tbuckley/cabot-search huggingface dataset:
Differential impact of TIM-3 ligands on NK cell function
Authors: Juncheng Wang, Housaiyin Li, Aditi Kulkarni, Jennifer L Anderson, Pragati Upadhyay, Onyedikachi Victor Onyekachi, Lidia M R B Arantes, Hridesh Banerjee, Lawrence P Kane, Xin Zhang, Tullia C Bruno, Riyue Bao, Robert L Ferris, Lazar Vujanovic
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background The transmembrane protein T-cell immunoglobulin and mucin-domain containing molecule 3 (TIM-3) is an immune checkpoint receptor that is expressed by a variety of leukocyte subsets, particularly in the tumor microenvironment. An effective TIM-3-targeting therapy should account for multiple biological factors, including the disease setting, the specific cell types involved and their varying sensitivities to the four putative TIM-3 ligands (galectin-9, phosphatidylserine, high mobility group protein B1 and carcinoembryonic antigen cell adhesion molecule 1), each of which engages a unique binding site on the receptor’s variable immunoglobulin domain. The primary objectives of this study were to assess the prevalence and function of TIM-3 + natural killer (NK) cells in patients with head and neck squamous cell carcinoma (HNSCC), determine whether the four TIM-3 ligands differentially affect TIM-3 + NK cell functions, identify the most immunosuppressive ligand, and evaluate whether targeting ligand-mediated TIM-3 signaling enhances NK cell effector functions. Methods Single-cell RNA sequencing and flow cytometry were used to study the prevalence, phenotypes and function of TIM-3 + NK cells in HNSCC patient tumors and blood. In vitro killing, proliferation and cytokine production assays were implemented to evaluate whether the four TIM-3 ligands differentially modulate TIM-3 + NK cell functions, and whether disruption of TIM-3/ligand interaction can enhance NK cell-mediated antitumor effector mechanisms. Finally, The Cancer Genome Atlas survival analysis and digital spatial profiling were employed to study the potential impact of etiology-associated differences on patients with HNSCC outcomes. Results We demonstrate that TIM-3 is highly prevalent on circulating and tumor-infiltrating NK cells. It co-expresses with CD44 and marks NK cells with heightened effector potential. Among the four putative TIM-3 ligands, galectin-9 most consistently suppresses NK cell-mediated cytotoxicity and proliferation through TIM-3 and CD44 signaling, respectively, but promotes IFN-γ release in a TIM-3-dependent manner. Among patients with HNSCC, an elevated intratumoral TIM-3 + NK cell gene signature associates with worse outcomes, specifically in those with human papillomavirus (HPV) + disease, potentially attributable to higher galectin-9 levels in HPV + versus HPV − patients. Conclusions Our findings underscore the complex functional impact of TIM-3 ligand signaling, which is consistent with recent clinical trials suggesting that targeting TIM-3 alone is suboptimal as an immunotherapeutic approach for treating malignancies.
Targeted inhibition of Aurora kinase A promotes immune checkpoint inhibition efficacy in human papillomavirus-driven cancers
Authors: Soma Ghosh, Madison P O'Hara, Pragya Sinha, Tuhina Mazumdar, Lacin Yapindi, Jagannadha K Sastry, Faye M Johnson
Journal: Journal for ImmunoTherapy of Cancer (2025)

Human papillomavirus (HPV)-driven cancers include head and neck squamous cell carcinoma and cervical cancer and represent approximately 5% of all cancer cases worldwide. Standard-of-care chemotherapy, radiotherapy, and immune checkpoint inhibitors (ICIs) are associated with adverse effects and limited responses in patients with HPV-driven cancers. The integration of targeted therapies with ICIs may improve outcomes. In a previous study, we demonstrated that Aurora kinase A (AURKA, Aurora A) inhibitors lead to apoptosis of human HPV-positive cancer cells in vitro and in vivo. Here, we explored the potential of Aurora A inhibition to enhance response to ICIs in immune-competent preclinical models of HPV-driven cancers. We assessed the induction of apoptosis, DNA damage, and immunogenic cell death (ICD) in response to treatment with the Aurora A inhibitor alisertib in vitro and antitumor efficacy of alisertib as a monotherapy and in combination with ICIs that inhibit programmed cell death protein-1 (PD-1) or cytotoxic T-lymphocyte associated protein 4 (CTLA-4) in murine HPV-positive immune-competent tumor models. In each treatment group, we determined the tumor growth kinetics and long-term survival and assessed the tumor immune microenvironment using polychromatic flow cytometry. Aurora A inhibition induced apoptosis, DNA damage, and ICD in vitro in multiple human and murine HPV-positive cancer cell lines. Importantly, Aurora A inhibition induced selective apoptotic depletion of myeloid-derived suppressor cells (MDSCs). In vivo experiments demonstrated that the combination of alisertib with ICIs, specifically anti-CTLA4, resulted in improved survival outcomes by altering the tumor immune microenvironment. This combination enhanced CD8 T-cell infiltration and decreased the frequencies of MDSCs, whereas neither alisertib nor ICIs (anti-PD-1/anti-CTLA-4) alone showed such effects. Our study establishes the potential of Aurora A inhibition to sensitize HPV-positive tumors to ICIs, specifically anti-CTLA-4 treatment. This combination strategy resulted in enhanced antitumor efficacy, driven by systemic and intratumoral increases in CD8 T-cell responses and reduced immunosuppressive cell populations, specifically MDSCs. These findings offer insights into the synergistic effects of Aurora A inhibition and ICIs and argue for further investigation and optimization of this combination approach in HPV-driven cancers.
