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Abstract
Severe congenital neutropenia (SCN) is frequently associated with dominant point mutations in ELANE, the gene encoding neutrophil elastase (NE). Chronic administration of granulocyte colony-stimulating factor (G-CSF) is a first-line treatment of ELANE-mutant (ELANEmut) SCN. However, some ELANEmut patients including patients with ELANE start codon mutations do not respond to G-CSF. Here, through directed granulopoiesis of gene-edited isogenic normal and patient-derived iPSCs, we demonstrate that ELANE start codon mutations suffice to induce G-CSF resistant granulocytic precursor cell death and refractory SCN. ELANE start codon mutated neutrophil precursors express predominantly nuclear N-terminal truncated alternate NE. Unlike G-CSF sensitive ELANE mutations that induce endoplasmic reticulum and unfolded protein response stress, we found that the mutation of the ELANE translation initiation codon resulted in NE aggregates and activated pro-apoptotic aggrephagy as determined by downregulated BAG1 expression, decreased BAG1/BAG3 ratio, NE co-localization with BAG3, and localized expression of autophagic LC3B. We found that SERF1, an RNA-chaperone protein, known to localize in misfolded protein aggregates in neurodegenerative diseases, was highly upregulated and interacted with cytoplasmic NE of mutant neutrophil precursors. Silencing of SERF1 enhanced survival and differentiation of iPSC-derived neutrophil precursors, restoring their responsiveness to G-CSF. These observations provide a mechanistic insight of G-CSF-resistant ELANEmut SCN, revealing targets for therapeutic intervention.
Authors
Ramesh C. Nayak, Sana Emberesh, Lisa Trump, Ashley Wellendorf, Abhishek Singh, Brice Korkmaz, Marshall S. Horwitz, Kasiani C. Myers, Theodosia A. Kalfa, Carolyn Lutzko, Jose A. Cancelas
Abstract
Recent progress in cancer cell-based therapies has led to effective targeting and robust immune responses against cancer. However, the inherent safety risks of using live cancer cells necessitate the creation of an optimized safety switch without hindering the efficacy of immunotherapy. The existing safety switches typically induce tolerogenic cell death, potentially leading to an immunosuppressive tumor immune microenvironment (TIME), which is counterproductive to the goals of immunotherapy. Here, we developed and characterized an inducible RIPK3-driven necroptotic system that serves as a dual function of safety switch as well as inducing immunogenic cell death which in turn stimulates antitumor immune responses. We showed that activating RIPK3 safety switch triggered immunogenic responses marked by an increased release of adenosine triphosphate (ATP) and damage-associated molecular patterns (DAMPs). Compared to other existing safety switches, incorporating RIPK3 system inhibited tumor growth, improved survival outcomes in tumor-bearing mice, and fostered long-term antitumor immunity. Moreover, RIPK3 system reinvigorated the TIME by promoting dendritic cell (DC) maturation, polarizing the macrophages towards the M1 phenotype, and reducing the exhaustion of CD4+ and CD8+ T lymphocytes. Our study highlights the dual role of RIPK3-driven necroptotic system in improving the safety and efficacy of cancer cell-based therapy, with broader implications for cellular therapies.
Authors
Kok-Siong Chen, Sarah Manoury-Battais, Nobuhiko Kanaya, Ioulia Vogiatzi, Paulo Borges, Sterre J. Kruize, Yi-Ching Chen, Laura Y. Lin, Filippo Rossignoli, Natalia Claire Mendonca, Khalid Shah
Abstract
The glioblastoma (GBM) microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly impact the immune system, but the mechanisms driving these interactions are not completely clear. Here we demonstrate that the polyamine metabolite spermidine (SPD) is elevated in the GBM tumor microenvironment. Exogenous administration of SPD drives tumor aggressiveness in an immune-dependent manner in pre-clinical mouse models via reduction of CD8+ T cell frequency and reduced cytotoxic function. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in spermidine synthesis, did not impact cancer cell growth in vitro but did result in extended survival. Furthermore, glioblastoma patients with a more favorable outcome had a significant reduction in spermidine compared to patients with a poor prognosis. Our results demonstrate that spermidine functions as a cancer cell-derived metabolite that drives tumor progression by reducing CD8+ T cell number and function.
