Protein kinase C delta regulates mononuclear phagocytes and hinders response to immunotherapy in cancer.

Mononuclear phagocytes (MPs) play a crucial role in tissue homeostasis; however, MPs also contribute to tumor progression and resistance to immune checkpoint blockade (ICB). Targeting MPs could be an effective strategy to enhance ICB efficacy. We report that protein kinase C delta (PKCδ), a serine/threonine kinase, is abundantly expressed by MPs in human and mouse tumors.

Three toes and three modes: Dynamics of terrestrial, suspensory, and vertical locomotion in brown-throated three-toed sloths (Bradypodidae, Xenarthra).

Living sloths exhibit numerous anatomical specializations towards inverted quadrupedalism, however, previous studies have noted a more varied locomotor repertoire than previously anticipated. In this study, we present spatiotemporal gait characteristics and triaxial kinetic data from the brown-throated three-toed sloth (Bradypus variegatus) across three locomotor modes: terrestrial quadrupedal "crawling", suspensory walking, and vertical climbing. Compared to quadrupedal crawling and suspensory walking, B.

PKC agonism restricts innate immune suppression, promotes antigen cross-presentation and synergizes with agonistic CD40 antibody therapy to activate CD8 T cells in breast cancer.

Myeloid-derived suppressor cells (MDSCs) are an immature innate cell population that expands in pathological conditions such as cancer and suppresses T cells via production of immunosuppressive factors. Conversely, efficient cytotoxic T cell priming is dependent on the ability of antigen-presenting cells (APCs) to cross-present tumor antigens to CD8 T cells, a process that requires a specific subtype of dendritic cells (DCs) called conventional DC1 (cDC1) which are often dysfunctional in cancer. One way to activate cDC1 is ligation of CD40 which is abundantly expressed by myeloid cells and its agonism leads to myeloid cell activation.

Metformin Suppresses Monocyte Immunometabolic Activation by SARS-CoV-2 Spike Protein Subunit 1.

A hallmark of COVID-19 is a hyperinflammatory state associated with severity. Monocytes undergo metabolic reprogramming and produce inflammatory cytokines when stimulated with SARS-CoV-2. We hypothesized that binding by the viral spike protein mediates this effect, and that drugs which regulate immunometabolism could inhibit the inflammatory response.

Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer.

Immune checkpoint blockade (ICB) has improved outcomes in some cancers. A major limitation of ICB is that most patients fail to respond, which is partly attributable to immunosuppression. Obesity appears to improve immune checkpoint therapies in some cancers, but impacts on breast cancer (BC) remain unknown.

Growth differentiation factor-15 is associated with age-related monocyte dysfunction.

Objective: Age-associated decreases in immune functions are precipitated by a variety of mechanisms and affect nearly every immune cell subset. In myeloid cells, aging reduces numbers of phagocytes and impairs their functional abilities, including antigen presentation, phagocytosis, and bacterial clearance. Recently, we described an aging effect on several functions in monocytes, including impaired mitochondrial function and reduced inflammatory cytokine gene expression during stimulation with lipopolysaccharide.

Macrophage Immunometabolism and Inflammaging: Roles of Mitochondrial Dysfunction, Cellular Senescence, CD38, and NAD.

Aging is a complex process that involves dysfunction on multiple levels, all of which seem to converge on inflammation. Macrophages are intimately involved in initiating and resolving inflammation, and their dysregulation with age is a primary contributor to inflammaging-a state of chronic, low-grade inflammation that develops during aging. Among the age-related changes that occur to macrophages are a heightened state of basal inflammation and diminished or hyperactive inflammatory responses, which seem to be driven by metabolic-dependent epigenetic changes.

Classical monocytes from older adults maintain capacity for metabolic compensation during glucose deprivation and lipopolysaccharide stimulation.

Inflammaging is the chronic low-grade inflammation that occurs with age that contributes to the pathology of age-related diseases. Monocytes are innate immune cells that become dysregulated with age and which can contribute to inflammaging. Metabolism plays a key role in determining immune cell functions, with anti-inflammatory cells primarily relying on fatty acid oxidation and pro-inflammatory cells primarily relying on glycolysis.

Classical monocytes maintain ex vivo glycolytic metabolism and early but not later inflammatory responses in older adults.

Background: Inflammaging is a condition of chronic low-grade inflammation due to the aging process and is associated with a variety of chronic diseases. Monocytes are innate immune cells which contribute to inflammation and are dysregulated during aging, demonstrated reduced phagocytosis, increased inflammation, and alterations in subset proportions. Metabolism is known to determine immune cell function, with quiescent and anti-inflammatory cells primarily relying on fatty acid oxidation, while activated and inflammatory cells primarily rely on glycolysis.

Aging impairs mitochondrial respiratory capacity in classical monocytes.

Aging is a critical healthcare concern, with age-related inflammation disposing individuals to a variety of diseases. Monocytes are affected by the aging process, with increased inflammation and impaired cellular functions such as phagocytosis. Mechanisms by which aging alters monocyte function are unknown, but recent research suggests that the balance of metabolic processes determine immune cell phenotype and function.