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Abstract
BACKGROUND. Asparaginase is essential for curing acute lymphoblastic leukemia (ALL), but its use is limited by asparaginase-associated pancreatitis (AAP), a severe and unpredictable toxicity lacking validated prospective biomarkers. We sought to define early systemic molecular features of susceptibility to AAP. METHODS. We performed longitudinal lipidomic and proteomic profiling in two independent pediatric ALL cohorts (n = 161; 79 AAP cases, 82 controls) using paired blood samples collected before asparaginase exposure and at the end of induction therapy (including a single dose of asparaginase), thereby capturing pre-injury biology rather than consequences of pancreatitis. We applied differential abundance and network-based analyses, and integrated lipid–cytokine associations using proteomics. RESULTS. Across cohorts, we identified a reproducible lysophosphatidylcholine (LPC)–centered signature characterized by attenuated induction therapy-associated LPC responses and disruption of LPC co-regulation at the network level. Proteomic profiling revealed enrichment of cytokine signaling pathways, and integrative analyses demonstrated altered lipid–cytokine coupling, including a flip in association direction for LPC species and interleukin-18 (IL-18) between cases and controls. Although IL-18/LPC ratios do not differ globally, elevated post-induction IL-18/LPC ratios identify AAP risk within a protocol-defined very high-risk ALL subgroup (AUC = 0.81). CONCLUSION. These findings support a systems-level model in which failure of coordinated lipid–immune responses under therapeutic stress confers vulnerability to AAP, providing a framework for validation and mitigation strategies. TRIAL REGISTRATION. NCT00400946; NCT01574274; NCT03020030 (parent trials). FUNDING. Servier Pharmaceuticals (IIT-95014-027-USA); SDRC (P30DK116074); Stanford SPARK; Fonds de Recherche du Québec – Santé; Fondation Charles-Bruneau; The Leukemia & Lymphoma Society of Canada.
Authors
Cheng-Yu Tsai, Na Bo, Thai Hoa Tran, Maisam Abu-El-Haija, Gayathri Swaminathan, Bomi Lee, Sudhir Ghandikota, Li Wen, Yves Théorêt, Steven D. Mittelman, Elena J. Ladas, Anil G. Jegga, Lewis B. Silverman, Ying Ding, Sohail Z. Husain
Abstract
Abdominal aortic aneurysm (AAA) lacks effective pharmacological therapies. Here, we investigate transcription factor 7-like 2 (TCF7L2), a genetic locus associated with both thoracic and abdominal aortic aneurysms, to elucidate its role in AAA pathogenesis. Integrating summary-data-based Mendelian randomization (SMR) with single-cell RNA sequencing (scRNA-seq) of human and mouse aortas, we identify TCF7L2 as a gene enriched in vascular smooth muscle cells (VSMCs) and causally linked to AAA development. Smooth muscle cell-specific TCF7L2 knockout significantly attenuates AAA formation across three distinct murine models (Ang II infusion-, BAPN/Ang II co-administration-, and elastase-induced AAA), independent of systemic blood pressure or lipid levels. Mechanistic studies reveal that TCF7L2 directly upregulates MMP14 and downregulates TIMP3 expression in vitro and in vivo, driving MMP2-mediated extracellular matrix (ECM) degradation. Concurrently, TCF7L2 represses integrin β1 (ITGB1) expression, reducing VSMC adhesion to the ECM. Collectively, these findings identify TCF7L2 as a key driver of pathological vascular remodeling in AAA, suggesting that targeting TCF7L2 may offer a novel therapeutic strategy for limiting AAA progression.
Authors
Yongjie Deng, Yaozhong Liu, Yang Zhao, Hongyu Liu, Guizhen Zhao, Zhenguo Wang, Xu Zhang, Chao Xue, Wei Huang, Tianqing Zhu, Haocheng Lu, Yanhong Guo, Lin Chang, Ida Surakka, Y. Eugene Chen, Jifeng Zhang
Abstract
Immune checkpoint inhibitors have transformed cancer therapy, yet many patients fail to achieve durable responses due to insufficient T cell reinvigoration. Cytokines offer promise for enhancing immunotherapy, but their clinical use is limited by toxicity and a narrow therapeutic index. Immunocytokines, engineered fusion proteins combining antibody specificity with cytokine activity, aim to overcome these challenges by targeting cytokine delivery to immune cells or the tumor microenvironment. We describe SAR445877 (SAR’877), a novel PD-1-targeted immunocytokine that fuses a high-affinity anti-PD-1 antibody with a detuned IL-15/IL-15Rα sushi domain complex. SAR’877 blocks PD-1/PD-L1 and PD-1/PD-L2 interactions while selectively delivering IL-15 signals to PD-1+ T cells, enhancing proliferation and activation of antigen-experienced CD8+ and CD4+ T cells and NK cells, while minimizing systemic inflammation. Mechanistically, SAR’877 activates STAT5 signaling in PD-1+ lymphocytes and restores effector function in exhausted T cells. In preclinical models, a murine surrogate of SAR’877 accelerated viral clearance and induced robust anti-tumor immunity by expanding cytotoxic CD8+ T cells and promoting Th1 polarization. Notably, SAR’877 outperformed anti-PD-1 plus untargeted IL-15, highlighting the therapeutic potential of targeted IL-15 delivery. These findings position SAR’877 as a promising next-generation immunotherapy with enhanced efficacy and reduced cytokine-associated toxicities.