Durvalumab and tremelimumab in combination with metronomic oral vinorelbine for recurrent advanced cervical cancer: an open-label phase I/II study
Authors: Jean-Sébastien Frenel, Laurent Mathiot, Claire Cropet, Edith Borcoman, Alice Hervieu, Elodie Coquan, Thibault De La Motte Rouge, Esma Saada-Bouzid, Renaud Sabatier, Pernelle Lavaud, Marta Jimenez, François Legrand, Olivia Le Saux, Emmanuelle Charafe, Anthony Gonçalves
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background The MOVIE phase I/II trial ( NCT03518606 ) evaluated the safety and antitumor activity of durvalumab and tremelimumab combined with metronomic oral vinorelbine in patients with advanced tumors. We present the results of the recurrent advanced cervical cancer cohort. Methods Patients received tremelimumab (intravenously, 75 mg, every four weeks (Q4W); four cycles max) plus durvalumab (intravenously, 1,500 mg, Q4W; 26 cycles max) and metronomic oral vinorelbine (40 mg, every three weeks (3QW)) until disease progression. The primary efficacy endpoint was the clinical benefit rate (CBR) based on the Response Evaluation Criteria in Solid Tumors V.1.1, which was analyzed using a Bayesian approach Results A total of 31 patients were enrolled and treated in the cervical cancer cohort. The median number of previous lines of chemotherapy for advanced disease was 2 (0–6), with all (100%) and 12 (38.7%) patients pretreated with cisplatin and bevacizumab, respectively. At the data cut-off, the median follow-up duration was 12.8 (Q1–Q3, 6.1–34.6) months. The CBR was 53.1% (95% CI, 36.0% to 69.8%), using a non-informative prior distribution (beta(1, 1)). The overall response rate was 41.9%, five patients achieved a complete response (16.1%), and eight patients (25.8%) had a partial response irrespective of histological subtype or programmed death-ligand 1 (PD-L1) expression. Of the 31 patients, 28 (90.3%) experienced treatment-related adverse events (TRAEs), 13 (41.9%) reported grade ≥3 immune-related adverse events (AEs), and 13 (41.9%) reported grade ≥3 chemotherapy-related AEs. The definitive discontinuation rate due to TRAEs was 16.1%. Conclusions Dual checkpoint blockade of PD-L1 and cytotoxic T-lymphocyte-associated antigen-4 combined with metronomic oral vinorelbine demonstrated meaningful and durable clinical activity in patients with previously treated advanced cervical cancer. Toxicity was significant but manageable.
Targeting the NLRP3 inflammasome abrogates cardiotoxicity of immune checkpoint blockers
Authors: Yang Lu, Jiamin Gao, Yachen Hou, Han Yang, Dashuai Wang, Ge Zhang, Zhen Qin, Pengchong Du, Zhenwei Wang, Yunzhe Wang, Quanzhou Chen, Zhaowei Sun, Ping Li, Jinying Zhang, Junnan Tang
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many malignant tumors. However, ICI-induced hyper-immune activation causes cardiotoxicity. Traditional treatments such as glucocorticoids and immunosuppressants have limited effectiveness and may even accelerate tumor growth. This study aimed to identify approaches that effectively reduce cardiotoxicity and simultaneously preserve or enhance the antitumor immunity of ICI therapy. Methods ICI injection in melanoma-bearing C57BL/6J female mice was used to simulate cardiotoxicity in patients with tumor undergoing immune therapy. MCC950 was used to block nod-like receptor protein 3 (NLRP3) inflammasome activity. Echocardiography, immunofluorescence, flow cytometry, and reverse transcription quantitative polymerase chain reaction were used to assess cardiac function, immune cell populations, and inflammatory factor levels. Bulk and single-cell RNA sequencing was used to detect the changes in cardiac transcriptome and immunological network. Results NLRP3 inhibition reduced inflammatory response and improved cardiac function. Notably, NLRP3 inhibition also resulted in a pronounced suppression of tumor growth. Single-cell RNA sequencing elucidated that MCC950 treatment reduced the cardiac infiltration of pathogenic macrophages, cytotoxic T cells, activated T cells, and their production of inflammatory cytokines, while enhancing the presence of reparative macrophages and naive T cells. In addition, MCC950 attenuated cardiotoxicity induced by dual programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immunotherapy and promoted tumor regression, and showed efficacy in treating established cardiotoxicity. Conclusions Our findings provide a promising clinical approach for preventing and treating cardiotoxicity induced by ICIs, dissociating the antitumor efficacy of ICI-based therapies from their cardiotoxic side effects.
