Top read articles in the last 30 days
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Abstract
Immune checkpoint inhibitors have transformed cancer therapy, yet many patients fail to achieve durable responses due to insufficient T cell reinvigoration. Cytokines offer promise for enhancing immunotherapy, but their clinical use is limited by toxicity and a narrow therapeutic index. Immunocytokines, engineered fusion proteins combining antibody specificity with cytokine activity, aim to overcome these challenges by targeting cytokine delivery to immune cells or the tumor microenvironment. We describe SAR445877 (SAR’877), a potentially novel PD-1–targeted immunocytokine that fuses a high-affinity anti–PD-1 antibody with a detuned IL-15/IL-15Rα sushi domain complex. SAR’877 blocks PD-1/PD-L1 and PD-1/PD-L2 interactions while selectively delivering IL-15 signals to PD-1+ T cells, enhancing proliferation and activation of antigen-experienced CD8+ and CD4+ T cells and NK cells, while minimizing systemic inflammation. Mechanistically, SAR’877 activates STAT5 signaling in PD-1+ lymphocytes and restores effector function in exhausted T cells. In preclinical models, a murine surrogate of SAR’877 accelerated viral clearance and induced robust antitumor immunity by expanding cytotoxic CD8+ T cells and promoting Th1 polarization. Notably, SAR’877 outperformed anti–PD-1 plus untargeted IL-15, highlighting the therapeutic potential of targeted IL-15 delivery. These findings position SAR’877 as a promising next-generation immunotherapy with enhanced efficacy and reduced cytokine-associated toxicities.
Authors
Isaraphorn Pratumchai, Marie Bernardo, Julien Tessier, Jaroslav Zak, Kristi L. Marquardt, Joon Sang Lee, Maheeka Bimal, AHyun Choi, Anthony M. Byers, Mikielia G. Devonish, Roberto Carrio, Dan Lu, Stella Martomo, Jeegar Patel, Yu-an Zhang, Ingeborg M. Langohr, Virna Cortez-Retamozo, Dinesh S. Bangari, Angela Hadjipanayis, Xiangming Li, Valeria R. Fantin, Donald R. Shaffer, John R. Teijaro
Total views: 2557
Abstract
Solute carrier family 39, member 8 (SLC39A8), is a transmembrane transporter that mediates the cellular uptake of zinc, iron, and manganese (Mn). Human genetic studies document the involvement of SLC39A8 in Mn homeostasis, brain development, and function. However, the role and pathophysiological mechanisms of SLC39A8 in the central nervous system remain elusive. We generated Slc39a8 neuron-specific knockout (Slc39a8-NSKO) mice to study SLC39A8 function in neurons. The Slc39a8-NSKO mice displayed markedly decreased Mn levels in the whole brain and brain regions, especially the cerebellum. Radiotracer studies using 54Mn revealed that Slc39a8-NSKO mice had impaired brain uptake of Mn. Slc39a8-NSKO cerebellums exhibited morphological defects and abnormal dendritic arborization of Purkinje cells. Reduced neurogenesis and increased apoptotic cell death occurred in the cerebellar external granular layer of Slc39a8-NSKO mice. Brain Mn deficiency in Slc39a8-NSKO mice was associated with motor dysfunction. Unbiased RNA-Seq analysis revealed downregulation of key pathways relevant to neurodevelopment and synaptic plasticity, including cAMP signaling pathway genes. We further demonstrated that Slc39a8 was required for the optimal transcriptional response to the cAMP-mediated signaling pathway. In summary, our study highlighted the essential roles of SLC39A8 in brain Mn uptake and cerebellum development and functions.
Authors
Eun-Kyung Choi, Luisa Aring, Yujie Peng, Adele B. Correia, Andrew P. Lieberman, Shigeki Iwase, Young Ah Seo
Total views: 2463
Abstract
Chronic kidney disease (CKD) is associated with renal metabolic disturbances, including impaired fatty acid oxidation (FAO). Nicotinamide adenine dinucleotide (NAD+) is a small molecule that participates in hundreds of metabolism-related reactions. NAD+ levels are decreased in CKD, and NAD+ supplementation is protective. However, both the mechanism of how NAD+ supplementation protects from CKD, as well as the cell types involved, are poorly understood. Using a mouse model of Alport syndrome, we show that nicotinamide riboside (NR), an NAD+ precursor, stimulated renal PPARα signaling and restored FAO in the proximal tubules, thereby protecting from CKD in both sexes. Bulk RNA-sequencing showed that renal metabolic pathways were impaired in Alport mice and activated by NR in both sexes. These transcriptional changes were confirmed by orthogonal imaging techniques and biochemical assays. Single-nuclei RNA sequencing and spatial transcriptomics, both the first of their kind to our knowledge from Alport mice, showed that NAD+ supplementation restored FAO in proximal tubule cells. Finally, we also report, for the first time to our knowledge, sex differences at the transcriptional level in this Alport model. In summary, the data herein identify a nephroprotective mechanism of NAD+ supplementation in CKD, and they demonstrate that this benefit localizes to the proximal tubule cells.
