Kayla Barekat,Soumita Ghosh,Christin Herrmann,Karl Keat,Charles-Antoine Assenmacher,Ceylan Tanes,Naomi Wilson,Ronan Lordan,Antonijo Mrčela,Lubica Rauova,Arjun Sengupta,Ujjalkumar Subhash Das,Robin Joshi,Elliot Friedman,Marylyn D Ritchie,Kyle Bittinger,Aalim Weljie,Ken Cadwell,Frederic D Bushman,Gary D Wu,Garret A FitzGerald,Emanuela Ricciotti
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used medications for the management of chronic pain; however, they are associated with numerous gastrointestinal (GI) adverse events. Although many mechanisms have been suggested, NSAID-induced enteropathy has been thought to be primarily due to inhibition of both cyclooxygenases (COX) -1 and -2, which results in suppression of prostaglandin synthesis. Yet surprisingly, we found that concomitant postnatal deletion of Cox-1 and -2 over 10 months failed to cause intestinal injury in mice unless they were treated with naproxen or its structural analog, phenylpropionic acid, which is not a COX inhibitor. Cox double knockout mice exhibit a distinct gut microbiome composition and cohousing them with controls rescues their dysbiosis and delays the onset of NSAID-induced GI bleeding. In both the UK Biobank and All of Us human cohorts, coadministration of antibiotics with NSAIDs is associated with an increased frequency of GI bleeding. These results show that prostaglandin suppression plays a trivial role in NSAID-induced enteropathy. However, Cox deletion causes dysbiosis of the gut microbiome that amplifies the enteropathic response to NSAIDs.
非甾体抗炎药（NSAIDs）是治疗慢性疼痛最广泛使用的药物；然而，它们与许多胃肠道（GI）不良事件有关。虽然有许多机制被提出，但nsaid诱导的肠病一直被认为主要是由于环氧化酶(COX) -1和-2的抑制，从而导致前列腺素合成的抑制。然而，令人惊讶的是，我们发现，出生后10个月内COX -1和-2的缺失不会引起小鼠肠道损伤，除非给它们服用萘普生或其结构类似物苯丙酸，而苯丙酸不是COX抑制剂。Cox双基因敲除小鼠表现出独特的肠道微生物组成，将它们与对照组放在一起可以挽救它们的生态失调，并延缓非甾体抗炎药诱导的胃肠道出血的发生。在UK Biobank和All of Us人类队列中，抗生素与非甾体抗炎药的联合使用与胃肠道出血的频率增加有关。这些结果表明前列腺素抑制在非甾体抗炎药诱导的肠病中起着微不足道的作用。然而，Cox缺失导致肠道微生物群失调，放大了对非甾体抗炎药的肠病反应。
{"title":"Concomitant COX-1 and COX-2 suppression is not sufficient to induce enteropathy associated with chronic NSAID use.","authors":"Kayla Barekat,Soumita Ghosh,Christin Herrmann,Karl Keat,Charles-Antoine Assenmacher,Ceylan Tanes,Naomi Wilson,Ronan Lordan,Antonijo Mrčela,Lubica Rauova,Arjun Sengupta,Ujjalkumar Subhash Das,Robin Joshi,Elliot Friedman,Marylyn D Ritchie,Kyle Bittinger,Aalim Weljie,Ken Cadwell,Frederic D Bushman,Gary D Wu,Garret A FitzGerald,Emanuela Ricciotti","doi":"10.1172/jci190575","DOIUrl":"https://doi.org/10.1172/jci190575","url":null,"abstract":"Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used medications for the management of chronic pain; however, they are associated with numerous gastrointestinal (GI) adverse events. Although many mechanisms have been suggested, NSAID-induced enteropathy has been thought to be primarily due to inhibition of both cyclooxygenases (COX) -1 and -2, which results in suppression of prostaglandin synthesis. Yet surprisingly, we found that concomitant postnatal deletion of Cox-1 and -2 over 10 months failed to cause intestinal injury in mice unless they were treated with naproxen or its structural analog, phenylpropionic acid, which is not a COX inhibitor. Cox double knockout mice exhibit a distinct gut microbiome composition and cohousing them with controls rescues their dysbiosis and delays the onset of NSAID-induced GI bleeding. In both the UK Biobank and All of Us human cohorts, coadministration of antibiotics with NSAIDs is associated with an increased frequency of GI bleeding. These results show that prostaglandin suppression plays a trivial role in NSAID-induced enteropathy. However, Cox deletion causes dysbiosis of the gut microbiome that amplifies the enteropathic response to NSAIDs.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Atopic dermatitis (AD) is a chronic inflammatory skin condition characterized by a type 2 immune response that is not fully understood. Single-cell RNA sequencing (scRNA-seq) of human AD skin and murine models of type 2 inflammation identified transcriptionally distinct fibroblast clusters, revealing unique, IL-4Rɑ-dependent populations of immune-acting fibroblasts. These unbiased findings prompted further investigation into the role of dermal fibroblasts during allergic inflammation. These studies demonstrated that, in an inflammatory environment including TNFɑ, IL-1β and IL-17A, IL-4 and IL-13 stimulate both mouse and human fibroblasts to produce multiple chemokines, including