Authors
Isaraphorn Pratumchai, Marie Bernardo, Julien Tessier, Jaroslav Zak, Kristi L. Marquardt, Joon Sang Lee, Maheeka Bimal, AHyun Choi, Anthony M. Byers, Mikielia G. Devonish, Roberto Carrio, Dan Lu, Stella A. Martomo, Jeegar Patel, Yu-an Zhang, Ingeborg M. Langohr, Virna Cortez-Retamozo, Dinesh S. Bangari, Angela Hadjipanayis, Xiangming Li, Valeria R. Fantin, Donald R. Shaffer, John R. Teijaro
Abstract
Tumor-infiltrating CD8 cells recognize neoantigens created by tumor-specific mutations. Nonetheless, even after checkpoint inhibitor therapy, most patients progress. A deeper understanding of anti-tumor responses could facilitate development of better therapies. To enable such studies, we applied TCXpress, a high throughput platform that clones fully expressible TCRs from single cells into retro- or lenti- viral vectors without sequencing or gene synthesis, to study TCRs from CD8 cells infiltrating mouse MC38 tumors. We expressed cloned TCRs in reporter cells and interrogated TCR specificity by coculturing them with B6WT3 cells transduced with tandem minigenes encoding predicted neoantigens. We isolated TCRs reactive against epitopes from mutant Rpl18, Adpgk, Psmd2, and Zc3h7b along with self-reactive TCRs that recognized normal B6 and MC38 cells. Importantly, we successfully treated MC38-bearing mice with T cells transduced with anti-Rpl18 TCRs. These results establish a system that could be used to study many types of T cell responses and validates a therapeutic approach that could be tested in the clinic.
Authors
Alexander M. Rowe, Smriti Chaurasia, Wenzhong Wei, Laura García-Diéguez, Katherine Querry, Johnathon G. Schiebel, Christy Smolak, Alexander G. Muralles, Daniel Wikenheiser, Kevin Quann, Collin Pirner, Kentin Codispot, Mark J. Shlomchik, Warren D. Shlomchik
Abstract
Enhancing NAD+ levels with nicotinamide riboside (NR) confers anti-inflammatory effects in human disease, although immunoregulatory mechanisms remain poorly characterized. We previously showed that ex vivo NR supplementation of primary CD4+ T cells from psoriatic individuals dampened immune responsiveness. To validate this in vivo, we performed a randomized, placebo-controlled NR supplementation study in individuals with mild-to-moderate psoriasis. Participants received oral NR (500 mg twice daily) or matching placebo for 4 weeks, with blood samples collected at baseline and after supplementation. NR reduced Th17 immune responsiveness. Bulk CD4+ T cell RNA-seq identified induction of the SLIT-ROBO signaling pathway. NR supplementation increased circulating SLIT2 levels and enhanced SLIT2 production in dermal fibroblasts. Pharmacologic and genetic interrogation in CD4+ T cells and fibroblasts demonstrated that SLIT2, acting through the ROBO1 receptor, inhibited Rho GTPase signaling, thereby attenuating canonical Th17 polarization and fibroblast inflammatory activation. These findings indicate that NAD+ augmentation exerts anti-inflammatory effects in psoriasis through SLIT2-ROBO1-mediated crosstalk between dermal fibroblasts and circulating CD4+ T cells, leading to suppression of Th17-driven inflammation.