Authors
Bryce A. Jones, Debora L. Gisch, Komuraiah Myakala, Amber Sadiq, Ying-Hua Cheng, Elizaveta Taranenko, Julia Panov, Kyle Korolowicz, Ricardo Melo Ferreira, Xiaoping Yang, Briana A. Santo, Katherine C. Allen, Teruhiko Yoshida, Xiaoxin X. Wang, Avi Z. Rosenberg, Sanjay Jain, Michael T. Eadon, Moshe Levi
Total views: 2368
Abstract
BACKGROUND Chimeric antigen receptor T-cell (CAR-T) therapies have revolutionized treatment for relapsed/refractory multiple myeloma (RRMM). However, cytokine release syndrome (CRS), a common and potentially severe complication, requires inpatient monitoring, limiting access and increasing costs. Wearable devices could support outpatient CAR-T delivery, but feasibility for CRS detection versus standard care remains unproven.METHODS We conducted a prospective, single-center observational pilot study to assess the feasibility of using wearable devices for monitoring vital signs and detecting CRS. Thirty patients receiving idecabtagene vicleucel (ide-cel) or ciltacabtagene autoleucel (cilta-cel) were enrolled; 25 with sufficient monitoring data were evaluable. Sensors collected skin and axillary temperature, oxygen saturation, respiratory and heart rate, and motion. Peripheral blood cytokines were analyzed pre- and postinfusion using a multiplex proteomic platform. The primary outcome was feasibility, assessed by CRS detection sensitivity and specificity; secondary outcomes included adherence, lead time, and performance of models integrating wearable and cytokine data.RESULTS CRS occurred in 20 of 25 patients. The best-performing wearable model detected 18 or 20 CRS episodes with a sensitivity of 0.72 (mean 0.75; 95% CI 0.60–0.91) and a specificity of 0.80 (mean 0.76; 95% CI 0.68–0.84), and a median lead time of 7:00 hours before nursing recognition. Median adherence during high-risk periods was 71%. Cytokine changes paralleled temperature elevations, and IFN-γ emerged as a consistent biomarker.CONCLUSION Wearable devices are feasible for early CRS detection and may support outpatient CAR-T care. Larger outpatient studies are warranted.TRIAL REGISTRATION This study did not meet the criteria for ClinicalTrials.gov registration.
Authors
Sridevi Rajeeve, Matt Wilkes, Nicole Zahradka, Lewis Tomalin, Mujahid Quidwai, Darren Pan, Nicholas J. Calafat, Martin Cusack, Adolfo Aleman, Kseniya Serebryakova, Katerina Kappes, Hayley Jackson, Sarita Agte, Santiago Thibaud, Larysa Sanchez, Shambavi Richard, Joshua Richter, Cesar Rodriguez, Hearn Jay Cho, Ajai Chari, Sundar Jagannath, Alessandro Laganà, Adriana C. Rossi, Samir Parekh
Total views: 1769
Abstract
The discovery of genes encoding the volume-regulated anion channel (VRAC) has enabled detailed exploration of its cell type–specific roles in the brain. LRRC8A (SWELL1) is the essential VRAC subunit. We observed seizure-induced, subunit-specific changes in microglial VRAC expression and investigated its function using conditional KO (cKO) of LRRC8A in microglia. SWELL1 cKO mice exhibited a male-specific increase in kainate-induced seizure severity, yet showed paradoxical neuroprotection against seizure-associated neuronal loss. Mechanistically, SWELL1 deletion led to a cell-autonomous reduction in microglial density and decreased release of VRAC-permeable neuroactive metabolites, including taurine, GABA, and glutamate in culture. Additionally, impaired phagocytic kinetics and reduced lysosomal biogenesis contributed to the observed neuroprotection. These findings reveal potentially novel roles for microglial VRAC in regulating seizure outcomes and microglia-neuron interactions.