Ccl8, which activates Ccr3 to attract T-cells. In the skin, fibroblasts are the primary source of many of these chemokines, and targeted deletion of IL--4rɑ in mouse fibroblasts reduces T-cell infiltration in a mouse model of AD. Additionally, pharmacologic inhibition of Ccr3, the receptor shared by many chemokines produced by fibroblasts, decreases T-cell infiltration and skin inflammation in AD mouse models. These findings demonstrate that dermal fibroblasts are more than passive structural cells; they actively participate in the type 2 immune response and contribute to AD by producing chemokines that increase inflammation. Targeting the functions of immune-acting fibroblasts could offer an alternative therapeutic approach for AD.
{"title":"Dermal fibroblasts respond to interleukin-4 and 13 and promote T-cell recruitment in atopic dermatitis.","authors":"Tomofumi Numata,Michael Shia,Yoshiyuki Nakamura,Fengwu Li,Hung Chan,Teruaki Nakatsuji,Kellen J Cavagnero,Jared Simmons,Henry Li,Aaroh Anand Joshi,Marta Palomo-Irigoyen,Richard L Gallo","doi":"10.1172/jci196108","DOIUrl":"https://doi.org/10.1172/jci196108","url":null,"abstract":"Atopic dermatitis (AD) is a chronic inflammatory skin condition characterized by a type 2 immune response that is not fully understood. Single-cell RNA sequencing (scRNA-seq) of human AD skin and murine models of type 2 inflammation identified transcriptionally distinct fibroblast clusters, revealing unique, IL-4Rɑ-dependent populations of immune-acting fibroblasts. These unbiased findings prompted further investigation into the role of dermal fibroblasts during allergic inflammation. These studies demonstrated that, in an inflammatory environment including TNFɑ, IL-1β and IL-17A, IL-4 and IL-13 stimulate both mouse and human fibroblasts to produce multiple chemokines, including Ccl8, which activates Ccr3 to attract T-cells. In the skin, fibroblasts are the primary source of many of these chemokines, and targeted deletion of IL--4rɑ in mouse fibroblasts reduces T-cell infiltration in a mouse model of AD. Additionally, pharmacologic inhibition of Ccr3, the receptor shared by many chemokines produced by fibroblasts, decreases T-cell infiltration and skin inflammation in AD mouse models. These findings demonstrate that dermal fibroblasts are more than passive structural cells; they actively participate in the type 2 immune response and contribute to AD by producing chemokines that increase inflammation. Targeting the functions of immune-acting fibroblasts could offer an alternative therapeutic approach for AD.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"341 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146021294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Parasvi S Patel,Jacob P Matson,Xiaojuan Ran,Marcello Stanzione,Ajinkya S Kawale,Mingchao Wang,Sneha Saxena,Conrad Sander,Jacquelyn Curtis,Jessica L Hopkins,Edmond Wong,Ryan B Corcoran,Daniel A Haber,Nicholas J Dyson,Shyamala Maheswaran,Lee Zou
Transitions of cancer cells between distinct cell states, which are typically driven by transcription reprogramming, fuel tumor plasticity, metastasis, and therapeutic resistance. Whether the transitions between cell states can be therapeutically targeted remains unknown. Here, using the epithelial-to-mesenchymal transition (EMT) as a model, we show that the transcription reprogramming during a cell-state transition induces genomic instability through R-loops and transcription-replication conflicts, and the cell-state transition cannot occur without the ATR kinase, a key regulator of the replication stress response. ATR inhibition during EMT not only increases transcription- and replication-dependent genomic instability but also disrupts transcription reprogramming. Unexpectedly, ATR inhibition elevates R-loop-associated DNA damage at the SNAI1 gene, a key driver of the transcription reprogramming during EMT, triggering ATM- and Polycomb-mediated transcription repression of SNAI1. Beyond SNAI1, ATR also suppresses R-loops and antagonizes repressive chromatin at a subset of EMT genes. Importantly, inhibition of ATR in tumors undergoing EMT reduces tumor growth and metastasis, suggesting that ATR inhibition eliminates cancer cells in transition. Thus, during EMT, ATR not only protects genome integrity but also enables transcription reprogramming, revealing that ATR is a safeguard of cell-state transitions and a target to suppress tumor plasticity.
