Zheng, et al. identify metabolic biomarkers in the circulation that accurately diagnose fumarate hydratase–deficient renal cell carcinoma, the most aggressive form of kidney cancer. These succinate-modified metabolites are produced via a unique enzymatic cascade that is initiated in response to the high concentration of fumarate in these tumors. Image credit: Liang Zheng and Kirsteen Liu.
Exaggerated Type 2 immune responses play critical roles in the pathogenesis of a variety of diseases including asthma, allergy, and pulmonary fibrosis. Recent studies have highlighted the importance of innate type 2 immune responses and innate lymphoid 2 cells (ILC2s) in these disorders. However, the mechanisms that control the development of pulmonary innate type 2 responses (IT2IR) and the recruitment and/or activation of ILC2 cells are poorly understood. In mouse models of pulmonary IT2IR, we demonstrated that Phospholipid scramblase-1 (PLSCR1), a type II transmembrane protein that mediates bidirectional and non-specific translocation of phospholipids between the inner and outer leaflets of the plasma membrane, was a critical regulator of IT2IR in the lung. We further suggested that PLSCR1 bound to and physically interacted with CRTH2 (Chemoattractant receptor-homologous molecule expressed on TH2 cells), a G-protein-coupled receptor that is expressed on multiple immune cells and commonly used to identify ILC2 cells, and the effects of PLSCR1 on ILC2 activation and IT2IR were mediated via CRTH2-dependent mechanisms. Overall, our studies demonstrated that PLSCR1 played an essential role in the pathogenesis of ILC2 responses, providing critical insights into biology and disease pathogenesis and identifying targets that can be manipulated in attempts to control IT2IR in chronic diseases such as asthma.
Ashley Hernandez-Gutierrez, Sonoor Majid, Adam T. Eberle, Ashley S. Choi, Parand Sorkhdini, Dongqin Yang, Alina Yang, Carmelissa Norbrun, Chuan He, Chang-min Lee, Chun Geun Lee, Jack A. Elias, Yang Zhou
Since T-box transcription factors (TFs) T-BET and EOMES are necessary for initiation of NK cell development, their ongoing requirement for mature NK cell homeostasis, function, and molecular programming remains unclear. To address this, T-BET and EOMES were deleted in unexpanded primary human NK cells using CRISPR/Cas9. Deleting these TFs compromised in vivo anti-tumor response of human NK cells. Mechanistically, T-BET and EOMES were required for normal NK cell proliferation and persistence in vivo. NK cells lacking T-BET and EOMES also exhibited defective responses to cytokine stimulation. Single-cell RNA-sequencing revealed a specific T-box transcriptional program in human NK cells, which was rapidly lost following T-BET and EOMES deletion. Further, T-BET and EOMES deleted CD56bright NK cells acquired an ILCP-like profile with increased expression of ILC-3-associated TFs RORC and AHR, revealing a role of T-box TF in maintaining mature NK cell phenotypes and an unexpected role of suppressing alternative ILC lineages. Our study reveals the critical importance of sustained EOMES and T-BET expression to orchestrate mature NK cell function and identity.
Pamela Wong, Jennifer A. Foltz, Lily Chang, Carly C. Neal, Tony Yao, Celia C. Cubitt, Jennifer Tran, Samantha Kersting-Schadek, Sathvik X. Palakurty, Natalia Jaeger, David A. Russler-Germain, Nancy D. Marin, Margery Gang, Julia A. Wagner, Alice Y. Zhou, Miriam T. Jacobs, Mark Foster, Timothy Schappe, Lynne Marsala, Ethan McClain, Patrick Pence, Michelle Becker-Hapak, Bryan Fisk, Allegra A. Petti, Obi L. Griffith, Malachi Griffith, Melissa M. Berrien-Elliott, Todd A. Fehniger
Cancer patients with high serum squamous cell carcinoma antigen (SCCA1/SERPINB3) are commonly associated with treatment resistance and poor prognosis. Despite being a clinical biomarker, the modulation of SERPINB3 in tumor immunity is poorly understood. We found positive correlations of SERPINB3 with CXCL1/8, S100A8/A9 and myeloid cell infiltration through RNAseq analysis of human primary cervix tumors. Induction of SERPINB3 resulted in increased CXCL1/8 and S100A8/A9, which promoted monocyte and MDSC migration in vitro. In mouse models, Serpinb3a-tumors showed increased MDSC and TAM infiltration contributing to T cell inhibition and this was further augmented upon radiation. Intratumoral knockdown of Serpinb3a demonstrated tumor growth inhibition and reduced CXCL1, S100A8/A9, MDSC, and M2 macrophage infiltration. These changes led to enhanced cytotoxic T cell function and sensitized tumors to radiotherapy. We further revealed SERPINB3 promoted STAT-dependent suppressive chemokine expression, whereby inhibiting STAT activation by ruxolitinib or siRNA abrogated CXCL1/8 and S100A8/A9 in SERPINB3 cells. Patients with elevated pre-treatment SCCA and high pSTAT3 had increased intratumoral CD11b+ myeloid cell compared to patients with low SCCA and pSTAT3 cohort that had overall improved survival after radiotherapy. These findings provide a preclinical rationale for targeting SERPINB3 in tumors to counteract the immunosuppression and improve response to radiation.