Authors
Kim Han, Rachael J. Klein, Thomas C. Recupero, Anna Chiara Russo, Rahul Sharma, Anand K. Gupta, Shahin Hassanzadeh, Rebecca D. Huffstutler, Pradeep K. Dagur, Bryan Fisk, Neelam R. Redekar, Michael N. Sack
Abstract
Physician-scientists represent one of the most impactful, yet underrecognized, innovations of 20th century academic medicine. Defined by a commitment to full-time careers in investigative work, physician-scientists have repeatedly demonstrated a unique ability to identify and solve problems of unmet medical need in a focused and intentional manner using their dual training in clinical medicine and the scientific method as both stethoscope and scalpel. Unfortunately, mounting financial pressures from both the clinical and research marketplaces have placed this storied workforce in jeopardy due to the absence of a dedicated and explicitly defined vocational structure and business model. This white paper reports the output of a consortium of academic medical centers, foundations and professional societies seeking to remedy this deficiency. This consortium specifically developed a framework to formalize the career path of physician-scientist faculty into a professionally unified and financially sustainable structure in a way that could be adopted to different U.S. academic medical centers and health systems. Key components of this framework included an administratively operational definition of physician-scientists, and three central and interconnected pillars (academic, financial, and organizational) that are rooted in this foundational definition. Herein, we detail core concepts and concrete recommendations.
Authors
Christopher S. Williams, Megan Allen, Paige Cooper Byas, John B. Hawley, Louis J. Muglia, E. Dale Abel, Julie A. Bastarache, Carolyn S. Calfee, John M. Carethers, David N. Cornfield, Oliver Eickelberg, Emily J. Gallagher, Anna Greka, Peter J. Gruber, Anthony N. Hollenberg, Heidi H. Kong, Barbara I. Kazmierczak, Gary A. Koretzky, Mark Lachs, Deborah J. Lenschow, Geoffrey S. Pitt, Don C. Rockey, Lisa M. Satlin, Barry P. Sleckman, David A. Stoltz, Jatin M. Vyas, Thomas J. Wang, Kyu Y. Rhee
Abstract
Germline BRCA1/2 pathogenic variant (PV) carriers have elevated young-onset breast cancer risk. To define the pretreatment genomic landscapes of young-onset gBRCA-associated breast cancer, we evaluated 136 treatment-naïve tumors diagnosed before age 50 (92.6% ≤40): gBRCA1 86(63.2%); gBRCA2 50(36.8%) in the prospective POSH study, and 66 noncarriers from The Cancer Genome Atlas. Using whole exome sequencing, we analyzed somatic variation, allele-specific loss of heterozygosity (asLOH), homologous recombination deficiency (HRD), and single-base substitution signatures (SBS). gBRCA1(93%) and gBRCA2(96%) breast cancers had high rates of asLOH, but differed significantly in average HRD scores (57.4 ± 1.3 vs 43.7 ± 1.5, P < 0.0001) and median SBS composition (%): SBS1 (aging-associated) 12.9 vs 7.3, P = 0.013; SBS18 (reactive oxygen species [ROS]-associated) 1.4 vs 0, P = 0.007; and SBS3 (HRD-associated) 27.3 vs 42.6, P = 0.002. Compared to gBRCA2 tumors, gBRCA1 tumors with asLOH were significantly enriched for alterations in Hallmark ROS, DNA repair, and epithelial-mesenchymal transition pathways. In ER-positive, HER2-negative tumors from gBRCA1/2 carriers compared to noncarriers, we found significant enrichment of RB1 (OR:6.3;95%CI:2.8–15.4;padj = 0.001), TP53 (OR:4.6;95%CI:1.9–12.1;padj = 0.017), FAT1 (OR:3.9;95%CI:1.84–8.7;padj = 0.013), and MYC (OR:4.0;95%CI:1.8–9.1;padj = 0.017) SNV/indels/CNVs, associated with CDK4/6i resistance. Together, these findings demonstrate significant differences between gBRCA1 and gBRCA2-associated breast cancers, and preexisting CDK4/6i resistance mechanisms supporting prospective trials with individualized therapy for gBRCA1 vs gBRCA2 carriers, and comparing PARPi to CDK4/6i for ER-positive gBRCA1/2-associated breast cancer.