Authors
Kristen E. Kay, Juyeun Lee, Ellen S. Hong, Julia Beilis, Sahil Dayal, Emily R. Wesley, Sofia Mitchell, Sabrina Z. Wang, Daniel J. Silver, Josephine Volovetz, Sarah Johnson, Mary McGraw, Matthew Grabowski, Tianyao Lu, Lutz Freytag, Vinod K. Narayana, Saskia Freytag, Sarah A. Best, James R. Whittle, Zeneng Wang, Ofer Reizes, Jennifer S. Yu, Stanley L. Hazen, J. Mark Brown, Defne Bayik, Justin Lathia
Abstract
Phenotypic plasticity is a hallmark of cancer and increasingly realized as a mechanism of resistance to androgen receptor (AR)-targeted therapy. Now that many prostate cancer (PCa) patients are treated upfront with AR-targeted agents, it’s critical to identify actionable mechanisms that drive phenotypic plasticity, to prevent the emergence of resistance. We showed that loss of tristetraprolin (TTP, gene ZFP36) increased NF-κB activation, and was associated with higher rates of aggressive disease and early recurrence in primary PCa. We also examined the clinical and biological impact of ZFP36 loss with co-loss of PTEN, a known driver of PCa. Analysis of multiple independent primary PCa cohorts demonstrated that PTEN and ZFP36 co-loss was associated with increased recurrence risk. Engineering prostate-specific Zfp36 deletion in vivo, induced prostatic intraepithelial neoplasia, and, with Pten co-deletion, resulted in rapid progression to castration-resistant adenocarcinoma. Zfp36 loss altered the cell state driven by Pten loss, demonstrated by enrichment of EMT, inflammation, TNFα/NF-κB, IL6-JAK/STAT3 gene sets. Additionally, our work revealed that ZFP36 loss also induced enrichment of multiple gene sets involved in mononuclear cell migration, chemotaxis, and proliferation. Use of the NF-κB inhibitor, dimethylaminoparthenolide (DMAPT) induced marked therapeutic responses in tumors with PTEN and ZFP36 co-loss and reversed castration resistance.
Authors
Katherine L. Morel, Beatriz Germán, Anis A. Hamid, Jagpreet S. Nanda, Simon Linder, Andries M. Bergman, Henk van der Poel, Ingrid Hofland, Elise M. Bekers, Shana Y. Trostel, Deborah L. Burkhart, Scott Wilkinson, Anson T. Ku, Minhyung Kim, Jina Kim, Duanduan Ma, Jasmine T. Plummer, Sungyong You, Xiaofeng A. Su, Wilbert Zwart, Adam G. Sowalsky, Christopher J. Sweeney, Leigh Ellis
Abstract
BACKGROUND. Cutaneous lichen planus (LP) is a recalcitrant, difficult-to-treat, inflammatory skin disease characterized by pruritic, flat-topped, violaceous papules on the skin. Baricitinib is an oral Janus kinase (JAK) 1/2 inhibitor that interrupts the signaling pathway of interferon gamma (IFN)-γ, a cytokine implicated in the pathogenesis of LP. METHODS. In this phase II trial, twelve patients with cutaneous LP received baricitinib 2 mg daily for 16 weeks, accompanied by in-depth spatial, single-cell, and bulk transcriptomic profiling of pre- and post-treatment samples. RESULTS. An early and sustained clinical response was seen, with 83.3% of patients responsive at week 16. Our molecular data identified a unique, oligoclonal IFN-γ, CD8+, CXCL13+ cytotoxic T-cell population in LP skin and demonstrated a rapid decrease in IFN signature within 2 weeks of treatment, most prominently in the basal layer of the epidermis. CONCLUSION. This study demonstrates the efficacy and molecular mechanisms of JAK inhibition in LP. TRIAL REGISTRATION. NCT05188521. ROLE OF FUNDING SOURCE. Eli Lilly, Appignani Benefactor Funds, 5P30AR075043, Mayo Clinic Clinical Trials Stimulus Funds.
