Enkephalin-producing regulatory T cells in the skin restrain local inflammation through control of nociception.

The skin integrates diverse signals discerned by sensory neurons and immune cells to elicit adaptive responses to a range of stresses. Considering interactions between nervous and immune systems, we examined whether regulatory T (T) cells, which suppress systemic and local inflammation, can modulate activation of peripheral neurons. Acute T cell "loss of function" increased neuronal activation to noxious stimuli independently of their immunosuppressive function.

Terminal differentiation and persistence of effector regulatory T cells essential for preventing intestinal inflammation.

Regulatory T (T) cells are a specialized CD4 T cell lineage with essential anti-inflammatory functions. Analysis of T cell adaptations to non-lymphoid tissues that enable their specialized immunosuppressive and tissue-supportive functions raises questions about the underlying mechanisms of these adaptations and whether they represent stable differentiation or reversible activation states. Here, we characterize distinct colonic effector T cell transcriptional programs.

Iron Chelation Therapy Elicits Innate Immune Control of Metastatic Ovarian Cancer.

Iron accumulation in tumors contributes to disease progression and chemoresistance. Although targeting this process can influence various hallmarks of cancer, the immunomodulatory effects of iron chelation in the tumor microenvironment are unknown. Here, we report that treatment with deferiprone, an FDA-approved iron chelator, unleashes innate immune responses that restrain ovarian cancer.

Regulatory T cells restrain skin inflammation by modulating peripheral neuron activation.

The skin integrates diverse signals discerned by sensory neurons and immune cells to elicit adaptive responses to a range of stresses. Considering interactions between nervous and immune systems, we questioned whether regulatory T cells (Treg cells), a T cell subset that suppresses systemic and local inflammation, can modulate activation of peripheral neurons. Short-term ablation of Treg cells increased neuronal activation to noxious stimuli independently from immunosuppressive function.

Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer.

IRE1α-XBP1 signaling is emerging as a central orchestrator of malignant progression and immunosuppression in various cancer types. Employing a computational XBP1s detection method applied to TCGA datasets, we demonstrate that expression of the XBP1s mRNA isoform predicts poor survival in non-small cell lung cancer (NSCLC) patients. Ablation of IRE1α in malignant cells delays tumor progression and extends survival in mouse models of NSCLC.

Tumor-Derived Lysophosphatidic Acid Blunts Protective Type I Interferon Responses in Ovarian Cancer.

Unlabelled: Lysophosphatidic acid (LPA) is a bioactive lipid enriched in the tumor microenvironment of immunosuppressive malignancies such as ovarian cancer. Although LPA enhances the tumorigenic attributes of cancer cells, the immunomodulatory activity of this phospholipid messenger remains largely unexplored. Here, we report that LPA operates as a negative regulator of type I interferon (IFN) responses in ovarian cancer.

Lactate dehydrogenase A-dependent aerobic glycolysis promotes natural killer cell anti-viral and anti-tumor function.

Natural killer (NK) cells are cytotoxic lymphocytes capable of rapid cytotoxicity, cytokine secretion, and clonal expansion. To sustain such energetically demanding processes, NK cells must increase their metabolic capacity upon activation. However, little is known about the metabolic requirements specific to NK cells in vivo.

IRE1α-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain.

Inositol-requiring enzyme 1[α] (IRE1[α])-X-box binding protein spliced (XBP1) signaling maintains endoplasmic reticulum (ER) homeostasis while controlling immunometabolic processes. Yet, the physiological consequences of IRE1α-XBP1 activation in leukocytes remain unexplored. We found that induction of prostaglandin-endoperoxide synthase 2 (/Cox-2) and prostaglandin E synthase (/mPGES-1) was compromised in IRE1α-deficient myeloid cells undergoing ER stress or stimulated through pattern recognition receptors.

Dendritic Cell Metabolism and Function in Tumors.

Dendritic cells (DCs) are fundamental for the initiation and maintenance of immune responses against malignant cells. Despite the unique potential of DCs to elicit robust anticancer immunity, the tumor microenvironment poses a variety of challenges that hinder competent DC function and consequently inhibit the development of protective immune responses. Here, we discuss recent studies uncovering new molecular pathways and metabolic programs that tumors manipulate in DCs to disturb their homeostasis and evade immune control.