytokines (type1 IFNs, IFN‐γ, IL‐27; STAT1, IL‐10, TGF‐β), transdifferentiation cytokines (IL‐12; STAT4, IL‐1β, IL‐18), lipid mediators (LTC4, LTD4, LTE4, PGD2; Ca²⁺‐NFAT pathways, PGE2, PGI2; AC/cAMP/PKA pathways, LXA4, LTB4), neuropeptides (NMU; Ca²⁺‐NFAT, MAPK pathways, VIP, CGRP, catecholamine, acetylcholine), sex hormones (androgen, estrogen), nutrients (butyrate; HDAC inhibitors, vitamins), and cell‐to‐cell interactions (ICOSL‐ICOS; STAT5, B7‐H6‐NKp30, E‐cadherin‐KLRG1). This comprehensive review affords a better understanding of the regulatory network system for ILC2s, providing impetus to develop new treatment strategies for ILC2‐related health problems.