Authors
Angelina S. Hwang, Jacob A. Kechter, Tran H. Do, Alysia N. Hughes, Nan Zhang, Xing Li, Rachael Bogle, Caitlin M. Brumfiel, Meera H. Patel, Blake Boudreaux, Puneet Bhullar, Shams Nassir, Miranda L. Yousif, Alyssa L. Stockard, Zachary Leibovit-Reiben, Ewoma Ogbaudu, David J. DiCaudo, Jennifer Fox, Mehrnaz Gharaee-Kermani, Xianying Xing, Samantha Zunich, Emily Branch, J. Michelle Kahlenberg, Allison C. Billi, Olesya Plazyo, Lam C. Tsoi, Mark R. Pittelkow, Johann E. Gudjonsson, Aaron R. Mangold
Abstract
Authors
Giang Pham, Raymond E. Diep, Lucien H. Turner, David B. Haslam, Sing Sing Way
Abstract
Authors
Jeffrey D. Steimle, Yi Zhao, Fansen Meng, Mikaela E. Taylor, Diwakar Turaga, Iki Adachi, Xiao Li, James F. Martin
Abstract
Skeletal muscle relies on resident muscle stem cells (MuSCs) for growth and repair. Aging and muscle diseases impair MuSC function, leading to stem cell exhaustion and regenerative decline that contribute to the progressive loss of skeletal muscle mass and strength. In the absence of clinically available nutritional solutions specifically targeting MuSCs, we used a human myogenic progenitor (hMP) high-content imaging screen of natural molecules from food to identify nicotinamide (NAM) and pyridoxine (PN) as bioactive nutrients that stimulate MuSCs and have history of safe human use. NAM and PN synergize via CK1-mediated cytoplasmic β-catenin activation and AKT signaling to promote amplification and differentiation of MuSCs. Oral treatment with a combination of NAM/PN accelerates muscle regeneration in vivo by stimulating MuSCs, increases muscle strength during recovery, and overcomes MuSC dysfunction and regenerative failure during aging. Levels of NAM and bioactive PN spontaneously decline during aging in model organisms and inter-independently associate with muscle mass and walking speed in a human cohort of 186 aged people. Collectively, our results establish NAM/PN as a new nutritional intervention that stimulates MuSCs, enhances muscle regeneration, and alleviates age-related muscle decline with a direct opportunity for clinical translation.
Authors
Sara Ancel, Joris Michaud, Eugenia Migliavacca, Charline Jomard, Aurélie Fessard, Pauline Garcia, Sonia Karaz, Sruthi Raja, Guillaume E. Jacot, Thibaut Desgeorges, José-Luis Sánchez-García, Loic Tauzin, Yann Ratinaud, Benjamin Brinon, Sylviane Métairon, Lucas Pinero, Denis Barron, Stephanie Blum, Leonidas G. Karagounis, Ramin Heshmat, Afshin Ostovar, Farshad Farzadfar, Isabella Scionti, Rémi Mounier, Julien Gondin, Pascal Stuelsatz, Jerome N. Feige
Abstract
Clonal hematopoiesis (CH) increases inflammasome-linked atherosclerosis but the mechanisms by which CH mutant cells transmit inflammatory signals to non-mutant cells are largely unknown. To address this question we transplanted 1.5% Jak2VF bone marrow (BM) cells with 98.5% WT BM cells into hyperlipidemic Ldlr–/– mice. Low allele burden (LAB) mice showed accelerated atherosclerosis with increased features of plaque instability, decreased levels of macrophage phagocytic receptors MERTK and TREM2, and increased neutrophil extracellular traps (NETs). These changes were reversed when Jak2VF BM was transplanted with Il1r1–/– BM. LAB mice with non-cleavable MERTK in WT BM showed improvements in necrotic core and fibrous cap formation and reduced NETs. An agonistic TREM2 antibody (4D9) markedly increased fibrous caps in both control and LAB mice eliminating the difference between groups. Mechanistically, 4D9 increased TREM2+PDGFB+ macrophages and PDGF receptor-α positive fibroblast-like cells in the cap region. TREM2 and PDGFB mRNA levels were positively correlated in human carotid plaques and co-expressed in macrophages. In summary, low frequency Jak2VF mutations promote atherosclerosis via IL-1 signaling from Jak2VF to WT macrophages and neutrophils promoting cleavage of phagocytic receptors and features of plaque instability. Therapeutic approaches that stabilize MERTK or TREM2 could promote plaque stabilization especially in CH- and inflammasome-driven atherosclerosis.
