Clinical Research
Abstract
Authors
Amit Prabhakar, Eckart M.D.D. De Bie, Jacqueline T. DesJardin, Prajakta Ghatpande, Stefan Gräf, Luke S. Howard, S. John Wort, Colin Church, David G. Kiely, Emily Sumpena, Thin Aung, Shenrae Carter, Jasleen Kukreja, Steven Hays, John R. Greenland, Jonathan P. Singer, Michael Wax, Paul J. Wolters, Marc A. Simon, Mark Toshner, Giorgio Lagna, Akiko Hata
Abstract
While immune checkpoint blockade (ICB) therapy has revolutionized the antitumor therapeutic landscape, it remains successful in only a small subset of cancer patients. Poor or loss of MHC-I expression has been implicated as a common mechanism of ICB resistance. Yet the molecular mechanisms underlying impaired MHC-I remain to be fully elucidated. Herein, we identified USP22 as a critical factor responsible for ICB resistance through suppressing MHC-I-mediated neoantigen presentation to CD8 T cells. Both genetic and pharmacologic USP22 inhibition increased immunogenicity and overcome anti-PD-1 immunotherapeutic resistance. At the molecular level, USP22 functions as a deubiquitinase for the methyltransferase EZH2, leading to transcriptional silencing of MHC-I gene expression. Targeted Usp22 inhibition resulted in increased tumoral MHC-I expression and consequently enhanced CD8 T cell killing, which was largely abrogated by Ezh2 reconstitution. Multiplexed immunofluorescence staining detected a strong reverse correlation between USP22 expression and both 2M expression and CD8+ T lymphocyte infiltration in solid tumors. Importantly, USP22 upregulation was associated with ICB immunotherapeutic resistance in patients with lung cancer. Collectively, this study highlights the role of USP22 as a diagnostic biomarker for ICB resistance and provides a potential therapeutic avenue to overcome the current ICB resistance through inhibition of USP22.
Authors
Kun Liu, Radhika Iyer, Yi Li, Jun Zhu, Zhaomeng Cai, Juncheng Wei, Yang Cheng, Amy Tang, Hai Wang, Qiong Gao, Nikita Lavanya Mani, Noah Marx, Beixue Gao, D. Martin Watterson, Seema A. Khan, William J. Gradishar, Huiping Liu, Deyu Fang
Abstract
Familial partial lipodystrophy 2 (FPLD2) is a rare disease characterized by adipose tissue loss and redistribution, and metabolic dysfunction. FPLD2 is caused by pathogenic variants in the LMNA gene, encoding nuclear lamins A/C, structural proteins that control nuclear function and gene expression. However, the mechanisms driving adipocyte loss in FPLD2 remain poorly defined. In this study, we recruited eight families with developing or established FPLD2 and performed clinical, histological, and transcriptomic analyses of subcutaneous adipose tissue biopsies. Bulk and single-nuclei RNA-sequencing revealed suppression of lipid metabolism and mitochondrial pathways, alongside increased inflammation. These signatures were mirrored in tamoxifen-inducible adipocyte-specific Lmna knockout mice, in which lamin A/C-deficient adipocytes shrank and disappeared. Lmna-deficient fibroblasts shared similar gene expression changes, linked to altered chromatin accessibility, underscoring lamin A/C’s potential regulatory role in lipid metabolism and inflammatory programs. By directly comparing atrophic and hypertrophic adipose depots in FPLD2, and integrating human, mouse, and in vitro models, this study provides new insights into disease progression and potential therapeutic targets.
Authors
Jessica N. Maung, Rebecca L. Schill, Akira Nishii, Maria Foss de Freitas, Bonje N. Obua, Marcus Nygård, Maria D. Mendez-Casillas, Isabel D.K. Hermsmeyer, Donatella Gilio, Ozge Besci, Yang Chen, Brian Desrosiers, Rose E. Adler, Anabela D. Gomes, Merve Celik Guler, Hiroyuki Mori, Romina M. Uranga, Ziru Li, Hadla Hariri, Liping Zhang, Anderson de Paula Souza, Keegan S. Hoose, Kenneth T. Lewis, Taryn A. Hetrick, Paul Cederna, Carey N. Lumeng, Susanne Mandrup, Elif A. Oral, Ormond A. MacDougald
Abstract
Sulfite oxidase (SOX) deficiency is a rare inborn error of cysteine metabolism resulting in severe neurological damage. In patients, sulfite accumulates to toxic levels, causing a rise in the downstream products S-sulfocysteine, which mediates excitotoxicity, and thiosulfate, a catabolic intermediate/product of hydrogen sulfide (H2S) metabolism. Here, we report a full-body knockout mouse model for SOX deficiency (SOXD) with a severely impaired phenotype. Among the urinary biomarkers, thiosulfate showed a 45-fold accumulation in SOXD mice, representing the major excreted S-metabolite. Consistently, we found increased plasma H2S, which was derived from sulfite-induced release from persulfides, as demonstrated in vitro and in vivo. Mass spectrometry analysis of total protein persulfidome identified a major loss of S-persulfidation in 20% of the proteome, affecting enzymes in amino acids, fatty acid metabolism, and cytosolic iron-sulfur cluster biogenesis. Urinary amino acid profiles indicated metabolic rewiring and mitochondrial dysfunction, thus identifying an altered H2S metabolism and persulfidation in SOXD. Finally, oxidized glutathione and glutathione trisulfide were able to scavenge sulfite in vitro and in vivo, extending the lifespan of SOXD mice and providing a mechanistic concept of sulfite scavenging for the treatment of this severe metabolic disorder of cysteine catabolism.