Divergent response to radio-immunotherapy is defined by intrinsic features of the tumor microenvironment
Authors: Jacob Gadwa, Justin Yu, Miles Piper, Michael W Knitz, Laurel B Darragh, Nicholas Olimpo, Sophia Corbo, Jessica I Beynor, Brooke Neupert, Alexander T Nguyen, Chloe Hodgson, Diemmy Nguyen, Khalid NM Abdelazeem, Anthony Saviola, Laurene Pousse, Ali Bransi, Mudita Pincha, Christian Klein, Maria Amann, Sana D Karam
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Treatment with immunotherapy can elicit varying responses across cancer types, and the mechanistic underpinnings that contribute to response vrsus progression remain poorly understood. However, to date there are few preclinical models that accurately represent these disparate disease scenarios. Methods Using combinatorial radio-immunotherapy consisting of PD-1 blockade, IL2Rβγ biased signaling, and OX40 agonism we were able to generate preclinical tumor models with conflicting responses, where head and neck squamous cell carcinoma (HNSCC) models respond and pancreatic ductal adenocarcinoma (PDAC) progresses. Results By modeling these disparate states, we find that regulatory T cells (Tregs) are expanded in PDAC tumors undergoing treatment, constraining tumor reactive CD8 T cell activity. Consequently, the depletion of Tregs restores the therapeutic efficacy of our treatment and abrogates the disparity between models. Moreover, we show that through heterotopic implantations the site of tumor development defines the response to therapy, as implantation of HNSCC tumors into the pancreas resulted in comparable levels of tumor progression. Conclusions This work highlights the complexity of combining immunotherapies within the tumor microenvironment (TME) and further defines the immune and non-immune components of the TME as an intrinsic feature of immune suppression.
Disruption of tumor-intrinsic PGAM5 increases anti-PD-1 efficacy through the CCL2 signaling pathway
Authors: Xiaoying Wei, Hong Wang, Huiquan Liu, Jianguo Wang, Peijie Zhou, Xiaoyang Li, Yuan He, Yan Li, Dong Han, Ting Mei, Yuwen Wang, Ziye Li, Junhao Ning, Zilong Xu, Anlin Wang, Yixuan Li, Jingjing Cheng, Dong Qian
Journal: Journal for ImmunoTherapy of Cancer (2025)

Immunosuppressive phenotype compromised immunotherapy efficacy of hepatocellular carcinoma. Tumor cells intrinsic mitochondria dynamics could pass effects on the extracellular microenvironment through mtDNA stress. PGAM5 anchors at mitochondria and regulates mitochondria functions. We aim to explore whether the regulation of tumor-intrinsic PGAM5 on mitochondria affects tumor-infiltrating immune cells in the microenvironment and whether tumor-intrinsic PGAM5 can be a therapeutic target to enhance the immunotherapy efficacy of hepatocellular carcinoma (HCC). We analyzed the correlation of PGAM5 expression and immune cells infiltration using Gene Expression Omnibus (GEO) and The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) data sets based on cibersort algorithm and tumor-tissue arrays from two independent cohorts. To further validate our findings, we established subcutaneous and orthotopic mouse HCC models with tumor-intrinsic Pgam5 deficiency and analyzed tumor-infiltrating immune cells by flow cytometry and single-cell RNA sequencing. Mechanistically, we established an in vitro co-culture system and analyzed proteomics data to find out the bridge between tumor cell PGAM5 and tumor-associated macrophages (TAMs) in the microenvironment. Immunofluorescence, chromatin-immunoprecipitation, ELISA, mass spectrometry were conducted to explore the molecular pathway. Macrophages were depleted to investigate whether the effects of tumor-intrinsic PGAM5 on TAMs could affect immunotherapy efficacy in HCC orthotopic and subcutaneous mouse models. PGAM5 expression in tumor was positively correlated with M2-phenotype TAM infiltration in patients with both HCC and mouse HCC tumor models. High tumor-intrinsic PGAM5 expression promoting M2 TAMs infiltration correlated with poor clinical-pathological characteristics and prognosis in patients with HCC. Disruption of tumor-intrinsic Pgam5 reduced TAM M2 polarization and inhibited HCC tumor growth in tumor-bearing mice. Mechanistically, in HCC cells PGAM5 deficiency inhibited mitochondria fission by promoting TRIM28 binding with DRP1, which increased ubiquitination and degradation of DRP1. Tumor-intrinsic PGAM5 deficiency mediated mitochondria fusion and reduced cytosolic mtDNA stress which attenuated TLR9 activation and downstream NF-κB-regulated CCL2 secretion. Furthermore, disruption of tumor-intrinsic Pgam5 significantly facilitated CD8+ T cells activation and improved anti-programmed cell death protein-1 therapeutic efficacy with macrophages depletion compromising synergistic antitumor immune response. Our results shed light on the effect of tumor mitochondria dynamics on TAMs in tumor microenvironment. Tumor-intrinsic PGAM5 can be a therapeutic target to improve immunotherapy efficacy in patients with HCC.
