Landscape of innate lymphoid cells in human head and neck cancer reveals divergent NK cell states in the tumor microenvironment.

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.

Targeting KDM2A Enhances T-cell Infiltration in NSD1-Deficient Head and Neck Squamous Cell Carcinoma.

In head and neck squamous cell carcinoma (HNSCC), a significant proportion of tumors have inactivating mutations in the histone methyltransferase NSD1. In these tumors, NSD1 inactivation is a driver of T-cell exclusion from the tumor microenvironment (TME). A better understanding of the NSD1-mediated mechanism regulating infiltration of T cells into the TME could help identify approaches to overcome immunosuppression. Here, we demonstrated that NSD1 inactivation results in lower levels of H3K36 dimethylation and higher levels of H3K27 trimethylation, the latter being a known repressive histone mark enriched on the promoters of key T-cell chemokines CXCL9 and CXCL10. HNSCC with NSD1 mutations had lower levels of these chemokines and lacked responses to PD-1 immune checkpoint blockade. Inhibition of KDM2A, the primary lysine demethylase that is selective for H3K36, reversed the altered histone marks induced by NSD1 loss and restored T-cell infiltration into the TME. Importantly, KDM2A suppression decreased growth of NSD1-deficient tumors in immunocompetent, but not in immunodeficient, mice. Together, these data indicate that KDM2A is an immunotherapeutic target for overcoming immune exclusion in HNSCC. SIGNIFICANCE: The altered epigenetic landscape of NSD1-deficient tumors confers sensitivity to inhibition of the histone-modifying enzyme KDM2A as an immunotherapeutic strategy to stimulate T-cell infiltration and suppress tumor growth.

Temporal and Quantitative Transcriptomic Differences Define Sexual Dimorphism in Murine Postnatal Bone Aging.

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.

Humanized Mouse Models for the Advancement of Innate Lymphoid Cell-Based Cancer Immunotherapies.

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.