Commentary
Abstract
Immune checkpoint inhibitors (ICIs) have improved patient outcomes substantially in non–small cell lung cancer (NSCLC). Despite considerable effort, our understanding of the features that predict for immunotherapy response and resistance in patients remains incomplete. In this issue of the JCI, Isomoto and colleagues utilized a multiplex IHC platform to profile the spatial organization of the lung cancer tumor immune microenvironment, enabling the identification of spatial immune features that correlate with immunotherapy efficacy. This study enhances our knowledge of the spatial organization of features impacting ICI efficacy by identifying a three-variable spatial composite — including CD73 upregulation in EGFR-mutant NSCLC — that substantially outperforms PD-L1 expression in predicting immunotherapy efficacy. Moreover, it establishes spatial proteomic profiling as a platform for generating therapeutic hypotheses that are actionable and mechanistic in NSCLC.
Authors
Tao Zou, John D. Minna
Abstract
Despite extensive advances in understanding sepsis pathophysiology, treatment outcomes have not substantially improved. In this issue, Takahama and colleagues identified phospholipase A2 Group V (PLA2G5) as a contributor to sepsis lethality in mouse models of endotoxemia and sepsis. Whole-mouse spatial profiling generated bodywide maps of systemic inflammation and uncovered intestinal goblet cells as a source of pathogenic PLA2G5. Pairs of inflammatory cytokines (TNF and IFN-γ, or TNF and IL-18) induced PLA2G5 expression in goblet cells. Mechanistically, circulating PLA2G5 triggered intravascular hemolysis through its lipolytic activity on erythrocyte membranes and contributed to organ failure and death. PLA2G5’s deleterious effects were blocked by specific antibodies and were absent in Pla2g5-deficient mice. In humans with bacterial or fungal sepsis or severe COVID-19, plasma PLA2G5 levels were elevated and predicted disease severity. This discovery highlights the contribution of hemolysis to sepsis, suggesting that PLA2G5 inhibitors, hemoglobin, or heme antagonists could represent valuable therapeutic tools.
Authors
Jean-Marc Cavaillon
Abstract
Fatty acid oxidation (FAO) provides the healthy heart with 60%–90% of its ATP, with the remainder coming from metabolism of glucose. Metabolic flexibility is key to heart function, ensuring an uninterrupted source of fuel. In heart failure, a shift from FAO to glucose-dependent metabolism occurs as disease progresses, supporting the widely held notion that fat is the optimal substrate in the heart. In this issue of the JCI, Kim et al. challenge this assumption. In studies of acetyl-CoA carboxylase–deficient (ACC-deficient) mice, they found that unregulated use of fat as a substrate led to cardiac damage. ACC-deficient mice developed cardiolipin deficiency as a result of excessive FAO depleting stores of linoleic acid, which is used as a substrate for cardiolipin maturation. The resulting mitochondrial dysfunction was associated with dilated cardiomyopathy and heart failure in these mice. The findings highlight potential for development of therapeutic strategies that balance energy sources and replenish cardiolipin levels.
Authors
Steven M. Claypool, Carla M. Koehler
Abstract
Chemotherapy-induced alopecia (CIA) is a common and highly visible adverse effect of chemotherapy with substantial psychosocial and quality-of-life burdens. In this issue, Gherardini and colleagues described a targeted strategy to prevent CIA using ALRN-6924, a stapled peptide that transiently activates p53 and induces cell cycle arrest in proliferating TP53 wild-type tissues, such as the hair follicle. In ex vivo human scalp hair follicle culture, ALRN-6924 protected matrix keratinocytes and bulge stem cells from paclitaxel- and cyclophosphamide-induced injury, reducing apoptosis, DNA damage, and other pathologic features. These findings nominate precision chemoprotection as a promising supportive care approach for mitigating CIA.
Authors
Edward B. Li, Meredith Klay, Rui Yi
Abstract
The immune response is essential for maintaining host integrity, and phagocytosis is widely considered as one of its most ancient cellular functions. Accordingly, professional phagocytes such as resident tissue macrophages (RTMs) populate virtually all organs and serve as primary sentinels capable of sensing, engulfing, and eliminating invading pathogens. Yet, reflecting their early evolutionary emergence, RTMs have acquired functions that extend far beyond phagocytosis. In this issue, Salm et al. extend the macrophage toolbox, showing that macrophages residing in the peritoneal cavity function as remote healers. Using various mouse models, they demonstrated that activated peritoneal macrophages accelerate distant skin wound healing through fibronectin secretion, thereby shaping tissue repair at sites beyond their anatomical location. These findings invite us to reconsider macrophages not only as phagocytes and mediators of inflammation but also as active regulators capable of shaping extracellular architecture at a distance.
