The era of single-cell multiomics has led to the identification of lung epithelial cells with features of both alveolar type 1 (AT1) and alveolar type 2 (AT2) pneumocytes, leading many to infer that these cells are a distinct cell type in the process of transitioning between AT2 and AT1 cells. In this issue of the JCI, Wang and colleagues demonstrated that many so-called “transitional cells” do not actually contribute to functional repair. The findings warrant a reimagining of these cells as existing in a nondirectional, intermediate cell state, rather than moving through a transitory process from one cell type to another. We look forward to further exploration of diverse cell state expression profiles and a more refined examination of hallmark gene function beyond population labeling.
Jennifer M.S. Sucre, A. Scott McCall, Jonathan A. Kropski
Glioblastoma (GBM) tumor-associated macrophages (TAMs) provide a major immune cell population contributing to growth and immunosuppression via the production of proinflammatory factors, including IL-1. In this issue of the JCI, Chen, Giotti, and colleagues investigated loss of ll1b in the immune tumor microenvironment (TME) in GBM models driven by PDGFB expression and Nf1 knockdown. Survival was only improved in PDGFB-driven GBM models, suggesting that tumor cell genotype influenced the immune TME. IL-1β in the TME increased PDGFB-driven GBM growth by increasing tumor-derived NF-κB, expression of monocyte chemoattractants, and increased infiltration of bone marrow–derived myeloid cells (BMDMs). In contrast, no requirement for IL-1β was evident in Nf1-silenced tumors due to high basal levels of NF-κB and monocyte chemoattractants and increased infiltration of BMDM and TAMs. Notably, treatment of mice bearing PDGFB-driven GBM with anti–IL-1β or an IL1R1 antagonist extended survival. These findings suggest that effective clinical immunotherapy may require differential targeting strategies.
C. Ryan Miller, Anita B. Hjelmeland
Although subsets of patients with lung squamous cell carcinoma (LSCC) benefit from immunotherapy, there are few effective molecularly targeted treatments for LSCC. Fibroblast growth factor receptor (FGFR) inhibitors provide a therapeutic option for patients with LSCC harboring FGFR aberrations, but their therapeutic efficacy has been limited to date. In this issue of the JCI, Malchers et al. identified tail-to-tail rearrangements, either within or near FGFR1, that are associated with FGFR1 dependency and sensitivity to FGFR inhibition in LSCC. These results may help improve the selection of patients with LSCC who are most likely to benefit from treatment with FGFR inhibitors.
Netta Mäkinen, Matthew Meyerson
Macrophages are key mediators of innate immunity whose functional state can be regulated by glucose transporters. Although abundantly expressed in macrophages, the specific function of GLUT3, an isoform of facilitative glucose transporters, has not been clearly established. In this issue of the JCI, Dong-Min Yu and colleagues identify an alternative role for GLUT3 in promoting M2 macrophage polarization. The authors demonstrated that GLUT3 was upregulated upon M2 stimulation and was required for efficient alternative macrophage polarization and function. They further showed that GLUT3-induced M2 polarization was independent of glucose transport and functioned through Ras-mediated regulation of IL-4R endocytosis and IL-4/STAT6 activation. These findings may guide the development of macrophage-targeted treatments.
Peng Zhang, Jason Miska, Amy B. Heimberger
Carcinogen exposure has been associated with enhanced cancer immunogenicity that is often attributed to neoantigen generation. However, the broader, neoantigen-independent impact of carcinogens on immune responses to cancer cells remains underexplored. In this issue of the JCI, Huang et al. uncover a mechanism wherein carcinogen-treated cancer cells exhibit an inability to establish an immunosuppressive tumor microenvironment (TME) due to reduced M-CSF expression. Intriguingly, the so-called carcinogen-induced tumor-associated macrophages (TAMs) within this TME exhibited anti-tumor properties instead of the conventional immunosuppressive phenotype. This phenomenon extended to human lung cancers, as evidenced by TAM reprogramming in smokers versus nonsmokers. This study substantially advances our understanding of carcinogen-mediated effects on cancer immunogenicity, potentially redirecting approaches to cancer immunotherapy.