Authors
Mwangala P. Akamandisa, Mingyi Xia, Wilson Cheah, Bradley Wubbenhorst, Kurt P. D'Andrea, Mengyao Fan, Jake S. Shilan, Dana Pueschl, Anupma Nayak, Hayley McKenzie, William Tapper, Ellen R. Copson, Ramsey I. Cutress, Susan M. Domchek, Diana M. Eccles, Katherine L. Nathanson
Abstract
CHI3L1, a chitinase-like protein, is implicated in pulmonary fibrosis, yet its mechanisms incompletely understood. In this study, we demonstrated that CHI3L1 coordinates profibrotic macrophage activation and invasive myofibroblast differentiation, and their crosstalk. In vitro, CHI3L1 drove M2-like macrophage polarization as evidenced by increased CD163, CD206, and PD-L1, and amplified TGF-β1-induced fibroblast responses, including myofibroblast transformation, migration, and invasion. Mechanistically, CHI3L1 enhanced TGF-β1 signaling through SMAD, AKT, and ERK pathways, and PD-L1 was required for CHI3L1/TGF-β1-driven myofibroblast transformation. Co-culture studies further demonstrated the ability of CHI3L1 to induce profibrotic macrophage activation that enhanced myofibroblast transformation mediated via a CD44–PD-L1 axis. In vivo, following bleomycin challenge, CHI3L1 transgenic mice exhibited increased PD-L1+ M2 macrophages, PD-L1+/PDGFRα+ fibroblasts, and PD-1+ immune cells compared with wild-type controls. Therapeutically, combined anti-CHI3L1 and anti-PD-1 antibodies, as well as a bispecific anti-CHI3L1-anti-PD-1 antibody, produced greater anti-fibrotic efficacy than monotherapy. These findings demonstrate crosstalk between CHI3L1 and the PD-1/PD-L1 pathway that promotes profibrotic macrophage activation and invasive fibroblast differentiation and support dual targeting of CHI3L1 and PD-1/PD-L1 as a promising therapeutic strategy for pulmonary fibrosis.
Authors
Han-Seok Jeong, Takayuki Sadanaga, Joyce H. Lee, Suchitra Kamle, Bing Ma, Yang Zhou, Sung Jae Shin, Jack A. Elias, Chun Geun Lee
Abstract
Aortic dissection or rupture is a leading cause of mortality in vascular Ehlers-Danlos syndrome (VEDS), a disorder caused by mutations in the COL3A1 gene. Col3a1G938D/+ mice recapitulate features of VEDS, including high risk of aortic rupture. As in people with VEDS, aortic risk in this model accelerates at the onset of puberty, especially in males. We identify developmentally regulated gene programs associated with this vulnerability and that are targeted by treatments that mitigate aortic risk. Both genetic and pharmacological inhibition of the androgen receptor (AR) eliminated survival differences between sexes, while treatment with a dual AR and mineralocorticoid receptor (MR) antagonist provided near-complete and durable protection in both sexes. Pathways targeted by dual AR/MR inhibition, including those related to extracellular matrix (ECM) organization and cell-ECM interactions, largely overlapped with those also modulated by isolated MR antagonism. Selective targeting of MR signaling emerged as an effective therapeutic strategy in both sexes that avoids sexual side effects in males.
Authors
Emily E. Juzwiak, Caitlin J. Bowen, Rhiannon Edwards, Leda Restrepo, Serena Lee, Cassie A. Parks, Anthony Zeng, Maya M. Black, Oscar E. Reyes Gaido, Emily E. Bramel, Dustin T. Shigaki, Michael A. Beer, Chiara Bellini, Harry C. Dietz, Elena Gallo MacFarlane
Abstract
Eosinophilic esophagitis (EoE) is a type 2 allergic disease characterized by esophageal inflammation and epithelial cell dysfunction. The acquired loss of the anti-serine protease of kazal type 7 (SPINK7) in the squamous epithelium of the esophagus has a causal role in EoE pathogenesis. Yet there is a limited understanding of the factors that regulate its expression and responsiveness to inflammatory stimuli. Herein, we have identified the transcription factor, ovo like transcriptional repressor 1 (OVOL1) as an esophageal selective gene product that regulates SPINK7 promoter activity. Overexpression of OVOL1 increased SPINK7 expression, whereas its depletion decreased SPINK7 expression, impaired epithelial barrier and increased production of the pro-atopy cytokine thymic stromal lymphopoietin (TSLP). Stimulation with IL-13 abrogated the nuclear translocation of OVOL1 and promoted enhanced degradation of OVOL1 protein. This effect of IL-13 was dependent on the esophageal specific cysteine protease calpain-14 at least in part. Analysis of human esophageal biopsies demonstrated that the expression of esophageal OVOL1 correlated with SPINK7 transcript expression and was lost as a function of EoE disease activity. In summary, our study identifies key regulatory mechanisms in EoE pathogenesis, demonstrating that OVOL1 promotes SPINK7 transcription, whereas IL-13 suppresses this pathway in EoE.
Authors
Nurit P. Azouz, Andrea M. Klingler, Sierra S. Beach, Kalen A. Rossey, Mark Rochman, Misu Paul, Julie M. Caldwell, Michael Brusilovsky, Alexander T. Dwyer, Xiaoting Chen, Daniel Miller, Carmy Forney, Leah C. Kottyan, Matthew T. Weirauch, Marc E. Rothenberg
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