Natural killer (NK) cells comprise one subset of the innate lymphoid cell (ILC) family. Despite reported antitumor functions of NK cells, their tangible contribution to tumor control in humans remains controversial. This is due to incomplete understanding of the NK cell states within the tumor microenvironment (TME). Here, we demonstrate that peripheral circulating NK cells differentiate down two divergent pathways within the TME, resulting in different end states. One resembles intraepithelial ILC1s (ieILC1) and possesses potent in vivo antitumor activity. The other expresses genes associated with immune hyporesponsiveness and has poor antitumor functional capacity. Interleukin-15 (IL-15) and direct contact between the tumor cells and NK cells are required for the differentiation into CD49a+CD103+ cells, resembling ieILC1s. These data explain the similarity between ieILC1s and tissue-resident NK cells, provide insight into the origin of ieILC1s, and identify the ieILC1-like cell state within the TME to be the NK cell phenotype with the greatest antitumor activity. Because the proportions of the different ILC states vary between tumors, these findings provide a resource for the clinical study of innate immune responses against tumors and the design of novel therapy.

Innate lymphoid cells (ILCs) are a branch of the immune system that consists of diverse circulating and tissue-resident cells, which carry out functions including homeostasis and antitumor immunity. The development and behavior of human natural killer (NK) cells and other ILCs in the context of cancer is still incompletely understood. Since NK cells and Group 1 and 2 ILCs are known to be important for mediating antitumor immune responses, a clearer understanding of these processes is critical for improving cancer treatments and understanding tumor immunology as a whole. Unfortunately, there are some major differences in ILC differentiation and effector function pathways between humans and mice. To this end, mice bearing patient-derived xenografts or human cell line-derived tumors alongside human genes or human immune cells represent an excellent tool for studying these pathways in vivo. Recent advancements in humanized mice enable unparalleled insights into complex tumor-ILC interactions. In this review, we discuss ILC behavior in the context of cancer, the humanized mouse models that are most commonly employed in cancer research and their optimization for studying ILCs, current approaches to manipulating human ILCs for antitumor activity, and the relative utility of various mouse models for the development and assessment of these ILC-related immunotherapies.

Transcriptomic analysis showed that the central circadian pathway genes had significantly altered expression in fracture calluses from mice fed a low phosphate diet. This led us to hypothesize that phosphate deficiency altered the circadian cycle in peripheral tissues. Analysis of the expression of the central clock genes over a 24–36 hour period in multiple peripheral tissues including fracture callus, proximal tibia growth plate and cardiac tissues after 12 days on a low phosphate diet showed higher levels of gene expression in the hypophosphatemia groups (p < 0.001) and a 3 to 6 hour elongation of the circadian cycle. A comparative analysis of the callus tissue transcriptome genes that were differentially regulated by hypophosphatemia with published data for the genes in bone that are diurnally regulated identified 1879 genes with overlapping differential regulation, which were shown by ontology assessment to be associated with oxidative metabolism and apoptosis. Network analysis of the central circadian pathway genes linked their expression to the up regulated expression of the histone methyltransferase gene EZH2, a gene that when mutated in both humans and mice controls overall skeletal growth. These data suggest that phosphate is an essential metabolite that controls circadian function in both skeletal and non skeletal peripheral tissues and associates its levels with the overall oxidative metabolism and skeletal growth of animals.

Time is a central element of the sexual dimorphic patterns of development, pathology, and aging of the skeleton. Because the transcriptome is a representation of the phenome, we hypothesized that both sex and sex‐specific temporal, transcriptomic differences in bone tissues over an 18‐month period would be informative to the underlying molecular processes that lead to postnatal sexual dimorphism. Regardless of age, sex‐associated changes of the whole bone transcriptomes were primarily associated not only with bone but also vascular and connective tissue ontologies. A pattern‐based approach used to screen the entire Gene Expression Omnibus (GEO) database against those that were sex‐specific in bone identified two coordinately regulated gene sets: one related to high phosphate–induced aortic calcification and one induced by mechanical stimulation in bone. Temporal clustering of the transcriptome identified two skeletal tissue‐associated, sex‐specific patterns of gene expression. One set of genes, associated with skeletal patterning and morphology, showed peak expression earlier in females. The second set of genes, associated with coupled remodeling, had quantitatively higher expression in females and exhibited a broad peak between 3 to 12 months, concurrent with the animals' reproductive period. Results of phenome‐level structural assessments of the tibia and vertebrae, and in vivo and in vitro analysis of cells having osteogenic potential, were consistent with the existence of functionally unique, skeletogenic cell populations that are separately responsible for appositional growth and intramedullary functions. These data suggest that skeletal sexual dimorphism arises through sex‐specific, temporally different processes controlling morphometric growth and later coupled remodeling of the skeleton during the reproductive period of the animal. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Antibodies to herpes simplex viral-induced antigens (HSVIA) were assayed by an indirect immunofluorescent technique in 93 regular cigarette smokers, 75 of whom also imbibed alcoholic beverages. Controls were 9 4 nonsmoking, nondrinking volunteers matched with the smokers for age and sex. IgA antibodies to HSVIA were detected six times more frequently in the sera of smokers than in nonsmoking controls, p < .0005. IgG and IgM anti-HSVIA were detected with comparable frequencies in both groups, but the antibody titers were significantly higher in the smoking group than in controls, p < .05. IgA anti-HSVIA was detected more frequently in smokers with 10 or more pack-years of cigarette exposure than in smokers with 10 o r less pack-years of smoking (p < .05) or in matched nonsmokers ( p < .02). IgA antibody titers to HSVIA were significantly higher in cigarette smokers who drank alcoholic beverages than in smokers who did not drink, p < .025. This study demonstrates that cigarette smoking and the use of alcoholic beverages are associated with heightened humoral immunity to HSV-induced antigens in a population at high risk for development of squamous cell carcinomas of the head a n d neck region. Received for publication December 1, 197.5 1 cell carcinomas of the head and neck as compared with controls.' A protein, antigenically related to this nonvirion antigen, has been isolated from a n extract of lip c a r~i n o m a .~ Because exposure to cigarette smoke, alcohol intake, and infection with HSV have each been independently associated with squamous cell carcinomas of the head and neck, this study was undertaken to determine if a relationship existed between these factors. A n indirect immunofluorescent assay was used to measure the immunoglobulin class-specific antibodies to HSV-induced antigens (HSVIA) in smokers and in nonsmoking controls. MATERIALS A N D METHODS Study PopulationsT h e study group consisted of 93 healthy volunteers, 35 men and 58 women, who smoked cigarettes on a daily basis and who had a mean age of 41.8 years. Data regarding tobacco and alcohol consumption were obtained by personal interview a n d questionnaire. Cigarette smoking was quantitated in pack-years, that is, cigarette packs smoked per day multiplied by the number of years of smoking. Alcohol consumption was graded as: Heavy-daily consumption of 8 oz or more of liquor, six or more cans of beer, or a history of alcoholism; Moderate-frequent but 55