Selection can favor a recombination landscape that limits polygenic adaptation
Authors: Tom Parée, Luke Noble, Denis Roze, Henrique Teotónio
Journal: Molecular Biology and Evolution (2025)

Abstract Modifiers of recombination rates have been described but the selective pressures acting on them and their effect on adaptation to novel environments remain unclear. We performed experimental evolution in the nematode Caenorhabditis elegans using alternative rec-1 alleles modifying the position of meiotic crossovers along chromosomes without detectable direct fitness effects. We show that adaptation to a novel environment is impaired by the allele that decreases recombination rates in the genomic regions containing fitness variation. However, the allele that impairs adaptation is indirectly favored by selection, because it increases recombination rates and reduces the associations among beneficial and deleterious variation located in its chromosomal vicinity. These results validate theoretical expectations about the evolution of recombination but suggest that genome-wide polygenic adaptation is of little consequence to indirect selection on recombination rate modifiers.
Phase 2 pilot trial of tislelizumab plus low-dose nab-paclitaxel for extensive very high-risk non-muscle-invasive bladder cancer
Authors: Yunkai Qie, Shiwang Huang, Chong Shen, Zhouliang Wu, La Da, Kaipeng Jia, Zhe Zhang, Gangjian Zhao, Lili Wang, Guoping Xu, Yang Zhao, Rui Liang, Jianing Guo, Changping Li, Hua Dong, Man Li, Hongjun Li, Houyuan Chen, Dawei Tian, Changli Wu, Wei Zhang, Zesheng An, Haitao Wang, Yuanjie Niu, Hailong Hu
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Combinations of immune checkpoint inhibitors and nab-paclitaxel have improved outcomes in advanced urothelial carcinoma and muscle-invasive bladder cancer. This study evaluates the safety and efficacy of tislelizumab combined with low-dose nab-paclitaxel in extensive very high-risk (VHR) non-muscle-invasive bladder cancer (NMIBC). Patients and Methods: TRUCE-02 was a single-arm phase 2 trial that included 63 patients with visually incomplete resection and/or high-volume high-grade T1 tumors (with or without carcinoma in situ), who were ineligible for or declined radical cystectomy. Patients received intravenous tislelizumab (200 mg on day 1) and nab-paclitaxel (200 mg on day 2) every 3 weeks, with assessment approximately 3 months after initial administration. The primary endpoint was the complete response rate of high-risk disease. Main secondary endpoints included safety and duration of complete response. Results: The safety analysis included all 63 patients and the efficacy analysis included 59 patients. Thirty-seven patients [62.7%; 95% confidence interval (CI), 49.1-75.0%] achieved a complete response of high-risk disease, with a 24-month sustained response rate of 96.3% (95% CI, 89.4-100.0%). Grade 3-4 treatment-related adverse events occurred in nine patients (14%), with no fatal events reported. Conclusions: Tislelizumab plus low-dose nab-paclitaxel was well-tolerated and showed promising antitumor activity, making it a potential alternative for extensive VHR NMIBC patients who are ineligible for or decline radical cystectomy.