Authors
Chun-Yu Fu, Joshua B. Kohl, Filip Liebsch, Davide D’Andrea, Tamás Ditrói, Seiryo Ogata, Franziska Neuser, Max Mai, Anna T. Mellis, Emilia Kouroussis, Masanobu Morita, Titus Gehling, José Angel Santamaria-Araujo, Sin Yuin Yeo, Heike Endepols, Michaela Křížková, Viktor Kozich, Marcus Krueger, Julia B. Hennermann, Uladzimir Barayeu, Takaaki Akaike, Peter Nagy, Milos Filipovic, Guenter Schwarz
Abstract
BACKGROUND Inter- and intraindividual fluctuations in pain intensity pose a major challenge to treatment efficacy, with a majority of people perceiving their pain relief as inadequate. Recent preclinical studies have identified circadian rhythmicity as a potential contributor to these fluctuations and a therapeutic target.METHODS We therefore sought to determine the impact of circadian rhythms in people with chronic low back pain (CLBP) through a detailed characterization, including questionnaires to evaluate biopsychosocial characteristics, ecological momentary assessment (7 day e-diaries at 8:00/14:00/20:00) to observe pain fluctuations, and intraday blood transcriptomics (at 8:00/20:00) to identify genes/pathways of interest.RESULTS While most individuals displayed constant or variable/mixed pain phenotypes, a distinct subset had daily fluctuations of increasing pain scores (>30% change in intensity over 12 hours in ≥4/7 days). This population had no opioid users, better biopsychosocial profiles, and differentially expressed transcripts relative to other pain phenotypes. The circadian-governed neutrophil degranulation pathway was particularly enriched among arrhythmic individuals; the link between neutrophil degranulation and opioid use was further confirmed in a separate CLBP cohort.CONCLUSION Our findings identified pain rhythmicity and the circadian expression of neutrophil degranulation pathways as indicators of CLBP outcomes, which may help provide a personalized approach to phenotyping biopsychosocial characteristics and medication use. This highlights the need to better understand the impact of circadian rhythmicity across chronic pain conditions.FUNDING This work was funded by grants from the Canadian Institutes of Health Research (CIHR; grant PJT-190170, to NG and MGP) and the CIHR-Strategy for Patient-Oriented Research Chronic Pain Network (grant SCA-145102, to NG, QD, LD, MGP, and MC). DT was funded by a MS Canada endMS Doctoral Research Award, AMZ by an Ontario Graduate Scholarship, HGMG by a CIHR Doctoral Research Award, MGP by a Junior 2 Research Scholarship from the Fonds de recherche du Québec – Santé, and LD by a Canadian Excellence Research Chairs and Pfizer Canada Professorship in Pain Research.
