Biology subjects

Stagg, J.

Publications and source records attributed to Stagg, J..

8 recordsLinked to original sources

bioRxiv2026

PRMT7 restricts CD8+ T cells expansion via the NF-κB pathway.

New therapeutics are needed to enhance cytotoxic T lymphocyte (CTL) expansion and effector function for effective tumor control. Here, we show that T cell specific deletion of Prmt7 using CD4-Cre mice increases CD8+ effector differentiation, cytokine secretion, cytolytic activity, and anti-tumor responses. Prmt7 deficiency transcriptionally reprogrammed CD8+ T cells by activating the NF-{kappa}B pathway, boosting proliferation, and elevating effector molecules such as CD25, CD69, and IFN{gamma}. Mechanistically, PRMT7 associated with RelA and restricted its nuclear translocation. To enable therapeutic translation, we developed a PRMT7-targeting PROTAC degrader (MS54). MS54-treated CTLs exhibited NF-{kappa}B pathway activation similar to Prmt7-deficient CTLs. Adoptive transfer of MS54-treated OT-I CTLs significantly improved tumor control in a syngeneic melanoma model. In human CTLs, MS54 enhanced proliferation, activation markers (CD69, CD137), IFN{gamma} production, and cytotoxicity toward melanoma. Together, these findings identify PRMT7 as a negative regulator of CD8+ T cell immunity and highlight MS54 as a promising strategy to improve adoptive T cell therapy.

molecular biology↗

bioRxiv2025

Distributed Biomarker Discovery for Immuno-Oncology

BackgroundIdentifying robust predictive biomarkers for immuno-oncology (IO) therapy response remains challenging due to the complexity of tumor host interactions and the limited availability of public datasets. While achieving clinical relevance requires biomarkers that generalize across diverse datasets, privacy concerns surrounding sensitive clinical and molecular data further restrict data sharing, impeding progress in biomarker discovery. Materials and MethodsWe developed a scalable, cloud-based distributed pipeline, implemented as an in-silico simulation of federated learning, to enable privacy-preserving integration of clinical and molecular data across institutions. This approach supports the development of genomic prediction algorithms without sharing sensitive patient data. Using curated gene expression profiles, we evaluated the association of tumor microenvironment and IO gene expression signatures with clinical outcomes across pan-cancer, cancer-specific, and treatment-specific settings, and developed a multivariable distributed model to predict IO response. ResultsWe implemented an integrated meta-analysis pipeline using harmonized data across 18 datasets comprising 967 patients and seven cancer types treated with PD-1/PD-L1, CTLA-4, or combination immunotherapies. This approach identified biomarkers specific to lung cancer and CTLA-4 therapy previously unreported in pan-cancer and pan-IO analyses, highlighting the value of context-specific associations. Similar gene expression signatures were associated with progression-free survival and response in both pan-cancer and melanoma datasets, with notable overlap between dual checkpoint blockade and PD-1/PD-L1 therapies. Distributed multivariable XGBoost models outperformed the average of locally trained models, indicating improved generalizability. ConclusionWe present a new distributed pipeline for biomarker discovery in immuno-oncology that preserves patient privacy through federated analysis and secure data handling. This study highlights the importance of larger, diverse datasets to refine cancer- and treatment-specific biomarkers, paving the way for more precise and personalized IO therapies.

bioinformatics↗

bioRxiv2023

Predicting developmental relationships of tumor resident and circulating T cells in ovarian cancer

Characterizing T cell populations and understanding their developmental relationships may help design more effective cancer immunotherapies. We coupled single-cell transcriptomics and T cell receptor (TCR) {beta} profiling of intratumoral and peripheral T cells in ovarian cancer patients to identify transcriptional programs and infer their relationship by trajectory and TCR overlap analyses. We proposed a model of differentiation pathway from an intermediate GZMH-expressing CD8 T cell subset found in the blood and tumor that progressively reinforces the exhaustion and tissue residency programs from a CCL4-expressing cluster towards XCL1- and CXCL13-expressing terminally exhausted cells. Inferred cell communication analysis suggests that interaction with CXCL13-expressing CD4 T cells, which we refer to as Tfh-like cells, sustains the effector function of this intermediate GZMH-expressing CD8 T cell subset. Moreover, our results suggest that Tfh-like cells attract cells expressing GPR183 through the production of its ligand 7,25 dihydroxycholesterol (7,25-HC). Finally, we demonstrated that GPR183 is highly expressed in a subset of pre-effector GZMK-expressing CD8 T cells and plasmacytoid dendritic cells. Collectively, our results suggest that Tfh-like cells expressing IL-21 help promote antitumor immunity against ovarian tumors by coordinating the action of immune cells responsive to 7,25-HC.

