Therapeutics
Abstract
Regulatory T (Treg) cells modulate immune responses and attenuate inflammation. Extracellular vesicles from human cardiosphere-derived cells (CDC-EVs) enhance Treg proliferation and IL10 production, but the mechanisms remain unclear. Here we focus on BCYRN1, a long noncoding RNA (lncRNA) highly abundant in CDC-EVs, and its role in Treg cell function. BCYRN1 acts as a "microRNA sponge," inhibiting miR-138, miR-150, and miR-98. Suppression of these miRs leads to increased Treg cell proliferation via ATG7-dependent autophagy, CCR6-dependent Treg migration, and enhanced Treg IL10 production. In a mouse model of myocardial infarction, CDC-EVs, particularly those overexpressing BCYRN1, were cardioprotective, reducing infarct size and troponin I levels even when administered after reperfusion. Underlying the cardioprotection, we verified that CDC-EVs overexpressing BCYRN1 increased cardiac Treg infiltration, proliferation, and IL10 production in vivo. These salutary effects were negated when BCYRN1 levels were reduced in CDC-EVs, or when Tregs were depleted systemically. Thus, we have identified BCYRN1 as a booster of Treg number and bioactivity, rationalizing its cardioprotective efficacy. While here we studied BCYRN1 overexpression in the context of ischemic injury, the same approach merits testing in other disease processes (e.g., autoimmunity or transplant rejection) where increased Treg activity is a recognized therapeutic goal.
Authors
Ke Liao, Jiayi Yu, Akbarshakh Akhmerov, Zahra Mohammadigoldar, Liang Li, Weixin Liu, Natasha Anders, Ahmed G.E. Ibrahim, Eduardo Marbán
Abstract
Despite advances in the development of direct KRAS inhibitors, KRAS-mutant cancers continue to exhibit resistance to the currently available therapies. Here, we identified REGγ as a mutant KRAS–associated factor that enhanced REGγ transcription through the KRAS intermediate NRF2, suggesting that the REGγ-proteasome is a potential target for pan-KRAS inhibitor development. We elucidated a mechanism involving the KRAS/NRF2/REGγ regulatory axis, which links activated KRAS to the ATP- and ubiquitin-independent proteasome. We subsequently developed RLY01, a REGγ-proteasome inhibitor that effectively suppressed tumor growth in KRAS-mutant cancer models and lung cancer organoids. Notably, the combination of RLY01 and the KRASG12C inhibitor AMG510 exhibited enhanced antitumor efficacy in KRASG12C cancer cells. Collectively, our data support the hypothesis that KRAS mutations enhance the capacity of the REGγ-proteasome by increasing REGγ expression, highlighting the potential of ubiquitin-independent proteasome inhibition as a therapeutic approach for pan-KRAS–mutant cancers.
Authors
Shihui Shen, Qiansen Zhang, Yuhan Wang, Hui Chen, Shuangming Gong, Yun Liu, Conghao Gai, Hansen Chen, Enhao Zhu, Bo Yang, Lin Liu, Siyuan Cao, Mengting Zhao, Wenjie Ren, Mengjuan Li, Zhuoya Peng, Lu Zhang, Shaoying Zhang, Juwen Shen, Bianhong Zhang, Patrick K.H. Lee, Kun Li, Lei Li, Huaiyu Yang
Abstract
Adipose tissue lipolysis is the process by which triglycerides in lipid stores are hydrolyzed into free fatty acids (FFAs), serving as fuel during fasting or cold-induced thermogenesis. Although cytosolic lipases are considered the predominant mechanism of liberating FFAs, lipolysis also occurs in lysosomes via lysosomal acid lipase (LIPA), albeit with unclear roles in lipid storage and whole-body metabolism. We found that adipocyte LIPA expression increased in adipose tissue of mice when lipolysis was stimulated during fasting, cold exposure, or β-adrenergic agonism. This was functionally important, as inhibition of LIPA genetically or pharmacologically resulted in lower plasma FFAs under lipolytic conditions. Furthermore, adipocyte LIPA deficiency impaired thermogenesis and oxygen consumption and rendered mice susceptible to diet-induced obesity. Importantly, lysosomal lipolysis was independent of adipose triglyceride lipase, the rate-limiting enzyme of cytosolic lipolysis. Our data suggest a significant role for LIPA and lysosomal lipolysis in adipocyte lipid metabolism beyond classical cytosolic lipolysis.