{"title":"ATR Safeguards Epithelial-to-Mesenchymal Transition by Countering R-loops and Enabling Transcription Reprogramming.","authors":"Parasvi S Patel,Jacob P Matson,Xiaojuan Ran,Marcello Stanzione,Ajinkya S Kawale,Mingchao Wang,Sneha Saxena,Conrad Sander,Jacquelyn Curtis,Jessica L Hopkins,Edmond Wong,Ryan B Corcoran,Daniel A Haber,Nicholas J Dyson,Shyamala Maheswaran,Lee Zou","doi":"10.1172/jci192225","DOIUrl":"https://doi.org/10.1172/jci192225","url":null,"abstract":"Transitions of cancer cells between distinct cell states, which are typically driven by transcription reprogramming, fuel tumor plasticity, metastasis, and therapeutic resistance. Whether the transitions between cell states can be therapeutically targeted remains unknown. Here, using the epithelial-to-mesenchymal transition (EMT) as a model, we show that the transcription reprogramming during a cell-state transition induces genomic instability through R-loops and transcription-replication conflicts, and the cell-state transition cannot occur without the ATR kinase, a key regulator of the replication stress response. ATR inhibition during EMT not only increases transcription- and replication-dependent genomic instability but also disrupts transcription reprogramming. Unexpectedly, ATR inhibition elevates R-loop-associated DNA damage at the SNAI1 gene, a key driver of the transcription reprogramming during EMT, triggering ATM- and Polycomb-mediated transcription repression of SNAI1. Beyond SNAI1, ATR also suppresses R-loops and antagonizes repressive chromatin at a subset of EMT genes. Importantly, inhibition of ATR in tumors undergoing EMT reduces tumor growth and metastasis, suggesting that ATR inhibition eliminates cancer cells in transition. Thus, during EMT, ATR not only protects genome integrity but also enables transcription reprogramming, revealing that ATR is a safeguard of cell-state transitions and a target to suppress tumor plasticity.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146021291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alveolar macrophages (AMs) help defend the lungs against infection, but during pneumonia many alveolar macrophages die. In this issue of the JCI, Malainou et al. explored the mechanism underpinning AM death during viral pneumonia and its effect on the outcomes of bacterial superinfection, a secondary infection that occurs before the first infection is cleared. In mouse models of influenza A infection, recruited neutrophils secreted TNF superfamily member 14 (TNFSF14), and AMs increased expression of the TNFSF14 receptors TNFSFR14 and type I transmembrane lymphotoxin β receptor (LTβR). TNFSF14 signaling via the LTβR was sufficient to cause AM apoptosis. TNFSF14 deficiency or blockade preserved AMs during influenza infection and diminished bacterial burdens and mouse mortality during pneumococcal superinfection. The adoptive transfer of AMs decreased the severity of pneumococcal superinfections, if those AMs lacked the LTβR. Thus, preserving AMs by interrupting TNFRSF14-LTβR interactions can make virus-infected lungs less susceptible to severe bacterial superinfection.