Authors
Abhijeet S. Barath, Aastha Dheer, Laura Montier, Mekenzie M Peshoff, Emily Dale, Flavia Goche, Thanh Thanh Le Nguyen, Mastura Akter, FangFang Qi, Dimitrios Kleidonas, Lauren Harris, Sarah A. Jewanee, Anthony D. Umpierre, Dale B. Bosco, Koichiro Haruwaka, Rajan Sah, Long-Jun Wu
Total views: 1631
Abstract
Antiviral immunity profoundly impacts host metabolism, which can, in turn, modulate immune responses and influence disease pathology. The liver orchestrates systemic bile acid (BA) metabolism, a pathway disrupted in chronic liver diseases such as viral hepatitis. BAs are increasingly recognized for their immunomodulatory properties. Thus, improved understanding of the interplay between immunity and BA metabolism may reveal novel therapeutic avenues. Using lymphocytic choriomeningitis virus (LCMV) as a model, we investigated the interplay between chronic virus infection, BA metabolism, and immunity. Chronic LCMV infection increased BA levels and shifted circulating and liver BA composition toward host-derived, conjugated BAs. Hepatic BA transport and synthesis genes were broadly downregulated, in part depending on CD8+ T cells. Pharmacological inhibition of the main hepatic transporter of conjugated BAs, NTCP (Slc10a1), increased hepatic damage, while combined genetic disruption of the BA transporters Slco1a1, Slco1a4, and Slco1b2, responsible for the hepatic reuptake of unconjugated BA, reduced liver pathology and impaired antiviral CD8+ T cell responses. These findings reveal a reciprocal interplay between BA metabolism and CD8+ T cells, expanding our understanding of adaptive immunity in viral hepatitis. They also highlight how immunometabolic changes in liver disease may affect adaptive immune responses against infections.
Authors
Felix Clemens Richter, Zsofia Keszei, Csilla Viczenczova, Maximilian Baumgartner, Henrique G. Colaço, Magdalena Siller, Lisa Holnsteiner, Hatoon Baazim, Anna Hofmann, Aubrey Burrett, Anna Schönbichler, Lukas Endler, Joel Xu En Wong, Laura Antonio-Herrera, Oleksandr Petrenko, Fabian Amman, Jakob-Wendelin Genger, Claudia D. Fuchs, Hubert Scharnagl, Hanns-Ulrich Marschall, Thomas Reiberger, Karl S. Lang, Clarissa Campbell, Michael Trauner, Andreas Bergthaler
Total views: 1620
Abstract
Community-acquired pneumonia is a major cause of morbidity and mortality globally. Specific molecular endotypes are currently not well defined, and different viral or bacterial pathogens may trigger specific host responses and pathogenic mechanisms. We performed longitudinal proteomic profiling of bronchoalveolar lavage fluid and plasma from bacterial, influenza, and SARS-CoV-2–driven pneumonia. Our analysis revealed highly pneumonia type–specific proteomic signatures, including COVID-19–specific antibodies locally produced in the lung. These antibodies showed biased immunoglobulin V–domain usage, linked to a CD69/CD83 plasma cell state associated with disease severity and degree of autoimmunity. Using mass spectrometry–driven autoantibody profiling in 2 independent COVID-19 cohorts, we identified 177 putative autoantibodies targeting extracellular matrix, nuclear, and immune-related proteins. Of note, temporal changes in autoantibody profiles correlated with clinical markers of inflammation, organ dysfunction, and duration of hospitalization. These findings highlight the autoimmune aspects of COVID-19 and provide potential biomarkers and therapeutic targets to help improve patient outcomes.
Authors
Anna Semenova, Taylor A. Poor, Johannes B. Müller-Reif, Sai Rama Sridatta Prakki, Phillip Geyer, Martin Mück-Häusl, Rogan A. Grant, Luke Rasmussen, Lesca M. Holdt, Daniel Teupser, Matthias Mann, Ali Ö. Yildirim, Richard G. Wunderink, Alexander V. Misharin, Ben D. Singer, G.R. Scott Budinger, Theodore S. Kapellos, Herbert B. Schiller
Total views: 1575
Abstract
Transcriptional reprogramming has an important role in kidney glomerular disease. Using in vivo murine models of podocyte injury, we studied the roles of the FOXC2 and WT1 transcription factors (TFs) in podocyte injury. Podocytes are a crucial cell type of glomeruli, the filtration units of each nephron. Podocyte injury is often the incipient event leading to chronic kidney disease. It is well established that the TFs FOXC2 and WT1 are required in podocytes to maintain the glomerular filtration barrier. Their role in the response to injury is less well understood. Here, we tested the hypothesis that FOXC2 and WT1 act together to mediate transcriptional reprogramming in response to podocyte injury. Similarly to that of WT1, genome-wide FOXC2 binding to target genes is dynamic during the course of injury, initially increasing, but late in injury there is a dramatic decrease in FOXC2 expression and in its binding to target genes. Podocyte-specific inactivation of FoxC2 or Wt1 in adult mice limits the transcriptional response to injury. Correlating FOXC2 and WT1 ChIP-seq analyses demonstrated that they co-bind many genes expressed in podocytes. Thus, reprogramming the transcriptome involves dynamic changes in the binding of FOXC2 and WT1 to their target genes during a reparative injury response.