Liyun Chen, Victoria Shi, Songyan Wang, Lulu Sun, Rebecca N. Freeman, Jasmine Yang, Matthew J. Inkman, Subhajit Ghosh, Fiona Ruiz, Kay Jayachandran, Yi Huang, Jingqin Luo, Jin Zhang, Pippa Cosper, Cliff J. Luke, Catherine S. Spina, Perry W. Grigsby, Julie K. Schwarz, Stephanie Markovina
Alzheimer’s disease (AD) is the most common cause of dementia. The APOE-ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset AD. APOE genotype modulates the effect of sleep disruption on AD risk, suggesting a possible link between apoE and sleep in AD pathogenesis which is relatively unexplored. We hypothesized that apoE modifies Aβ deposition and Aβ plaque-associated tau seeding and spreading in the form of neuritic plaque (NP)-tau pathology in response to chronic sleep deprivation (SD) in an apoE isoform-dependent fashion. To test this hypothesis, we used APPPS1 mice expressing human APOE-ε3 or -ε4 with or without AD-tau injection. We found that SD in APPPS1 mice significantly increased Aβ deposition and peri-plaque NP-tau pathology in the presence of APOE4, but not APOE3. SD in APPPS1 mice significantly decreased microglial clustering around plaques and aquaporin-4 (AQP4) polarization around blood vessels in the presence of APOE4 but not APOE3. We also found that sleep deprived APPPS1:E4 mice injected with AD tau had significantly altered sleep behaviors as compared to APPPS1:E3 mice. These findings suggest that APOE-ε4 genotype is a critical modifier in the development of AD pathology in response to SD.
Chanung Wang, Aishwarya Nambiar, Michael R. Strickland, Choonghee Lee, Samira Parhizkar, Alec C. Moore, Erik S. Musiek, Jason D. Ulrich, David M. Holtzman
Sepsis remains a leading cause of human death and currently has no pathogenesis-specific therapy. Hampered progress is partly due to a lack of insight into deep mechanistic processes. In the last decade, deciphering the functions of small non-coding microRNAs (miRNAs) in sepsis pathogenesis became a dynamic research topic. To screen for new miRNA targets for sepsis therapeutics, we used human samples for miRNA array from peripheral blood mononuclear cells from sepsis patients and controls, blood samples from two cohorts of sepsis patients, and multiple animal models: mouse cecum ligation-puncture (CLP)-induced sepsis, mouse viral miRNA challenge, and baboon Gram-positive and Gram-negative sepsis models. miR-93-5p met the criteria for a therapeutic target, being overexpressed in baboons that died early after induction of sepsis, downregulated in humans who survived after sepsis, and correlated with negative clinical prognosticators for sepsis. Therapeutically, inhibiting miR-93-5p prolonged the overall survival of mice with CLP-induced sepsis, with a stronger effect in older mice. Mechanistically, anti-miR-93-5p therapy reduced inflammatory monocytes and increased circulating effector memory T cells, especially the CD4+ subset. AGO2-immunoprecipitation in miR-93-knockout T cells identified important regulatory receptors, such as CD28, as direct miR-93-5p target genes. In conclusion, miR-93-5p is a potential therapeutic target in sepsis through regulating both innate and adaptive immunity with possibly more benefit for the elderly than the young patients.
Mihnea P. Dragomir, Enrique Fuentes-Mattei, Melanie Winkle, Keishi Okubo, Recep Bayraktar, Erik Knutsen, Aiham Qdaisat, Meng Chen, Yongfeng Li, Masayoshi Shimizu, Lan Pang, Kevin Liu, Xiuping Liu, Simone Anfossi, Huanyu Zhang, Ines Koch, Anh M. Tran, Swati Mohapatra, Anh Ton, Mecit Kaplan, Matthew W. Anderson, Spencer J. Rothfuss, Robert Silasi, Ravi S. Keshari, Manuela Ferracin, Cristina Ivan, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Constantin Georgescu, Pinaki P. Banerjee, Rafet Basar, Ziyi Li, David Horst, Catalin Vasilescu, Maria Teresa S. Bertilaccio, Katayoun Rezvani, Florea Lupu, Sai-Ching Yeung, George A. Calin
JCI This Month is a digest of the research, reviews, and other features published each month.
Glioblastomas are high-grade and aggressive CNS tumors. Due to heterogeneous composition, rapid growth, and suppressive immune microenvironment, gliomablastomas remain difficult to successfully treat. JCI editors Amy Heimberger, Daniel Brat, and Maciej Lesniak curated the reviews in this issue’s series to confront the many aspects of immune involvement in these clinically challenging tumors. Reviews in this series describe how tumor-associated macrophages, microglia, and neutrophils modulate glioblastoma progression and therapy response. They also explore new concepts for targeting the immune microenvironment in glioblastoma, including strategies targeting immunometabolism or epigenetic regulation, personalized immunotherapy approaches, and next-generation antigen presenting cell-based therapies.