Authors
Wenli Liu, Brian D. Hardaway, Eunyoung Kim, Jessica Pauli, Justus Leonard Wettich, Mustafa Yalcinkaya, Cheng-Chieh Hsu, Tong Xiao, Muredach P. Reilly, Ira Tabas, Lars Maegdefessel, Kai Schlepckow, Haass Christian, Nan Wang, Alan R. Tall
Abstract
Human cytomegalovirus (HCMV) profoundly impacts host T and natural killer (NK) cells across the lifespan, yet how this common congenital infection modulates developing fetal immune cell compartments remains underexplored. Using cord blood from neonates with and without congenital HCMV (cCMV) infection, we identify an expansion of Fcγ receptor III (FcγRIII)-expressing CD8+ T cells following HCMV exposure in utero. Most FcγRIII+ CD8+ T cells express the canonical αβ T cell receptor (TCR) but a proportion express non-canonical γδ TCR. FcγRIII+ CD8+ T cells are highly differentiated and have increased expression of NK cell markers and cytolytic molecules. Transcriptional analysis reveals FcγRIII+ CD8+ T cells upregulate T-bet and downregulate BCL11B, known transcription factors that govern T/NK cell fate. We show that FcγRIII+ CD8+ T cells mediate antibody-dependent IFNγ production and degranulation against IgG-opsonized target cells, similar to NK cell antibody-dependent cellular cytotoxicity (ADCC). FcγRIII+ CD8+ T cell Fc effector functions were further enhanced by interleukin-15 (IL-15), as has been observed in neonatal NK cells. Our study reveals that FcγRIII+ CD8+ T cells elicited in utero by HCMV infection can execute Fc-mediated effector functions bridging cellular and humoral immunity and may be a promising target for antibody-based therapeutics and vaccination in early life.
Authors
Eleanor C. Semmes, Danielle R. Nettere, Ashley N. Nelson, Jillian H. Hurst, Derek W. Cain, Trevor D. Burt, Joanne Kurtzberg, R. Keith Reeves, Carolyn B. Coyne, Genevieve G. Fouda, Justin Pollara, Sallie R. Permar, Kyle M. Walsh
Abstract
Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancer, the most common type of breast cancer, is facing challenges such as endocrine therapy resistance and distant relapse. Immunotherapy has shown progress in treating triple-negative breast cancer, but immunological research on HR+/HER2- breast cancer is still in its early stages. Here, we performed a multi-omics analysis of a large cohort of HR+/HER2- breast cancer patients (n = 351) and revealed that HR+/HER2- breast cancer possessed a highly heterogeneous tumor immune microenvironment. Notably, the immunological heterogeneity of HR+/HER2- breast cancer was related to MAP3K1 mutation and we validated experimentally that MAP3K1 mutation could attenuate CD8+ T cell-mediated antitumor immunity. Mechanistically, MAP3K1 mutation suppressed MHC-I-mediated tumor antigen presentation through promoting the degradation of antigen peptide transporter 1/2 (TAP1/2) mRNAs, thereby driving tumor immune escape. In preclinical models, the postbiotics tyramine could reverse the MAP3K1 mutation-induced MHC-I reduction, thereby augmenting the efficacy of immunotherapy. Collectively, our study identified the vital biomarker driving the immunological heterogeneity of HR+/HER2- breast cancer and elucidated the underlying molecular mechanisms, which provided the promise of tyramine as a novel therapeutic strategy to enhance the efficacy of immunotherapy.