Authors
Doriana Taccardi, Amanda M. Zacharias, Hailey G.M. Gowdy, Mitra Knezic, Marc Parisien, Etienne J. Bisson, Zhi Yi Fang, Sara A. Stickley, Elizabeth Brown, Daenis Camiré, Rosemary Wilson, Lesley N. Singer, Jennifer Daly-Cyr, Manon Choinière, Zihang Lu, M. Gabrielle Pagé, Luda Diatchenko, Qingling Duan, Nader Ghasemlou
Abstract
BACKGROUND. A key objective in managing HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) is reducing radiation therapy (RT) doses without compromising cure rates. A recent Phase 2/3 HN005 trial revealed that clinical factors alone are insufficient to guide safe RT dose de-escalation. Our prior research demonstrated that the Genomic Adjusted Radiation Dose (GARD) predicts RT benefit and may inform dose selection. We hypothesize that GARD can guide personalized RT de-escalation in HPV-positive OPSCC patients. METHODS. Gene expression profiles were analyzed in 191 HPV-positive OPSCC patients enrolled in an international, multi-institutional observational study (AJCC 8th edition stages I–III). Most patients received 70 Gy in 35 fractions or 69.96 Gy in 33 fractions (median dose: 70 Gy, range: 51.0–74.0 Gy). Overall survival (OS) was 94.1% at 36 months and 87.3% at 60 months. Cox proportional hazards models assessed association between GARD and OS, and time-dependent ROC analyses compared GARD with traditional clinical predictors. RESULTS. Despite uniform RT dosing, GARD showed wide heterogeneity ([15.4–71.7]). Higher GARD values were significantly associated with improved OS in univariate (HR = 0.941, P = 0.041) and multivariable analyses (HR = 0.943, P = 0.046), while T and N stage were not. GARD demonstrated superior predictive performance at 36 months (AUC = 78.26) versus clinical variables (AUC = 71.20). Two GARD-based RT de-escalation strategies were identified, offering potential survival benefits while reducing radiation exposure. CONCLUSIONS. GARD predicts overall survival and outperforms clinical variables, supporting its integration into the diagnostic workflow for personalized RT in HPV-positive OPSCC.
Authors
Emily Ho, Loris De Cecco, Steven A. Eschrich, Stefano Cavalieri, Geoffrey Sedor, Frank J. Hoebers, Ruud H. Brakenhoff, Kathrin Scheckenbach, Tito Poli, Kailin Yang, Jessica A. Scarborough, Shivani Nellore, Shauna R. Campbell, Neil M. Woody, Timothy A. Chan, Jacob Miller, Natalie L. Silver, Shlomo Koyfman, James E. Bates, Jimmy J. Caudell, Michael W. Kattan, Lisa Licitra, Javier F. Torres-Roca, Jacob G. Scott
Abstract
The immune ecosystem is central to maintaining effective defensive responses. However, it remains largely understudied how immune cells in the peripheral blood interact with circulating tumor cells (CTCs) in metastasis. Here, blood analysis of patients with advanced breast cancer revealed that over 75% of CTC-positive blood specimens contained heterotypic CTC clusters with CD45+ white blood cells (WBCs), which correlates with breast cancer subtypes, racial groups, and decreased survival. CTC-WBC clusters included overrepresented T cells and underrepresented neutrophils. Specifically, a rare subset of CD4 and CD8 double-positive T (DPT) cells was 140-fold enriched in CTC clusters versus their frequency in WBCs. DPT cells shared properties with CD4+ and CD8+ T cells but exhibited unique features of T cell exhaustion and immune suppression. Mechanistically, the integrin heterodimer α4β1, also named very late antigen 4 (VLA-4), in DPT cells and its ligand, VCAM1, in tumor cells are essential mediators of DPT-CTC clusters. Neoadjuvant administration of anti-VLA-4 neutralizing antibodies markedly blocked CTC–DPT clusters, inhibited metastasis, and extended mouse survival. These findings highlight a pivotal role of rare DPT cells in fostering cancer dissemination through CTC clustering. It lays a foundation for developing innovative biomarker-guided therapeutic strategies to prevent and target cancer metastasis.
Authors
David Scholten, Lamiaa El-Shennawy, Yuzhi Jia, Youbin Zhang, Elizabeth Hyun, Carolina Reduzzi, Andrew D. Hoffmann, Hannah F. Almubarak, Fangjia Tong, Nurmaa K. Dashzeveg, Yuanfei Sun, Joshua R. Squires, Janice Lu, Leonidas C. Platanias, Clive H. Wasserfall, William J. Gradishar, Massimo Cristofanilli, Deyu Fang, Huiping Liu
Abstract
BACKGROUND. Spinal muscular atrophy (SMA) is a rare genetic neuromuscular disease caused by deletions or mutations of the survival motor neuron 1 gene. Despite the availability of genetically-based treatments for SMA, functional impairments and weakness persist in treated symptomatic individuals. This study addresses whether additional treatment after gene transfer therapy could provide further clinical benefits. METHODS. Interim Day 302 findings are described from the phase 4 open-label RESPOND trial evaluating nusinersen in participants aged ≤ 36 months who had suboptimal clinical status following onasemnogene abeparvovec (OA) treatment, as determined by the investigator. RESULTS. Thirty-seven participants included in the interim analysis were symptomatic at the time of OA administration. Most (92%) had two survival motor neuron 2 gene copies. Age at first nusinersen dose (median [range]) was 9.1 (3–33) months for participants with two SMN2 copies and 34.2 (31–36) months for those with three SMN2 copies, while time from OA dose to first nusinersen dose (median [range]) was 6.3 (3–31) and 13.3 (10–22) months, respectively. Participants had elevated neurofilament light chain (NfL) levels and low compound muscle action potential (CMAP) amplitudes at baseline, suggesting active neurodegeneration and severe denervation at study entry. Improvements from baseline were observed across a range of outcomes at Day 302, including motor function outcomes (HINE-2 and CHOP-INTEND total score), achievement of independent sitting, NfL levels, CMAP, and investigator- and caregiver-reported outcomes. Mean NfL levels decreased rapidly from baseline to Day 183 and remained low at Day 302. Mean ulnar and peroneal CMAP amplitudes increased. No safety concerns were identified. CONCLUSION. Improvements in clinical and biomarker outcomes support the benefit of nusinersen treatment in infants and children with suboptimal clinical status following OA. TRIAL REGISTRATION. ClinicalTrials.gov ID, NCT04488133; EudraCT number, 2020-003492-18. FUNDING. This study was sponsored by Biogen (Cambridge, MA, USA).