Evidence for Public Policies to Prevent Suicide Death in the United States
Authors: Jonathan Purtle, Amanda I. Mauri, Michael A. Lindsey, Katherine M. Keyes
Journal: Annual Review of Public Health (2025)

Suicide rates have increased in the United States in recent years. Public policies have great potential to prevent suicide death, and well-designed quasi-experimental studies have identified policies that are effective at reducing suicide rates; however, evidence about these policies has not been synthesized. This review summarizes evidence across three domains of public policies: ( a ) policies that affect structural determinants of suicide risk (e.g., policies that improve economic security), ( b ) policies that promote access to clinical services (e.g., Medicaid expansion), and ( c ) policies that limit access to lethal means for completing suicide (e.g., policies that restrict access to firearms). The historical context of suicide prevention in US public policy is provided, considerations for successful suicide prevention policy implementation are discussed—such as policy awareness among key groups, enforcement, and sufficient funding—and priority areas for future research are enumerated.
Graph neural networks in histopathology: Emerging trends and future directions
Authors: Siemen Brussee, Giorgio Buzzanca, Anne M R Schrader, Jesper Kers
Journal: Medical Image Analysis (2025)

Histopathological analysis of whole slide images (WSIs) has seen a surge in the utilization of deep learning methods, particularly Convolutional Neural Networks (CNNs). However, CNNs often fail to capture the intricate spatial dependencies inherent in WSIs. Graph Neural Networks (GNNs) present a promising alternative, adept at directly modeling pairwise interactions and effectively discerning the topological tissue and cellular structures within WSIs. Recognizing the pressing need for deep learning techniques that harness the topological structure of WSIs, the application of GNNs in histopathology has experienced rapid growth. In this comprehensive review, we survey GNNs in histopathology, discuss their applications, and explore emerging trends that pave the way for future advancements in the field. We begin by elucidating the fundamentals of GNNs and their potential applications in histopathology. Leveraging quantitative literature analysis, we explore four emerging trends: Hierarchical GNNs, Adaptive Graph Structure Learning, Multimodal GNNs, and Higher-order GNNs. Through an in-depth exploration of these trends, we offer insights into the evolving landscape of GNNs in histopathological analysis. Based on our findings, we propose future directions to propel the field forward. Our analysis serves to guide researchers and practitioners towards innovative approaches and methodologies, fostering advancements in histopathological analysis through the lens of graph neural networks.
Impact of resistance training on cardiometabolic health-related indices in patients with type 2 diabetes and overweight/obesity: a systematic review and meta-analysis of randomised controlled trials
Authors: Sameer Badri Al-Mhanna, Barry A Franklin, John M Jakicic, Emmanuel Stamatakis, Linda S Pescatello, Deborah Riebe, Walter R Thompson, James Skinner, Sheri R Colberg, Nouf H Alkhamees, Bodor Bin Sheeha, Mehmet Gülü, Abdullah F Alghannam, Alexios Batrakoulis
Journal: British Journal of Sports Medicine (2025)

Objective To evaluate the effects of resistance training on cardiometabolic health-related outcomes in patients with type 2 diabetes mellitus (T2DM) and overweight/obesity. Design Systematic review and meta-analysis of randomised controlled trials (RCTs). Data sources PubMed, Web of Science, Scopus, Science Direct, Cochrane Library and Google Scholar databases were searched from inception up to May 2024. The search strategy included the following keywords: diabetes, resistance exercise and strength training. Eligibility criteria for selecting studies RCTs published in English comparing resistance training alone with non-exercising standard treatment. Participants were adults diagnosed with T2DM and concurrent overweight/obesity (body mass index (BMI) ≥25 kg/m 2 ). Results A total of 18 RCTs qualified involving 1180 patients (48.6/51.4 female/male ratio; 63.3±7.0 years; 29.3±4.3 kg/m 2 ). Waist circumference (standardised mean differences (SMD) −0.85 cm, 95% CI −1.66 to −0.04), waist-to-hip ratio (SMD −0.72, 95% CI −1.30 to −0.15), high-density lipoprotein cholesterol (SMD +0.40 mg/dL, 95% CI 0.07 to −0.72), triglycerides (SMD −0.54 mg/dL, 95% CI −1.06 to −0.02), fasting blood glucose (SMD −0.65 mmol/L, 95% CI −1.19 to −0.12), fasting insulin (SMD −0.74 uIU/mL, 95% CI −1.12 to −0.36) and glycated haemoglobin (SMD −0.32%, 95% CI −0.63 to −0.01) improved compared with standard treatment. The risk of bias was low to unclear, and the quality of evidence was very low to moderate. Conclusions Resistance training as a standalone exercise intervention in the management and treatment of T2DM with concurrent overweight/obesity is associated with many cardiometabolic benefits when compared with standard treatment without exercise. PROSPERO registration number CRD42022355612.