Authors
Yuwen Cai, Cui-cui Liu, Yanwu Zhang, Yiming Liu, Lie Chen, Xin Xiong, Zhiming Shao, Ke-Da Yu
Abstract
Background: While most hypertriglyceridemia is asymptomatic, hypertriglyceridemia-associated acute pancreatitis (HTG-AP) can be more severe than other AP etiologies. The reasons underlying this are unclear. We thus studied whether lipolytic generation of non-esterified fatty acids (NEFA) from circulating triglycerides (TGs) could worsen clinical outcomes. Methods: Admission serum TGs, NEFA compositions and concentrations were analyzed prospectively in 269 patients with AP. These and demographics, clinical outcomes were compared between HTGAP (TGs >500mg/dL; American Heart Association 2018 guidelines) and other AP etiologies. Serum NEFAs were correlated with the serum triglyceride fatty acids (TGFAs) alone, and with the product of TGFA x serum lipase (NEFA-TGFA x lipase). Studies in mice, rats were done to understand the role of HTG lipolysis in organ failure and to interpret the NEFA-TGFA correlations. Results: HTG-AP patients had higher serum NEFAs and TGs and more severe AP (19% vs. 7% p<0.03) than other etiologies. Correlations of long-chain unsaturated NEFA with corresponding TGFAs increased with TG concentrations up to 500mg/dL and declined thereafter. However, NEFA-TGFA x lipase correlations got stronger with TGs >500mg/dL. AP, and intravenous lipase infusion in rodents caused lipolysis of circulating TGs to NEFA. This led to multi-system organ failure, which was prevented by pancreatic triglyceride lipase deletion, or lipase inhibition. Conclusions: HTG-AP is made severe by the NEFAs generated form intravascular lipolysis of circulating TGs. Strategies that prevent TG lipolysis may be effective in improving clinical outcomes of HTG-AP. Trial registration: Not applicable. Funding: This project was supported by Grant numbers RO1DK092460, R01DK119646 from the NIDDK, PR191945 under W81XWH-20-1-0400 from the DOD (VPS), and R01AA031257 from the NIAAA (VPS).
Authors
Prasad Rajalingamgari, Biswajit Khatua, Megan J. Summers, Sergiy Kostenko, Yu-Hui H Chang, Mohamed Elmallahy, Arti Anand, Anoop Narayana Pillai, Mahmoud Morsy, Shubham Trivedi, Bryce McFayden, Sarah Jahangir, Christine LH Snozek, Vijay P. Singh
Abstract
Local immunoinflammatory events instruct skeletal stem cells (SSCs) to repair/regenerate bone after injury, but mechanisms are incompletely understood. We hypothesized that specialized Regulatory T (Treg) cells are necessary for bone repair and interact directly with SSCs through organ-specific messages. Both in human patients with bone fracture and mouse model of bone injury, we identified a bone injury-responding Treg subpopulation with bone-repair capacity marked by CCR8. Local production of CCL1 induced a massive migration of CCR8+ Treg cells from periphery to the injury site. Depending on secretion of progranulin (PGRN), a protein encoded by the granulin (Grn) gene, CCR8+ Treg cells supported the accumulation and osteogenic differentiation of SSCs, and thereby bone repair. Mechanistically, we revealed that CCL1 enhanced expression level of basic leucine zipper ATF-like transcription factor (BATF) in CCR8+ Treg cells, which bound to Grn promoter and increased Grn translational output and then PGRN secretion. Together, our work provides a new perspective in osteoimmunology and highlights possible ways of manipulating Treg cell signaling to enhance bone repair and regeneration.
Authors
Ruiying Chen, Xiaomeng Zhang, Bin Li, Maurizio S. Tonetti, Yijie Yang, Yuan Li, Beilei Liu, Shujiao Qian, Yingxin Gu, Qingwen Wang, Kairui Mao, Hao Cheng, Hongchang Lai, Junyu Shi
Abstract
Background Considering trophoblast cell surface antigen 2 (Trop2) is overexpressed in a wide range of human epithelial cancers, it presents an attractive target for the diagnosis and treatment of multiple types of cancer. Herein, we have developed a Trop2-specific radiotracer, 68Ga-MY6349, and present a prospective, investigator-initiated trial to explore the clinical values of 68Ga-MY6349 PET/CT. Methods In this translational study, 90 patients with 15 types of cancer, who underwent 68Ga-MY6349 PET/CT, were enrolled prospectively. Among them, 78 patients underwent paired 68Ga-MY6349 and 18F-FDG PET/CT, and 12 patients with prostate cancer underwent paired 68Ga-MY6349 and 68Ga-PSMA-11 PET/CT. Results Among the 90 patients across 15 types of cancer, 68Ga-MY6349 uptake in tumors was generally high but heterogeneous, varying among lesions, patients, and cancer types. Trop2 expression level determined by immunohistochemistry was highly correlated with 68Ga-MY6349 uptake at primary and metastatic tumor sites. 68Ga-MY6349 PET/CT showed higher tumor uptake (quantified by SUVmax) than 18F-FDG PET/CT in certain types of cancer, including breast (7.2 vs. 5.4, P < 0.001), prostate (9.2 vs. 3.0, P < 0.001), and thyroid cancers (8.5 vs. 3.7, P < 0.001). When compared with 68Ga-PSMA-11, 68Ga-MY6349 PET/CT exhibited comparable lesion uptake (12.2 vs. 12.5, P = 0.223) but a better tumor-to-background contrast (15.8 vs. 12.2, P < 0.001) for primary and metastatic prostate cancer, allowing visualization of more metastatic lesions. Conclusion 68Ga-MY6349 PET/CT is a non-invasive method for comprehensively assessing Trop2 expression in tumors, which can improve the diagnosis and staging for cancer patients, and aid in the decision-making for Trop2-targeted therapies and advancing personalized treatment.