{"title":"Helping alveolar macrophages live to fight another day during viral pneumonia.","authors":"Elise Mr Armstrong,Joseph P Mizgerd","doi":"10.1172/jci201457","DOIUrl":"https://doi.org/10.1172/jci201457","url":null,"abstract":"Alveolar macrophages (AMs) help defend the lungs against infection, but during pneumonia many alveolar macrophages die. In this issue of the JCI, Malainou et al. explored the mechanism underpinning AM death during viral pneumonia and its effect on the outcomes of bacterial superinfection, a secondary infection that occurs before the first infection is cleared. In mouse models of influenza A infection, recruited neutrophils secreted TNF superfamily member 14 (TNFSF14), and AMs increased expression of the TNFSF14 receptors TNFSFR14 and type I transmembrane lymphotoxin β receptor (LTβR). TNFSF14 signaling via the LTβR was sufficient to cause AM apoptosis. TNFSF14 deficiency or blockade preserved AMs during influenza infection and diminished bacterial burdens and mouse mortality during pneumococcal superinfection. The adoptive transfer of AMs decreased the severity of pneumococcal superinfections, if those AMs lacked the LTβR. Thus, preserving AMs by interrupting TNFRSF14-LTβR interactions can make virus-infected lungs less susceptible to severe bacterial superinfection.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Despite overexpression of N-acetyltransferase 10 (NAT10) in colorectal cancer (CRC), its immunomodulatory role in the tumor microenvironment remains elusive. Here, we reveal that NAT10 promotes immune evasion through N4-acetylcytosine-dependent (ac4C-dependent) mRNA stabilization. Using syngeneic mouse models (MC38/CT-26), intestinal epithelial-cell specific Nat10 conditional KO (Nat10cKO) mice, patient-derived organoids, and clinical specimens, we show that Nat10 ablation enhanced CD8+ T cell-mediated antitumor immunity. Single-cell RNA-seq revealed increased cytotoxic CD8+ T cell infiltration in Nat10cKO tumors, which was corroborated by the inverse correlation of tumoral NAT10 expression and CD8+ T cell number in clinical specimens. Multi-omics integration analysis identified DKK2 as the predominant NAT10-regulated transcript. NAT10 stabilized DKK2 mRNA via ac4C modification, leading to high expression of the DKK2 protein. Secreted DKK2 engaged LRP6 receptors to activate AKT-mTOR signaling, inducing cholesterol accumulation in CD8+ T cells and impairing their cytotoxicity. Pharmacological NAT10 inhibition (Remodelin treatment) or DKK2 neutralization restored CD8+ T cell function and synergized with anti-PD-1 therapy. Our findings establish the NAT10/DKK2/LRP6/AKT-mTOR/cholesterol axis as a critical regulator of CD8+ T cell dysfunction in CRC, positioning NAT10/DKK2 as a potential target to enhance immunotherapy efficacy.
{"title":"Targeting the N-acetyltransferase 10/DKK2 axis enhances CD8+ T cell antitumor activity in colorectal cancer models.","authors":"Mengmeng Li,Xiaoya Zhao,Jun Wu,Shimeng Zhou,Yao Fu,Chen Chen,Zhuang Ma,Jiawen Xu,Yun Qian,Zhangding Wang,Bo Wang,Qiang Wang,Qingqing Ding,Changyu Chen,Honggang Wang,Xiaozhong Yang,Weijie Dai,Wenjie Zhang,Shouyu Wang","doi":"10.1172/jci196722","DOIUrl":"https://doi.org/10.1172/jci196722","url":null,"abstract":"Despite overexpression of N-acetyltransferase 10 (NAT10) in colorectal cancer (CRC), its immunomodulatory role in the tumor microenvironment remains elusive. Here, we reveal that NAT10 promotes immune evasion through N4-acetylcytosine-dependent (ac4C-dependent) mRNA stabilization. Using syngeneic mouse models (MC38/CT-26), intestinal epithelial-cell specific Nat10 conditional KO (Nat10cKO) mice, patient-derived organoids, and clinical specimens, we show that Nat10 ablation enhanced CD8+ T cell-mediated antitumor immunity. Single-cell RNA-seq revealed increased cytotoxic CD8+ T cell infiltration in Nat10cKO tumors, which was corroborated by the inverse correlation of tumoral NAT10 expression and CD8+ T cell number in clinical specimens. Multi-omics integration analysis identified DKK2 as the predominant NAT10-regulated transcript. NAT10 stabilized DKK2 mRNA via ac4C modification, leading to high expression of the DKK2 protein. Secreted DKK2 engaged LRP6 receptors to activate AKT-mTOR signaling, inducing cholesterol accumulation in CD8+ T cells and impairing their cytotoxicity. Pharmacological NAT10 inhibition (Remodelin treatment) or DKK2 neutralization restored CD8+ T cell function and synergized with anti-PD-1 therapy. Our findings establish the NAT10/DKK2/LRP6/AKT-mTOR/cholesterol axis as a critical regulator of CD8+ T cell dysfunction in CRC, positioning NAT10/DKK2 as a potential target to enhance immunotherapy efficacy.