Shaofeng Liu, Mary Saunders, Tak W. Mak
Enabling the early detection and prevention of diabetic kidney damage has potential to substantially reduce the global burden of kidney failure. There is a critical need for identification of mechanistic biomarkers that can predict progression and serve as therapeutic targets. In this issue of the JCI, Sharma and colleagues used an integrated multiomics approach to identify the metabolite adenine as a noninvasive biomarker of progression in early diabetic kidney disease (DKD). The highest tertile of urine adenine/creatinine ratio (UAdCR) was associated with higher risk for end-stage kidney disease and mortality across independent cohorts, including participants with early DKD without macroalbuminuria. Spatial metabolomics, single-cell transcriptomics, and experimental studies localized adenine to regions of tubular pathology and implicated the mTOR pathway in adenine-mediated tissue fibrosis. Inhibition of endogenous adenine production was protective in a diabetic model. These findings exemplify the potential for multiomics to uncover mechanistic biomarkers and targeted therapies in DKD.
Yelena Drexler, Alessia Fornoni
In the lungs, the cystic fibrosis transmembrane conductance regulator (CFTR) regulates ion transport in surface-airway epithelia and submucosal glands, thus determining airway surface liquid (ASL) volume and mucus hydration. In this issue of the JCI, Lei Lei and colleagues report that the CFTR-rich and barttin/Cl– channel–expressing ionocytes mediate chloride absorption across airway epithelia, whereas the more abundant basal cells and secretory cells mediate chloride secretion. Thus, CFTR-mediated secretion and absorption of chloride ions in the lung are segregated by cell type, which has implications for future molecular therapies for cystic fibrosis lung disease.
Burkhard Tümmler
Suppression of antitumor immunity is a prominent feature of the tumor microenvironment. In this issue of the JCI, Taves, Otsuka, and authors show that glucocorticoids (GCs), which are potent immunosuppressive hormones mainly produced by the adrenals, can be reconverted from their inactive form to active metabolites via the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme expressed by murine tumor cell lines. In the tumor microenvironment, GCs acted on CD4+ regulatory T cells to enhance their immunosuppressive function and promote tumor growth. The findings suggest that targeting GC recycling as a strategy for modulating tumor immunosuppression has the potential to improve therapeutic efficacy of immune checkpoint blockade.
Julian Swatler, Young-Jun Ju, Ana C. Anderson, Enrico Lugli
Severe, early-onset fetal growth restriction is a leading cause of medically indicated preterm birth and substantially increases the risk for perinatal death or disability. No treatments exist to improve fetal growth or safely prolong pregnancy. Furthermore, wide-ranging phenotypes limit the accurate prediction of pregnancy outcome. In this issue of the JCI, Spencer and colleagues combine a discovery-science approach with ultrasound parameters to identify the most discriminative models for predicting either the primary outcome of fetal or neonatal death, or a secondary outcome of death or delivery at 28 weeks of gestation or earlier. Their findings can better individualize patient counseling but, just as compellingly, provide the capacity to identify those pregnancies that are at such considerable risk as to justify enrollment in paradigm-shifting interventional trials that are in the pipeline.
Emily J. Su
Infectious diarrhea is a major cause of morbidity and mortality, particularly for children in low- and middle-income countries. Cryptosporidium is a diarrheal pathogen for which there is no vaccine and current therapies are only partially effective. In this issue of the JCI, Gilchrist, Campo, and colleagues surveyed a large cohort of Bangladeshi children to profile antibody responses against an array of Cryptosporidium proteins. They discovered 233 proteins to which children developed antibodies, identified seven as being associated with protection from reinfection, and provided insights regarding the longevity of Cryptosporidium antibodies and the development of antibody breadth. In this commentary, we discuss the burden of disease caused by Cryptosporidium and how these studies highlight the strategies to better manage this parasite.
Ian S. Cohn, Christopher A. Hunter
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