Authors
Haojun Chen, Liang Zhao, Yizhen Pang, Jiyun Shi, Hannan Gao, Yining Sun, Jianhao Chen, Hao Fu, Jiayu Cai, Lingyu Yu, Ru Zeng, Long Sun, Hua Wu, Zhanxiang Wang, Fan Wang
Abstract
Cancer patients undergoing chemotherapy often experience anorexia and weight loss that substantially deteriorates overall health, reduces treatment tolerance and quality of life, and worsens oncologic outcomes. There are currently few effective therapeutic options to mitigate these side effects. The central melanocortin system, which plays a pivotal role in regulating appetite and energy homeostasis, presents a logical target for treating anorexia and weight loss. In this preclinical study, we evaluated the efficacy of TCMCB07, a synthetic antagonist of the melanocortin-4 receptor, in mitigating anorexia and weight loss in several rat models of chemotherapy: cisplatin, 5-fluorouracil, cyclophosphamide, vincristine, doxorubicin, and a combination of irinotecan and 5-fluorouracil. Our results indicate that peripheral administration of TCMCB07 improved appetite, stabilized body weight, preserved fat and heart mass, and slightly protected lean mass after multiple cycles of chemotherapy. Furthermore, combining TCMCB07 with a growth differentiation factor 15 antibody enhanced treatment effectiveness. Similar effects from TCMCB07 treatment were observed in a rat tumor model following combination chemotherapy. No notable adverse effects nor increased chemotherapy-related toxicities were observed with TCMCB07 treatment. These findings suggest that peripheral administration of TCMCB07 holds promise as a therapeutic approach for alleviating chemotherapy-induced anorexia and weight loss, potentially benefiting numerous patients undergoing chemotherapy.
Authors
Xinxia Zhu, Russell Potterfield, Kenneth A. Gruber, Emma Zhang, Samuel D. Newton, Mason A. Norgard, Peter R Levasseur, Peng Bai, Xu Chen, Qingyang Gu, Aaron J. Grossberg, Daniel L. Marks
Abstract
Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions with tumor-MSC co-cultures and used an integrated transcriptome-proteome-network-analyses workflow to identify a comprehensive catalog of contact-induced changes. Conditioned media from MSCs failed to recapitulate genes and proteins, some borrowed and others tumor-intrinsic, induced in cancer cells by direct contact. Protein-protein interaction networks revealed the rich connectome between ‘borrowed’ and ‘intrinsic’ components. Bioinformatics prioritized one of the ‘borrowed’ components, CCDC88A/GIV, a multi-modular metastasis-related protein that has recently been implicated in driving a hallmark of cancer, growth signaling autonomy. MSCs transferred GIV protein to ER+ breast cancer cells (that lack GIV) through tunnelling nanotubes via connexin (Cx)43-facilitated intercellular transport. Reinstating GIV alone in GIV-negative breast cancer cells reproduced approximately 20% of both the ‘borrowed’ and the ‘intrinsic’ gene induction patterns from contact co-cultures; conferred resistance to anti-estrogen drugs; and enhanced tumor dissemination. Findings provide a multiomic insight into MSC→tumor cell intercellular transport and validate how transport of one such candidate, GIV, from the haves (MSCs) to have-nots (ER+ breast cancer) orchestrates aggressive disease states.