Authors
Crystal M. Proud, Richard S. Finkel, Julie A. Parsons, Riccardo Masson, John F. Brandsema, Nancy L. Kuntz, Richard Foster, Wenjing Li, Ross Littauer, Jihee Sohn, Stephanie Fradette, Bora Youn, Angela D. Paradis
Abstract
Authors
Elena Godoy-Molina, Natalia L. Serrano, Aquilina Jiménez-González, Miquel Villaronga, Rosa M. Marqués Pérez-Bryan, Rubén Varela-Fernández, Stephanie Lotz-Esquivel, Alba Hevia Tuñón, Prachi P. Trivedi, Nina Horn, Joseph F. Standing, Víctor Mangas-Sanjuan, Mercè Capdevila, Aurora Mateos, Denis Broun, Svetlana Lutsenko, Ines Medina-Rivera, Rafael Artuch, Cristina Jou, Mònica Roldán, Pedro Arango-Sancho, Mónica Saez-Villafañe, Juan J. Ortiz-de-Urbina, Angela Pieras-López, Marta Duero, Rosa Farré, Jordi Pijuan, Janet Hoenicka, James C. Sacchettini, Michael J. Petris, Vishal M. Gohil, Francesc Palau
Abstract
BACKGROUND. Endocrine therapy (ET) with tamoxifen (TAM) or aromatase inhibitors (AI) is highly effective against hormone receptor (HR) positive early breast cancer (BC), but resistance remains a major challenge. The primary objectives of our study were to understand the underlying mechanisms of primary resistance and to identify potential biomarkers. METHODS. We selected >800 patients in three sub-cohorts (Discovery, N=364, matched pairs), Validation 1, N=270, Validation 2, N= 176) of the West German Study Group (WSG) Adjuvant Dynamic marker-Adjusted Personalized Therapy (ADAPT) trial who underwent short-term pre-operative TAM or AI treatment. Treatment response was assessed by immunohistochemical labeling of proliferating cells with Ki67 before and after ET. We performed comprehensive molecular profiling, including targeted next-generation sequencing (NGS) and DNA methylation analysis using EPIC arrays, on post-treatment tumor samples. RESULTS.TP53 mutations were strongly associated with primary resistance to both TAM and AI. In addition, we identified distinct DNA methylation patterns in resistant tumors, suggesting alterations in key signaling pathways and tumor microenvironment composition. Based on these findings and patient age, we developed the Predictive Endocrine ResistanCe Index (PERCI). PERCI accurately stratified responders and non-responders in both treatment groups in all three sub-cohorts and predicted progression-free survival in an external validation cohort and in the combined sub-cohorts. CONCLUSION. Our results highlight the potential of PERCI to guide personalized endocrine therapy and improve patient outcomes. TRIAL REGISTRATION. WSG-ADAPT, ClinicalTrials.gov NCT01779206, Registered 2013-01-25, retrospectively registered.
Authors
Guokun Zhang, Vindi Jurinovic, Stephan Bartels, Matthias Christgen, Henriette Christgen, Leonie Donata Kandt, Lidiya Mishieva, Hua Ni, Mieke Raap, Janin Klein, Anna-Lena Katzke, Winfried Hofmann, Doris Steinemann, Ronald E. Kates, Oleg Gluz, Monika Graeser, Sherko Kuemmel, Ulrike Nitz, Christoph Plass, Ulrich Lehmann, Christine zu Eulenburg, Ulrich Mansmann, Clarissa Gerhauser, Nadia Harbeck, Hans H. Kreipe
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