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"50 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have become an essential drug class for treating type 2 diabetes, offering proven benefits in glycemic control, weight reduction, and cardiovascular and renal protection. However, growing evidence of heterogeneity in GLP-1RA treatment effects highlights the potential for developing precision medicine approaches to more accurately allocate GLP-1RAs to maximize patient benefit. In this Review, we explore the evidence for treatment effect heterogeneity with GLP-1RAs, focusing on clinical and genetic factors that robustly influence established therapeutic outcomes. We also highlight the potential of recent predictive models that integrate routine clinical data with personalize treatment decisions, comparing GLP-1RA to other major type 2 diabetes drug classes. While such models have shown considerable promise in identifying optimal type 2 diabetes treatment based on glycemic response, their utility for informing treatment choice for other clinical outcomes remains largely unexplored.
{"title":"GLP-1RA precision medicine in people with type 2 diabetes: current insights and future prospects.","authors":"Pedro Cardoso,John M Dennis,Ewan R Pearson","doi":"10.1172/jci194742","DOIUrl":"https://doi.org/10.1172/jci194742","url":null,"abstract":"Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have become an essential drug class for treating type 2 diabetes, offering proven benefits in glycemic control, weight reduction, and cardiovascular and renal protection. However, growing evidence of heterogeneity in GLP-1RA treatment effects highlights the potential for developing precision medicine approaches to more accurately allocate GLP-1RAs to maximize patient benefit. In this Review, we explore the evidence for treatment effect heterogeneity with GLP-1RAs, focusing on clinical and genetic factors that robustly influence established therapeutic outcomes. We also highlight the potential of recent predictive models that integrate routine clinical data with personalize treatment decisions, comparing GLP-1RA to other major type 2 diabetes drug classes. While such models have shown considerable promise in identifying optimal type 2 diabetes treatment based on glycemic response, their utility for informing treatment choice for other clinical outcomes remains largely unexplored.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sarah R DiNapoli,Katharine M Wright,Brian J Mog,Alexander H Pearlman,Tushar D Nichakawade,Nikita Marcou,Emily Han-Chung Hsiue,Michael S Hwang,Jacqueline Douglass,Qiang Liu,Evangeline Watson,Marco Dal Molin,Joshua D Cohen,Maria Popoli,Suman Paul,Maximilian F Konig,Nicolas Wyhs,P Aitana Azurmendi,Stephanie Glavaris,Jiaxin Ge,Tolulope O Awosika,Jin Liu,Kathleen L Gabrielson,Sandra B Gabelli,Drew M Pardoll,Chetan Bettegowda,Nickolas Papadopoulos,Kenneth W Kinzler,Shibin Zhou,Bert Vogelstein
Mutation-associated neoantigens (MANAs) are highly cancer-specific targets for immunotherapy where peptides derived from intracellular mutant proteins are presented on the cell surface via HLA molecules. T cell-engaging bispecific antibodies and CAR T cells can target MANAs to eliminate cancer cells via T cell activation. However, the low antigen density of MANAs on the cell surface can limit therapeutic efficacy. Here, we investigated whether increasing the affinity of the H2 single-chain variable fragment (scFv) targeting the p53 R175H MANA (HMTEVVRHC presented on HLA-A*02:01) improves its therapeutic effect. We identified higher-affinity H2 variants via phage biopanning and a thiocyanate elution method. Increasing bispecific antibody affinity to the low nanomolar range increased cancer cell killing and tumor control in mouse xenograft models without sacrificing antigen specificity. We next asked how increasing scFv affinity impacts CAR T cell function - a matter of debate. We appended each variant scFv to a CD28z CAR, CD3γ, or the T cell receptor. In striking contrast to the bispecific antibody results, increasing CAR affinity decreased function in each CAR format due to lower T cell activation upon interaction with target cancer cells. These results have important implications for the design of future immunotherapeutic approaches targeting low-density antigens.