Authors
Yu-Sheng Yeh, Trent D. Evans, Mari Iwase, Se-Jin Jeong, Xiangyu Zhang, Ziyang Liu, Arick Park, Ali Ghasemian, Borna Dianati, Ali Javaheri, Dagmar Kratky, Satoko Kawarasaki, Tsuyoshi Goto, Hanrui Zhang, Partha Dutta, Francisco J. Schopfer, Adam C. Straub, Jaehyung Cho, Irfan J. Lodhi, Babak Razani
Abstract
Biological targeting is crucial for effective cancer treatment with reduced toxicity but is limited by the availability of tumor surface markers. To overcome this, we developed a nanoparticle-based, Tumor-specific suRfACE maRker-independent (TRACER) targeting approach. Utilizing the unique biodistribution properties of nanoparticles, we encapsulated Ac4ManNAz to selectively label tumors with azide reactive groups. Surprisingly, while NP-delivered Ac4ManNAz was cleared by the liver, it did not label macrophages, potentially reducing off-target effects. To exploit this tumor-specific labeling, we functionalized anti-4-1BB antibodies with dibenzocyclooctyne (DBCO) to target azide-labeled tumor cells and activate the immune response. In syngeneic B16F10 melanoma and orthotopic 4T1 breast cancer models, TRACER enhanced anti-4-1BB’s therapeutic efficacy, increasing median survival time. Immunofluorescence analyses revealed increased tumor infiltration of CD8+ T and NK cells with TRACER. Importantly, TRACER reduced hepatotoxicity associated with anti-4-1BB, resulting in normal serum ALT and AST levels and decreased CD8+ T cell infiltration in the liver. Quantitative analysis confirmed a 4.5-fold higher tumor-to-liver ratio of anti-4-1BB accumulation with TRACER compared to conventional anti-4-1BB antibodies. Our work provides a promising approach for developing targeted cancer therapies that circumvent limitations imposed by the paucity of tumor-specific markers, potentially improving efficacy and reducing off-target effects to overcome liver toxicity associated with anti-4-1BB.
Authors
Hyesun Hyun, Bo Sun, Mostafa Yazdimamaghani, Albert Wielgus, Yue Wang, Stephanie Ann Montgomery, Tian Zhang, Jianjun Cheng, Jonathan S. Serody, Andrew Z. Wang
Abstract
Translocations involving FGFR2 gene fusions are common in cholangiocarcinoma and predict response to FGFR kinase inhibitors. However, response rates and durability are limited due to the emergence of resistance, typically involving FGFR2 kinase domain mutations, and to sub-optimal dosing, relating to drug adverse effects. Here, we develop biparatopic antibodies targeting the FGFR2 extracellular domain (ECD), as candidate therapeutics. Biparatopic antibodies can overcome drawbacks of bivalent monospecific antibodies, which often show poor inhibitory or even agonist activity against oncogenic receptors. We show that oncogenic transformation by FGFR2 fusions requires an intact ECD. Moreover, by systematically generating biparatopic antibodies targeting distinct epitope pairs in FGFR2 ECD, we identified antibodies that effectively block signaling and malignant growth driven by FGFR2-fusions. Importantly, these antibodies demonstrate efficacy in vivo, synergy with FGFR inhibitors, and activity against FGFR2 fusions harboring kinase domain mutations. Thus, biparatopic antibodies may serve as an innovative treatment option for patients with FGFR2-altered cholangiocarcinoma.
Authors
Saireudee Chaturantabut, Sydney Oliver, Dennie T. Frederick, Jiwan J. Kim, Foxy P. Robinson, Alessandro Sinopoli, Tian-Yu Song, Yao He, Yuan-Chen Chang, Diego J. Rodriguez, Liang Chang, Devishi Kesar, Meilani Ching, Ruvimbo Dzvurumi, Adel Atari, Yuen-Yi Tseng, Nabeel Bardeesy, William R. Sellers
Abstract
Tumor cells often employ many ways to restrain type I interferon signaling to evade immune surveillance. However, whether cellular amino acid metabolism regulate this process remains unclear and its effects on antitumor immunity are relatively unexplored. Here, we find that asparagine inhibits IFN-I signaling and promotes immune escape in bladder cancer. Depletion of asparagine synthetase (ASNS) strongly limits in vivo tumor growth in a CD8+ T cell-dependent manner and boosts immunotherapy efficacy. Moreover, clinically approved ASNase synergizes with anti-PD-1 therapy in suppressing tumor growth. Mechanistically, asparagine can directly bind to RIG-I and facilitate CBL-mediated RIG-I degradation, thereby suppressing IFN signaling and antitumor immune responses. Clinically, tumors with higher ASNS expression show decreased responsiveness to ICIs therapy. Together, our findings uncover asparagine as a natural metabolite to modulate RIG-I-mediated IFN-I signaling, providing the basis for developing the combinatorial use of ASNase and anti-PD-1 for bladder cancer.
