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The functional diversity of natural killer (NK) cell repertoires stems from differentiation, homeostatic, receptor–ligand interactions and adaptive-like responses to viral infections. In the present study, we generated a single-cell transcriptional reference map of healthy human blood- and tissue-derived NK cells, with temporal resolution and fate-specific expression of gene-regulatory networks defining NK cell differentiation. Transfer learning facilitated incorporation of tumor-infiltrating NK cell transcriptomes (39 datasets, 7 solid tumors, 427 patients) into the reference map to analyze tumor microenvironment (TME)-induced perturbations. Of the six functionally distinct NK cell states identified, a dysfunctional stressed CD56 bright state susceptible to TME-induced immunosuppression and a cytotoxic TME-resistant effector CD56 dim state were commonly enriched across tumor types, the ratio of which was predictive of patient outcome in malignant melanoma and osteosarcoma. This resource may inform the design of new NK cell therapies and can be extended through transfer learning to interrogate new datasets from experimental perturbations or disease conditions. Malmberg and colleagues generated a single-cell transcriptional reference map to investigate pan-cancer profiles of tumor-infiltrating natural killer cells.

During early pregnancy, decidual innate lymphoid cells (dILCs) interact with surrounding maternal cells and invading fetal extravillous trophoblasts (EVT). Here, using mass cytometry, we characterise five main dILC subsets: decidual NK cells (dNK)1–3, ILC3s and proliferating NK cells. Following stimulation, dNK2 and dNK3 produce more chemokines than dNK1 including XCL1 which can act on both maternal dendritic cells and fetal EVT. In contrast, dNK1 express receptors including Killer-cell Immunoglobulin-like Receptors (KIR), indicating they respond to HLA class I ligands on EVT. Decidual NK have distinctive organisation and content of granules compared with peripheral blood NK cells. Acquisition of KIR correlates with higher granzyme B levels and increased chemokine production in response to KIR activation, suggesting a link between increased granule content and dNK1 responsiveness. Our analysis shows that dILCs are unique and provide specialised functions dedicated to achieving placental development and successful reproduction. As an interface between maternal and fetal tissues, decidua hosts immune cells specialized in fostering a successful pregnancy. Here the authors carry out high-dimensional characterization of function, morphology and surface markers of human decidual innate lymphoid cells (ILCs), identifying subsets with features distinct from blood ILC.

The implementation of immune checkpoint inhibitors to the oncology clinic signified a new era in cancer treatment. After the first indication of melanoma, an increasing list of additional cancer types are now treated with immune system targeting antibodies to PD-1, PD-L1 and CTLA-4, alleviating inhibition signals on T cells. Recently, we published proof-of-concept results on a novel checkpoint inhibitor, NKG2A. This receptor is expressed on cytotoxic lymphocytes, including NK cells and subsets of activated CD8+ T cells. Blocking antibodies to NKG2A unleashed the reactivity of these effector cells resulting in tumor control in multiple mouse models and an early clinical trial. Monalizumab is inhibiting this checkpoint in human beings and future clinical trials will have to reveal its potency in combination with other cancer treatment options.

Human immunogenetic variation in the form of HLA and KIR types has been shown to be strongly associated with a multitude of immune-related phenotypes. However, association studies involving immunogenetic loci most commonly involve simple analyses of classical HLA allelic diversity, resulting in limitations regarding the interpretability and reproducibility of results. We here present MiDAS, a comprehensive R package for immunogenetic data transformation and statistical analysis. MiDAS recodes input data in the form of HLA alleles and KIR types into biologically meaningful variables, allowing HLA amino acid fine mapping, analyses of HLA evolutionary divergence as well as experimentally validated HLA-KIR interactions. Further, MiDAS enables comprehensive statistical association analysis workflows with phenotypes of diverse measurement scales. MiDAS thus closes the gap between the inference of immunogenetic variation and its efficient utilization to make relevant discoveries related to immune and disease biology. It is freely available under a MIT license.

Background The mostly indolent natural history of prostate cancer (PCa) provides an opportunity for men to explore the benefits of lifestyle interventions. Current evidence suggests appropriate changes in lifestyle including diet, physical activity (PA) and stress reduction with or without dietary supplements may improve both disease outcomes and patient's mental health. Objective This article aims to review the current evidence on the benefits of all lifestyle programmes for PCa patients including those aimed at reducing obesity and stress, explore their affect on tumour biology and highlight any biomarkers that have clinical utility. Evidence acquisition Evidence was obtained from PubMed and Web of Science using keywords for each section on the affects of lifestyle interventions on (a) mental health, (b) disease outcomes and (c) biomarkers in PCa patients. PRISMA guidelines were used to gather the evidence for these three sections (15, 44 and 16 publications, respectively). Evidence synthesis For lifestyle studies focused on mental health, 10/15 demonstrated a positive influence, although for those programmes focused on PA it was 7/8. Similarly for oncological outcomes, 26/44 studies demonstrated a positive influence, although when PA was included or the primary focus, it was 11/13. Complete blood count (CBC)‐derived inflammatory biomarkers show promise, as do inflammatory cytokines; however, a deeper understanding of their molecular biology in relation to PCa oncogenesis is required (16 studies reviewed). Conclusions Making PCa‐specific recommendations on lifestyle interventions is difficult on the current evidence. Nevertheless, notwithstanding the heterogeneity of patient populations and interventions, the evidence that dietary changes and PA may improve both mental health and oncological outcomes is compelling, especially for moderate to vigorous PA. The results for dietary supplements are inconsistent, and although some biomarkers show promise, significantly more research is required before they have clinical utility.