{"title":"Bispecific antibodies and CAR T cells targeting a TP53 mutation-associated neoantigen show discordant affinity requirements.","authors":"Sarah R DiNapoli,Katharine M Wright,Brian J Mog,Alexander H Pearlman,Tushar D Nichakawade,Nikita Marcou,Emily Han-Chung Hsiue,Michael S Hwang,Jacqueline Douglass,Qiang Liu,Evangeline Watson,Marco Dal Molin,Joshua D Cohen,Maria Popoli,Suman Paul,Maximilian F Konig,Nicolas Wyhs,P Aitana Azurmendi,Stephanie Glavaris,Jiaxin Ge,Tolulope O Awosika,Jin Liu,Kathleen L Gabrielson,Sandra B Gabelli,Drew M Pardoll,Chetan Bettegowda,Nickolas Papadopoulos,Kenneth W Kinzler,Shibin Zhou,Bert Vogelstein","doi":"10.1172/jci192885","DOIUrl":"https://doi.org/10.1172/jci192885","url":null,"abstract":"Mutation-associated neoantigens (MANAs) are highly cancer-specific targets for immunotherapy where peptides derived from intracellular mutant proteins are presented on the cell surface via HLA molecules. T cell-engaging bispecific antibodies and CAR T cells can target MANAs to eliminate cancer cells via T cell activation. However, the low antigen density of MANAs on the cell surface can limit therapeutic efficacy. Here, we investigated whether increasing the affinity of the H2 single-chain variable fragment (scFv) targeting the p53 R175H MANA (HMTEVVRHC presented on HLA-A*02:01) improves its therapeutic effect. We identified higher-affinity H2 variants via phage biopanning and a thiocyanate elution method. Increasing bispecific antibody affinity to the low nanomolar range increased cancer cell killing and tumor control in mouse xenograft models without sacrificing antigen specificity. We next asked how increasing scFv affinity impacts CAR T cell function - a matter of debate. We appended each variant scFv to a CD28z CAR, CD3γ, or the T cell receptor. In striking contrast to the bispecific antibody results, increasing CAR affinity decreased function in each CAR format due to lower T cell activation upon interaction with target cancer cells. These results have important implications for the design of future immunotherapeutic approaches targeting low-density antigens.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"249 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Elevated tRNA halves in olfactory epithelial cells of patients with schizophrenia.","authors":"Justin T Gumas,Megumi Shigematsu,Karin E Borgmann-Winter,Chang-Gyu Hahn,Yohei Kirino","doi":"10.1172/jci195148","DOIUrl":"https://doi.org/10.1172/jci195148","url":null,"abstract":"Schizophrenia patients' olfactory epithelial cells contain abundant immune-activating tRNA fragments, linking small RNA biology to inflammation and suggesting avenues for diagnostics.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The glucagon-like peptide-1 receptor (GLP-1R) is a class B1 G protein-coupled receptor and major therapeutic target in type 2 diabetes and obesity. Beyond its canonical role in Gαs/cAMP signaling, GLP-1R is increasingly recognized as an organizer of spatiotemporally defined signaling nanodomains, or "signalosomes." This Review highlights our current knowledge on the mechanisms of assembly and regulation of GLP-1R signalosomes, including the involvement of biomolecular condensates formed by liquid-liquid phase separation, and the role of membrane contact sites between the endoplasmic reticulum (ER) and other organelles as key locations for GLP-1R signaling assemblies. Furthermore, we discuss existing data on the molecular composition and functional impact of two predicted GLP-1R nanodomains, one at ER-plasma membrane contact sites, where GLP-1R might interact with ion channels and transporters to influence local excitability and coordinated insulin secretion, and another at ER-mitochondria membrane contact sites, with the capacity to control lipid and calcium signaling and modulate ER and/or mitochondrial activity. We additionally discuss the role of GLP-1R posttranslational modifications as critical modulators of GLP-1R signal specification and nanodomain organization. Conceptualizing GLP-1R as a dynamic architect of spatiotemporally encoded signalosomes opens new avenues for a deeper understanding of incretin biology with the potential for identification of novel GLP-1R effectors and the development of refined therapeutic strategies for metabolic disease.