Authors
Saptarshi Sinha, Brennan W. Callow, Alex P. Farfel, Suchismita Roy, Siyi Chen, Maria Masotti, Shrila Rajendran, Johanna M. Buschhaus, Celia R. Espinoza, Kathryn E. Luker, Pradipta Ghosh, Gary D. Luker
TMED4 facilitates Treg suppressive function via ROS homeostasis in tumor and autoimmune mouse models
Abstract
Endoplasmic reticulum stress (ERS) plays crucial roles in maintaining regulatory T cells (Treg) stability and function, yet the underlying mechanism remains largely unexplored. Here we demonstrate that ERS-related protein transmembrane p24 trafficking protein 4 (TMED4) Treg-specific knockout (Tmed4ΔTreg) mice contain more Treg cells with impaired Foxp3 stability, Treg signature and suppressive activity, which leads to T cell hyperactivation, exacerbated inflammatory phenotype and boosted anti-tumor immunity in mice. Mechanistically, loss of Tmed4 causes defects in ERS and nuclear factor erythroid 2–related factor 2 (NRF2)-related antioxidant response, which results in excessive reactive oxygen species (ROS) that reduces Foxp3 stability and suppressive function of Treg cells in an IRE1α-XBP1 axis-dependent manner. The abnormalities can be effectively rescued by ROS scavenger, NRF2 inducer or forcible expression of IRE1α. Moreover, TMED4 suppresses IRE1α proteosome degradation via the ER-associated degradation (ERAD) system including BIP. Our study reveals that TMED4 maintains Treg cell stability and suppressive function through IRE1α-dependent ROS and the NRF2-related antioxidant response.
Authors
Zhenyan Jiang, Huizi Wang, Xiaoxia Wang, Hongrui Duo, Yuexiao Tao, Jia Li, Xin Li, Jiamin Liu, Jun Ni, Emily Jiatong Wu, Hongrui Xiang, Chenyang Guan, Xinyu Wang, Kun Zhang, Peng Zhang, Zhaoyuan Hou, Yong Liu, Zhengting Wang, Bing Su, Bo Li, Youjin Hao, Bin Li, Xuefeng Wu
Abstract
Authors
Andrés R. Muñoz-Rojas, Adam C. Wang, Lisa E. Pomeranz, Elizabeth L. Reizis, Heather W. Stout-Delgado, Ileana C. Miranda, Krishnan Rajagopalan, Tadiwanashe Gwatiringa, Roger R. Fan, Ahmad A. Huda, Neha Maskey, Roseline P. Olumuyide, Aryan S. Patel, Jeffrey M. Friedman, Diane Mathis, Kartik N. Rajagopalan
Abstract
Myocardial infarction (MI) is characterized by massive cardiomyocytes death and cardiac dysfunction, and effective therapies to achieve cardioprotection are sorely needed. Here we reported that flavin containing monooxygenase 2 (FMO2) level was markedly increased in cardiomyocytes both in ex vivo and in vivo models of ischemia injury. Genetic deletion of FMO2 resulted in reduced cardiomyocyte survival and enhanced cardiac dysfunction, whereas cardiomyocyte-specific FMO2 overexpression exerted a protective effect in infarcted rat hearts. Mechanistically, FMO2 inhibited the activation of endoplasmic reticulum (ER) stress-induced apoptotic proteins, including caspase 12 and C/EBP homologous protein (CHOP), by down-regulating unfolded protein response (UPR) pathway. Furthermore, we identified FMO2 as a chaperone that catalyzed disulfide-bond formation in unfolded/misfolded proteins through its GVSG motif. GVSG-mutated FMO2 failed to catalyze disulfide-bond formation and lost its protection against ER stress and cardiomyocyte death. Finally, we demonstrated the protective effect of FMO2 in human induced pluripotent stem cell–derived cardiomyocyte (hiPSC-CM) model. Collectively, this study highlights FMO2 as a key modulator of oxidative protein folding in cardiomyocytes and underscores its therapeutic potential for treating ischemic heart disease.