Head and neck squamous cell carcinoma (HNSCC) encompasses a set of cancers arising from the epithelia of the upper aerodigestive tract, accounting for a significant burden of disease worldwide due to the disease’s mortality, morbidity, and predilection for recurrence. Prognosis of HNSCC in the recurrent and/or metastatic (R/M-HNSCC) setting is especially poor and effective treatment options increasingly rely on modulating T-cell antitumor responses. Still, immunotherapy response rates are generally low, prompting the exploration of novel strategies that incorporate other effector cells within the tumor microenvironment. Within the last decade, important advances have been made leveraging the powerful innate antitumor function of natural killer (NK) cells to treat solid tumors, including head and neck squamous cell carcinoma. NK cells are hybrid innate-adaptive effector cells capable of directly eliminating tumor cells in addition to initiating adaptive antitumor immune responses. In the setting of HNSCC, NK cells are important for tumor surveillance and control, and NK cell infiltration has repeatedly been associated with a favorable prognosis. Yet, HNSCC-infiltrating NK cells are susceptible to an array of immune evasion strategies employed by tumors that must be overcome to fully realize the antitumor potential of NK cells. We believe that a conceptual framework informed by the basic biological understanding of the mechanisms underlying NK cell activation can improve treatment of HNSCC, in part by selecting for patients most likely to respond to NK cell-based immunotherapy. Herein, we review the activity of NK cells in HNSCC, paying special attention to the role of environmental and genetic determinants of NK cell antitumor function. Moreover, we explore the evidence that NK cells are a crucial determinant of the efficacy of both established and emerging treatments for HNSCC.

All- trans -retinoic acid (ATRA), the retinoic acid receptors (RARs) agonist, regulates cell growth, differentiation, immunity, and survival. We report that ATRA-treatment repressed cancer growth in syngeneic immunocompetent, but not immunodeficient mice. The tumor microenvironment was implicated: CD8 +  T cell depletion antagonized ATRA’s anti-tumorigenic effects in syngeneic mice. ATRA-treatment with checkpoint blockade did not cooperatively inhibit murine lung cancer growth. To augment ATRA’s anti-tumorigenicity without promoting its pro-tumorigenic potential, an RARγ agonist (IRX4647) was used since it regulates T cell biology. Treating with IRX4647 in combination with an immune checkpoint (anti-PD-L1) inhibitor resulted in a statistically significant suppression of syngeneic 344SQ lung cancers in mice—a model known for its resistance to checkpoints and characterized by low basal T cell and PD-L1 expression. This combined treatment notably elevated CD4 +  T-cell presence within the tumor microenvironment and increased IL-5 and IL-13 tumor levels, while simultaneously decreasing CD38 in the tumor stroma. IL-5 and/or IL-13 treatments increased CD4 +  more than CD8 +  T-cells in mice. IRX4647-treatment did not appreciably affect in vitro lung cancer growth, despite RARγ expression. Pharmacokinetic analysis found IRX4647 plasma half-life was 6 h in mice. Yet, RARα antagonist (IRX6696)-treatment with anti-PD-L1 did not repress syngeneic lung cancer growth. Together, these findings provide a rationale for a clinical trial investigating an RARγ agonist to augment check point blockade response in cancers.

The vaginal microbiota is critical for reproductive health, and its disruption, particularly the loss of Lactobacillus spp. and dominance of anaerobes such as Mobiluncus mulieris (community state type IV, CST IV), is associated with bacterial vaginosis, sexually transmitted infections, and adverse reproductive outcomes, including preterm birth (PTB). While Gardnerella spp. have been widely studied, the role of M. mulieris remains poorly understood. This study used an unbiased discovery approach to examine host-microbe interactions driven by M. mulieris across distinct epithelial barriers of the lower reproductive tract. RNA sequencing revealed that live bacteria, cell-free supernatant, and bacterial extracellular vesicles (bEVs) each induced unique transcriptional responses in epithelial cells. All three components activated immune and inflammatory pathways, with bEVs eliciting the strongest response, particularly via toll-like receptor (TLR) 2 and TLR5 signaling. M. mulieris also altered extracellular matrix (ECM) remodeling pathways, including upregulation of matrix metalloproteinase 9 (MMP9), a key mediator linked to PTB. These findings were supported by clinical data showing elevated MMP9 in pregnant women with M. mulieris -containing vaginal microbiota. Collectively, these results highlight the broad impact of M. mulieris on epithelial responses and identify mechanisms by which specific anaerobes contribute to inflammation and ECM disruption in adverse reproductive outcomes.