{"title":"Signaling architecture of the glucagon-like peptide-1 receptor.","authors":"Gregory Austin,Alejandra Tomas","doi":"10.1172/jci194752","DOIUrl":"https://doi.org/10.1172/jci194752","url":null,"abstract":"The glucagon-like peptide-1 receptor (GLP-1R) is a class B1 G protein-coupled receptor and major therapeutic target in type 2 diabetes and obesity. Beyond its canonical role in Gαs/cAMP signaling, GLP-1R is increasingly recognized as an organizer of spatiotemporally defined signaling nanodomains, or \"signalosomes.\" This Review highlights our current knowledge on the mechanisms of assembly and regulation of GLP-1R signalosomes, including the involvement of biomolecular condensates formed by liquid-liquid phase separation, and the role of membrane contact sites between the endoplasmic reticulum (ER) and other organelles as key locations for GLP-1R signaling assemblies. Furthermore, we discuss existing data on the molecular composition and functional impact of two predicted GLP-1R nanodomains, one at ER-plasma membrane contact sites, where GLP-1R might interact with ion channels and transporters to influence local excitability and coordinated insulin secretion, and another at ER-mitochondria membrane contact sites, with the capacity to control lipid and calcium signaling and modulate ER and/or mitochondrial activity. We additionally discuss the role of GLP-1R posttranslational modifications as critical modulators of GLP-1R signal specification and nanodomain organization. Conceptualizing GLP-1R as a dynamic architect of spatiotemporally encoded signalosomes opens new avenues for a deeper understanding of incretin biology with the potential for identification of novel GLP-1R effectors and the development of refined therapeutic strategies for metabolic disease.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"390 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Historically, antiobesity medications have been modestly effective at best, with side-effect profiles that limit compliance and often preclude the long-term therapy required to maintain weight loss. Recently developed therapies based on analogs of the gut hormone glucagon-like peptide-1 (GLP-1) have transformed the medical management of obesity, leading both to a degree of weight loss that rivals bariatric surgery and a reduction in morbidity and mortality associated with obesity-related complications. GLP-1 receptor agonist (GLP-1RA) therapies were developed to mimic the peripheral effects of GLP-1, but it is now well established that their efficacy in the treatment of obesity depends on reducing energy intake through their action in the central nervous system (CNS). Recent data indicate that the aversive gastrointestinal side effects of GLP-1RAs are also CNS mediated. Although a complete understanding of the neural circuits underlying GLP-1RA-induced weight loss remains elusive, a great deal has been learned in recent years. This Review summarizes proposed gut-brain and central mechanisms through which GLP-1 and its synthetic analogs regulate food intake and bodyweight.
{"title":"GLP-1 physiology and pharmacology along the gut-brain axis.","authors":"Lisa R Beutler","doi":"10.1172/jci194744","DOIUrl":"https://doi.org/10.1172/jci194744","url":null,"abstract":"Historically, antiobesity medications have been modestly effective at best, with side-effect profiles that limit compliance and often preclude the long-term therapy required to maintain weight loss. Recently developed therapies based on analogs of the gut hormone glucagon-like peptide-1 (GLP-1) have transformed the medical management of obesity, leading both to a degree of weight loss that rivals bariatric surgery and a reduction in morbidity and mortality associated with obesity-related complications. GLP-1 receptor agonist (GLP-1RA) therapies were developed to mimic the peripheral effects of GLP-1, but it is now well established that their efficacy in the treatment of obesity depends on reducing energy intake through their action in the central nervous system (CNS). Recent data indicate that the aversive gastrointestinal side effects of GLP-1RAs are also CNS mediated. Although a complete understanding of the neural circuits underlying GLP-1RA-induced weight loss remains elusive, a great deal has been learned in recent years. This Review summarizes proposed gut-brain and central mechanisms through which GLP-1 and its synthetic analogs regulate food intake and bodyweight.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"39 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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