Authors
Qingnian Liu, Jiniu Huang, Hao Ding, Yue Tao, Jinliang Nan, Changchen Xiao, Yingchao Wang, Rongrong Wu, Cheng Ni, Zhiwei Zhong, Wei Zhu, Jinghai Chen, Chenyun Zhang, Xiao He, Danyang Xiong, Xinyang Hu, Jian'an Wang
Abstract
BACKGROUND. Despite an overall poor prognosis, about 15% of patients with advanced-stage tubo-ovarian high-grade serous carcinoma (HGSC) survive ten or more years after standard treatment. METHODS. We evaluated the tumor microenvironment of this exceptional, understudied group using a large international cohort enriched for long-term survivors (LTS; 10+ years; n = 374) compared to medium-term (MTS; 5–7.99 years; n = 433) and short-term survivors (STS; 2–4.99 years; n = 416). Primary tumor samples were immunostained and scored for intra-epithelial and intra-stromal densities of 10 immune-cell subsets (including T cells, B cells, plasma cells, myeloid cells, PD-1+ cells, and PD-L1+ cells) and epithelial content. RESULTS. Positive associations with LTS compared to STS were seen for 9/10 immune-cell subsets. In particular, the combination of intra-epithelial CD8+ T cells and intra-stromal B cells showed near five-fold increased odds of LTS compared to STS. All of these associations were stronger in tumors with high epithelial content and/or the C4/Differentiated molecular subtype, despite immune-cell densities generally being higher in tumors with low epithelial content and/or the C2/Immunoreactive molecular subtype. CONCLUSIONS. The tumor microenvironment of HGSC long-term survivors is distinguished by the intersection of T and B cell co-infiltration, high epithelial content and C4/Differentiated molecular subtype, features which may inspire new approaches to immunotherapy. FUNDING. Ovarian Cancer Research Program (OCRP) of the Congressionally Directed Medical Research Program (CDMRP), U.S. Department of Defense (DOD); American Cancer Society; BC Cancer Foundation; Canada's Networks of Centres of Excellence; Canadian Cancer Society; Canadian Institutes of Health Research; Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania, Cancer Foundation of Western Australia; Cancer Institute NSW; Cancer Research UK; Deutsche Forschungsgesellschaft; ELAN Funds of the University of Erlangen-Nuremberg; Fred C. and Katherine B. Andersen Foundation; Genome BC; German Cancer Research Center; German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research; Instituto de Salud Carlos III; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Ministerio de Economía y Competitividad; MRC; National Center for Advancing Translational Sciences; National Health and Medical Research Council of Australia (NHMRC); Ovarian Cancer Australia; Peter MacCallum Foundation; Sydney West Translational Cancer Research Centre; Terry Fox Research Institute; The Eve Appeal (The Oak Foundation); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; University of Pittsburgh School of Medicine; U.S. National Cancer Institute of the National Institutes of Health; VGH & UBC Hospital Foundation; Victorian Cancer Agency.
Authors
Brad H. Nelson, Phineas T. Hamilton, Minh Tung Phung, Katy Milne, Bronwyn Harris, Shelby Thornton, Donald L.I. Stevens, Shreena Kalaria, Karanvir Singh, Céline M. Laumont, Elena Moss, Aliya Alimujiang, Nicola S. Meagher, Adelyn Bolithon, Sian Fereday, Catherine J. Kennedy, Joy Hendley, Dinuka Ariyaratne, Kathryn Alsop, Nadia Traficante, Ellen L. Goode, Anthony N. Karnezis, Hui Shen, Jean Richardson, Cindy McKinnon Deurloo, Anne Chase, Bronwyn Grout, Jennifer A. Doherty, Holly R. Harris, Kara L. Cushing-Haugen, Michael S. Anglesio, Karolin Heinze, David Huntsman, Aline Talhouk, Gillian E. Hanley, Jennifer Alsop, Mercedes Jimenez-Linan, Paul D.P. Pharoah, Jessica Boros, Alison H. Brand, Paul R. Harnett, Raghwa Sharma, Jonathan L. Hecht, Naoko Sasamoto, Kathryn L. Terry, Beth Y. Karlan, Jenny Lester, Michael E. Carney, Marc T. Goodman, Brenda Y. Hernandez, Lynne R. Wilkens, Sabine Behrens, Renée Turzanski Fortner, Peter A. Fasching, Christiani Bisinotto, Francisco José Candido dos Reis, Prafull Ghatage, Martin Köbel, Esther Elishaev, Francesmary Modugno, Linda S. Cook, Nhu D. Le, Aleksandra Gentry-Maharaj, Usha Menon, María J. García, Cristina Rodriguez-Antona, Kyo M. Farrington, Linda E. Kelemen, Stefan Kommoss, Annette Staebler, Dale W. Garsed, James D. Brenton, Anna M. Piskorz, David D.L. Bowtell, Anna DeFazio, Susan J. Ramus, Malcolm C. Pike, Celeste Leigh Pearce
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ISSN: 0021-9738 (print), 1558-8238 (online)