Authors
Wenjie Wei, Hongzhao Li, Shuo Tian, Chi Zhang, Junxiao Liu, Wen Tao, Tianwei Cai, Yuhao Dong, Chuang Wang, Dingyi Lu, Yakun Ai, Wanlin Zhang, Hanfeng Wang, Kan Liu, Yang Fan, Yu Gao, Qingbo Huang, Xin Ma, Baojun Wang, Xu Zhang, Yan Huang
Abstract
Neuroretinal degenerations including retinitis pigmentosa (RP) comprise a heterogeneous collection of pathogenic mutations that ultimately result in blindness. Despite recent advances in precision medicine, therapies for rarer mutations are hindered by burdensome developmental costs. To this end, Von Hippel-Lindau (VHL) is an attractive therapeutic target to treat RP. By ablating VHL in rod photoreceptors and elevating hypoxia-inducible factor (HIF) levels, we demonstrate a path to therapeutically enhancing glycolysis independent of the underlying genetic variant that slows degeneration of both rod and cone photoreceptors in a preclinical model of retinitis pigmentosa. This rod-specific intervention also resulted in reciprocal, decreased glycolytic activity within the retinal pigment epithelium (RPE) cells despite no direct genetic modifications to the RPE. Suppressing glycolysis in the RPE provided notable, non-cell-autonomous therapeutic benefits to the photoreceptors, indicative of metabolically sensitive crosstalk between different cellular compartments of the retina. Surprisingly, targeting HIF2A in RPE cells did not impact RPE glycolysis, potentially implicating HIF1A as a major regulator in mouse RPE and providing a rationale for future therapeutic efforts aimed at modulating RPE metabolism.
Authors
Salvatore Marco Caruso, Xuan Cui, Brian M. Robbings, Noah Heaps, Aykut Demikrol, Bruna Lopes da Costa, Daniel T. Hass, Peter M.J. Quinn, Jianhai Du, James B. Hurley, Stephen H. Tsang
Abstract
Myotonic Dystrophy Type 1 (DM1) is an autosomal dominant disease caused by a CTG repeat expansion in the DMPK gene. The expanded CUG repeat RNA (CUGexp RNA) transcribed from the mutant allele sequesters the muscleblind-like (MBNL) family of RNA-binding proteins, causing their loss of function and disrupting regulated pre-mRNA processing. We used a DM1 heart mouse model that inducibly expresses CUGexp RNA to test the contribution of MBNL loss to DM1 cardiac abnormalities and explore MBNL restoration as a potential therapy. AAV9-mediated overexpression of MBNL1 and/or MBNL2 significantly rescued DM1 cardiac phenotypes including conduction delays, contractile dysfunction, hypertrophy, and mis-regulated alternative splicing and gene expression. While robust, rescue was partial compared to reduced CUGexp RNA and plateaued with increased exogenous MBNL expression. These findings demonstrate that MBNL loss is a major contributor to DM1 cardiac manifestations, and suggest that additional mechanisms play a role, highlighting the complex nature of DM1 pathogenesis.
Authors
Rong-Chi Hu, Yi Zhang, Larissa Nitschke, Sara J. Johnson, Ayrea E. Hurley, William R. Lagor, Zheng Xia, Thomas A. Cooper
Abstract
Fibrosis is the final common pathway leading to end stage chronic kidney disease (CKD). However, the function of protein palmitoylation in renal fibrosis and underlying mechanisms remain unclear. In this study, we observed that the expression of the palmitoyltransferase ZDHHC18 was significantly elevated in unilateral ureteral obstruction (UUO) and folic acid (FA)-induced renal fibrosis mouse models, and was significantly upregulated in the fibrotic kidneys of chronic kidney disease patients. Functionally, tubule-specific deletion of ZDHHC18 attenuated tubular epithelial cells partial epithelial-to-mesenchymal transition (EMT), then reduced production of profibrotic cytokine and alleviates tubulointerstitial fibrosis. In contrast, ZDHHC18 overexpression exacerbated progressive renal fibrosis. Mechanistically, ZDHHC18 catalyzed the palmitoylation of HRAS, which is pivotal for its translocation to the plasma membrane and subsequent activation. HRAS palmitoylation promoted downstream phosphorylation of MEK/ERK and further activated RREB1, enhancing SMAD binding to the Snai1 cis-regulatory regions. Taken together, our findings suggest that ZDHHC18 plays a crucial role in renal fibrogenesis and presents a potential therapeutic target for combating kidney fibrosis.
Authors
Di Lu, Gulibositan Aji, Guanyu Li, yue li, Wenlin Fang, Shuai Zhang, ruiqi yu, Sheng Jiang, xia gao, Yuhang Jiang, Qi Wang
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Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)