Authors
Sandrine Ettou, Anya Greenberg, Sangyoon Lee, Arjun Rajesh, Liang Sun, Nahid Tabibzadeh, Haruka Oishi, Ran Konoe, Phillip J. McCown, Sean Eddy, Victoria Driscoll, Tomoya Miyoshi, Ken Hiratsuka, Jason Lam, R. Sathish Srinivasan, Youngsook L. Jung, Biju Isaac, Mingwei Sun, Mary E. Taglienti, Keith Keller, Hong Chen, Matthias Kretzler, Astrid Weins, Ryuji Morizane, Shira Rockowitz, Valerie A. Schumacher, Dongwon Lee, Jordan A. Kreidberg
Total views: 1488
Abstract
CD4+ T cells contribute to antitumor immunity and are implicated in the efficacy of cancer immunotherapies. In particular, CD4+ T helper 2 (Th2) cells were recently found to block spontaneous breast carcinogenesis. However, the antitumor potential of Th2 cells in targeting established breast cancer remains uncertain. Herein, we demonstrate that Th2 cells induced by the topical calcipotriol/thymic stromal lymphopoietin cytokine axis suppressed the growth of established mammary tumors in mice. Interleukin-24 (IL-24), an anticancer cytokine, was highly upregulated in macrophages infiltrating calcipotriol-treated mammary tumors. Macrophages expressed IL-24 in response to IL-4 signaling in combination with Toll-like receptor 4 (TLR4) agonists (e.g., HMGB1) in vitro. Calcipotriol treatment significantly increased HMGB1 release by tumor cells in vivo. CD4+ T cell depletion reduced HMGB1 and IL-24 expression, reversing calcipotriol’s therapeutic efficacy. Macrophage depletion and TLR4 inhibition also reduced the therapeutic efficacy of calcipotriol. Importantly, calcipotriol treatment failed to control mammary tumors lacking the IL-24 receptor on tumor cells. Collectively, our findings reveal that Th2 cell–macrophage crosstalk leads to IL-24–mediated tumor cell death, highlighting a promising therapeutic strategy to tackle breast cancer.
Authors
Bo Wang, Yun Xia, Can Zhou, Yuhan Zeng, Heehwa G. Son, Shadmehr Demehri
Total views: 1454
Abstract
BACKGROUND Enhancing NAD+ levels with nicotinamide riboside (NR) confers antiinflammatory effects in human disease, although immunoregulatory mechanisms remain poorly characterized. We previously showed that ex vivo NR supplementation of primary CD4+ T cells from psoriatic individuals dampened immune responsiveness.METHODS To validate this in vivo, we performed a randomized, placebo-controlled NR supplementation study in individuals with mild-to-moderate psoriasis. Participants received oral NR (500 mg twice daily) or matching placebo for 4 weeks, with blood samples collected at baseline and after supplementation. NR reduced Th17 immune responsiveness.RESULTS Bulk CD4+ T cell RNA-seq identified induction of the SLIT-ROBO signaling pathway. NR supplementation increased circulating SLIT2 levels and enhanced SLIT2 production in dermal fibroblasts. Pharmacologic and genetic interrogation in CD4+ T cells and fibroblasts demonstrated that SLIT2, acting through the ROBO1 receptor, inhibited Rho GTPase signaling, thereby attenuating canonical Th17 polarization and fibroblast inflammatory activation.CONCLUSION These findings indicate that NAD+ augmentation exerts anti-inflammatory effects in psoriasis through SLIT2-ROBO1-mediated crosstalk between dermal fibroblasts and circulating CD4+ T cells, leading to suppression of Th17-driven inflammation.TRIAL REGISTRATION ClinicalTrials.gov NCT04271735 (registration date – 2020-08026), NCT01143454 (registration date - 2010-07-21), NCT01778569 (registration date – 2013-01-22), and NCT00001846 (registration date – 2001-01-11).FUNDING The NHLBI Division of Intramural Research (HL005102 – MNS).
Authors
Kim Han, Rachael J. Klein, Thomas C. Recupero, Anna Chiara Russo, Rahul Sharma, Anand K. Gupta, Shahin Hassanzadeh, Rebecca D. Huffstutler, Pradeep K. Dagur, Bryan Fisk, Neelam R. Redekar, Michael N. Sack
Total views: 1440
