MEF2C regulates NK cell effector functions through control of lipid metabolism.

Natural killer (NK) cells are a critical first line of defense against viral infection. Rare mutations in a small subset of transcription factors can result in decreased NK cell numbers and function in humans, with an associated increased susceptibility to viral infection. However, our understanding of the specific transcription factors governing mature human NK cell function is limited.

Multimodal immune phenotyping reveals microbial-T cell interactions that shape pancreatic cancer.

Microbes are an integral component of the tumor microenvironment. However, determinants of microbial presence remain ill-defined. Here, using spatial-profiling technologies, we show that bacterial and immune cell heterogeneity are spatially coupled.

Treatment Response in First-Line Metastatic Pancreatic Ductal Adenocarcinoma Is Stratified By a Composite Index of Tumor Proliferation and CD8 T-Cell Infiltration.

Purpose: Determinants of treatment outcomes to chemotherapy-based regimens in metastatic pancreatic ductal adenocarcinoma (PDA) remain ill-defined. Our aim was to examine tissue-based correlates of treatment response and resistance using matched baseline and on-treatment biopsies collected from patients with PDA treated in the first-line metastatic setting.

Experimental Design: Patients with treatment-naïve metastatic PDA were enrolled in a Phase II trial (NCT02077881) investigating gemcitabine plus nab-paclitaxel in combination with indoximod, an orally administered small-molecule inhibitor of the IDO pathway.

Regulation of systemic metabolism by tissue-resident immune cell circuits.

Recent studies have demonstrated that tissue homeostasis and metabolic function are dependent on distinct tissue-resident immune cells that form functional cell circuits with structural cells. Within these cell circuits, immune cells integrate cues from dietary contents and commensal microbes in addition to endocrine and neuronal signals present in the tissue microenvironment to regulate structural cell metabolism. These tissue-resident immune circuits can become dysregulated during inflammation and dietary overnutrition, contributing to metabolic diseases.

The X-linked epigenetic regulator UTX controls NK cell-intrinsic sex differences.

Viral infection outcomes are sex biased, with males generally more susceptible than females. Paradoxically, the numbers of antiviral natural killer (NK) cells are increased in males. We demonstrate that while numbers of NK cells are increased in male mice, they display decreased effector function compared to females in mice and humans.

Immunologic Features in De Novo and Recurrent Glioblastoma Are Associated with Survival Outcomes.

Glioblastoma (GBM) is an immunologically "cold" tumor characterized by poor responsiveness to immunotherapy. Standard of care for GBM is surgical resection followed by chemoradiotherapy and maintenance chemotherapy. However, tumor recurrence is the norm, and recurring tumors are found frequently to have acquired molecular changes (e.

The transcription factor Fli1 restricts the formation of memory precursor NK cells during viral infection.

Natural killer (NK) cells are innate lymphocytes that possess traits of adaptive immunity, such as memory formation. However, the molecular mechanisms by which NK cells persist to form memory cells are not well understood. Using single-cell RNA sequencing, we identified two distinct effector NK cell (NK) populations following mouse cytomegalovirus infection.

Back to the Future: Spatiotemporal Determinants of NK Cell Antitumor Function.

NK cells play a crucial role in host protection during tumorigenesis. Throughout tumor development, however, NK cells become progressively dysfunctional through a combination of dynamic tissue-specific and systemic factors. While a number of immunosuppressive mechanisms present within the tumor microenvironment have been characterized, few studies have contextualized the spatiotemporal dynamics of these mechanisms during disease progression and across anatomical sites.

A Fresh Approach to Targeting Aging Cells: CAR-T Cells Enhance Senolytic Specificity.

Senescence is a critical factor in several diseases, yet senolytic therapies targeting senescent cells remain hindered by lack of specificity. In the June issue of Nature, Amor et al. (2020) develop chimeric antigen receptor (CAR)-T cells targeting uPAR, a novel senescent-cell marker, to treat liver adenocarcinoma and liver fibrosis.

Hepatocytes direct the formation of a pro-metastatic niche in the liver.

The liver is the most common site of metastatic disease. Although this metastatic tropism may reflect the mechanical trapping of circulating tumour cells, liver metastasis is also dependent, at least in part, on the formation of a 'pro-metastatic' niche that supports the spread of tumour cells to the liver. The mechanisms that direct the formation of this niche are poorly understood.

IQGAP1 Maintains Pancreatic Ductal Adenocarcinoma Clonogenic Growth and Metastasis.

Objectives: IQ motif containing GTPase-activating protein 1 (IQGAP1) acts as a scaffold for aberrant mitogen-activated protein kinase (MAPK) signaling driven by KRAS mutations in pancreatic ductal adenocarcinoma (PDAC). We determined the role of IQGAP1 in clonogenic growth and metastasis in PDAC.

Methods: We inhibited IQGAP1 expression using shRNA and assessed clonogenic growth, cell migration, and MAPK signaling in vitro and tumor initiation and metastasis in vivo.