Authors
Camille Blériot, Florent Ginhoux
Abstract
Abdominal aortic aneurysms (AAAs) are an age-related cause of sudden cardiac death and cardiovascular disease (CVD) morbidity with limited nonsurgical treatment options. In this issue of the JCI, Yonekawa et al. addressed the pathobiologic mechanisms of clonal hematopoiesis (CH), the age-related acquisition of expanded somatic clones in blood cells, as a potential driver of AAA. CH prevalence was high in patients being treated for AAA, and faster AAA expansion occurred over a period of one year in CH carriers. In an angiotensin II–induced model of AAA, mice carrying ten-eleven translocation 2 (Tet2) mutations (Tet2-CH) displayed accelerated AAA development and macrophage reprograming to an osteoclast-like state. Inhibition of this differentiation, targeting RANK/RANKL with FDA-approved therapies like alendronate and denosumab, suppressed aneurysmal growth. These findings suggest that macrophage-to-osteoclast differentiation may underlie the risk and progression of AAA associated with age-related CH, a mechanism that is modifiable through existing therapeutics.
Authors
Jessica A. Regan, Svati H. Shah
Abstract
Skeletal muscle has the impressive capacity to completely regenerate even after relatively severe injuries in young individuals, but this process is dysregulated in multiple cell types in the microenvironment in numerous diseases and aging. In this issue of the JCI, Cao et al., using an elegant set of genetic mouse models and pharmacological approaches, demonstrated that gasdermin E (GSDME) was required in myeloid cells after sterile muscle injury to normally regenerate muscle and that downstream IL-18 release prevented intramuscular ectopic fat deposition. GSDME expression was reduced in human muscles from aged individuals, and Gsdme was increased after muscle injury in young, but not old, mice. The ability of IL-18 to partially improve regeneration in aged GSDME-knockout mice demonstrates the potential clinical relevance of this finding in dysregulated muscle regeneration associated with aging.
Authors
Swathy Krishna, Jill A. Rafael-Fortney
Abstract
Thyroid hormones provide crucial regulation of energy expenditure through their effects on thermogenesis, lipid metabolism, and mitochondrial function. Given their close relationship with overall metabolism, a deficit in thyroid hormones fittingly leads to a positive energy balance and weight gain. The direction of this process may also operate in reverse, according to recent research from Rampy et al. in this issue of JCI. These investigators found that mice introduced to a high-fat, high-sugar diet developed marked short-term intracellular stress and functional impairment in the thyroid gland, leading to alterations in serum thyroid hormone levels prior to measurable weight gain. This finding opens the possibility that thyroid dysfunction originates from persistent damage to the thyroid gland caused by sustained overnutrition.
Authors
Arturo Hernandez, Francesco S. Celi
Abstract
Approximately 25% of individuals with type 1 diabetes (T1D) experience impaired awareness of hypoglycemia (IAH), a weakening of symptomatic neurohumoral responses to falling glucose levels that sharply increases risk of severe hypoglycemia. A recent study by Filip et al. used MRI-based arterial spin labeling to compare regional cerebral blood flow (CBF) responses to experimental hypoglycemia across 3 groups: individuals without T1D and individuals with T1D, with or without IAH. All groups showed a CBF response to hypoglycemia in brain regions involved in learning and interoception, among others, but the responses were qualitatively different between groups and blunted in the presence of IAH. The association between the regional CBF and the hormonal responses to hypoglycemia was inverted in IAH, compared with that in individuals with preserved awareness. The findings add to work linking changes in cognitive processing to IAH development and its persistence in some individuals.
Authors
Stephanie A Amiel, Fernando O Zelaya
Abstract
Alcohol use disorder (AUD) is linked with changes in brain structure and function, with robust evidence for neurodegenerative changes, including synaptic loss in preclinical models. Developing therapeutic strategies to target synaptic loss will require human studies that clarify their clinical relevance of these changes. In the current issue, Zakiniaeiz et al. demonstrate that AUD and alcohol consumption are associated with lower synaptic vesicle glycoprotein 2a (SV2A) expression, indexed by regional [11C]UCB-J PET. This is, to our knowledge, the first in vivo evidence of relationships between synaptic density and alcohol use, and, as such, it represents an important step toward understanding how AUD influences brain structure and function. Here, we describe two longstanding clinical issues in the AUD population — relapse and dementia risk — and how the results of the present study may guide future investigations of these issues.
Authors
Sarah K. Royse, Rajesh Narendran
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