immunology↗

bioRxiv2022

The CD73 immune checkpoint promotes tumor cell metabolic fitness

CD73 is an ectonucleotidase overexpressed on tumor cells that suppresses anti-tumor immunity. Accordingly, several CD73 inhibitors are currently being evaluated in the clinic, including in large randomized clinical trials. Yet, the tumor cell-intrinsic impact of CD73 remain largely uncharacterized. Using metabolomics, we discovered that CD73 significantly enhances tumor cell mitochondrial respiration and aspartate biosynthesis. Importantly, rescuing aspartate biosynthesis was sufficient to restore proliferation of CD73-deficient tumors in immune deficient mice. Seahorse analysis of a large panel of mouse and human tumor cells demonstrated that CD73 enhanced oxidative phosphorylation (OXPHOS) and glycolytic reserve. Targeting CD73 decreased tumor cell metabolic fitness, increased genomic instability and suppressed poly ADP ribose polymerase (PARP) activity. Our study thus uncovered an important immune-independent function for CD73 in promoting tumor cell metabolism, and provides the rationale for previously unforeseen combination therapies incorporating CD73 inhibition.

cancer biology↗

bioRxiv2020

1-Methylnicotinamide is an immune regulatory metabolite in human ovarian cancer

Immune regulatory metabolites are key features of the tumor microenvironment (TME), yet with a few notable exceptions, their identities remain largely unknown. We uncovered the immune regulatory metabolic states and metabolomes of sorted tumor and stromal, CD4+, and CD8+ cells from the tumor and ascites of patients with high-grade serous ovarian cancer (HGSC) using high-dimensional flow cytometry and metabolomics supplemented with single cell RNA sequencing. Flow cytometry revealed that tumor cells show a consistently greater uptake of glucose than T cells, but similar mitochondrial activity. Cells within the ascites and tumor had pervasive metabolite differences, with a striking enrichment in 1-methylnicotinamide (MNA) in T cells infiltrating the tumor compared to ascites. Despite the elevated levels of MNA in T cells, the expression of nicotinamide N-methyltransferase, the gene encoding the enzyme that catalyses the transfer of a methyl group from S-adenosylmethionine to nicotinamide, was restricted to fibroblasts and tumor cells. Treatment of T cells with MNA resulted in an increase in T cell-mediated secretion of the tumor promoting cytokine tumor necrosis factor alpha. Thus, the TME-derived metabolite MNA contributes to an alternative and non-cell autonomous mechanism of immune modulation of T cells in HGSC. Collectively, uncovering the tumor-T cell metabolome may reveal metabolic vulnerabilities that can be exploited using T cell-based immunotherapies to treat human cancer.

immunology↗

bioRxiv2020

Immunotherapy efficacy in colorectal cancer is dependent on activation of a microbial-metabolite-immune circuit

Cancer is a leading cause of death globally. Checkpoint blockade therapies offer a promising treatment for many cancers, but have been ineffective for colorectal cancers. Previous studies have shown a dependency of immunotherapies on the microbiota. Consequently, we hypothesized that specific gut bacteria promote immunotherapy for colorectal cancer. We identify three commensal bacteria and a microbial metabolite, inosine, that enhance the efficacy of immune checkpoint blockade therapy in colorectal cancer. We show that inosine interacts with the adenosine A2A receptor on T cells resulting in intestinal Th1 cell differentiation. Decreased gut barrier function induced by immunotherapy increased the translocation of bacterial metabolites and promoted cancer protective Th1 cell activation. This microbial-metabolite-immune circuit provides a mechanism for a new class of bacteria-enhanced checkpoint blockade therapies. The efficacy of this mechanism differs among colorectal cancer subtypes and highlights the strengths as well as potential limitations of this novel bacterial co-therapy for cancer.

cancer biology↗

bioRxiv2018

Olfactory Projection Neurons From the Moth Antennal Lobe Lateral Cluster Exhibit Diverse Morphological and Neurophysiological Characteristics

Olfactory projection neurons convey information from the insect antennal lobe (AL) to higher centers in the brain. Many studies on moths have reported excitatory projection neurons with cell bodies in the medial cell cluster (mcPNs) that predominantly send an axon from the AL to calyces of the mushroom body (CA) via the medial antennal lobe tract (mALT) and then to the lateral horn (LH) of the protocerebrum. These neurons tend to have dendritic arbors restricted to a single glomerulus (i.e. they are uniglomerular). In this study, we report on the physiological and morphological properties of a group of pheromone-responsive olfactory projection neurons with cell bodies in the moth AL lateral cell cluster (lcPNs) of two heliothine moth species. While mcPNs typically exhibit a narrow odor tuning range related to the restriction of their dendritic arbors within a single glomerulus, lcPNs exhibited an array of morphological and physiological configurations. Pheromone-responsive lcPNs varied in their associations with glomeruli (uniglomerular and multiglomerular), dendritic arborization structure and connections to higher brain centers with projections primarily through the lateral antennal lobe tract and to a lesser extent the mediolateral antennal lobe tract to a variety of protocerebral targets including ventrolateral and superior neuropils as well as LH. Physiological characterization of lcPNs also revealed a diversity of response profiles including those either enhanced by or reliant upon presentation of a pheromone blend. These responses manifested themselves as higher maximum firing rates and/or improved temporal resolution of pulsatile stimuli. lcPNs therefore participate in conveying a variety of olfactory information relating to qualitative and temporal facets of the pheromone stimulus to a more expansive number of protocerebral targets than their mcPN counterparts. The role of lcPNs in the overall scheme of olfactory processing is discussed.

neuroscience↗

bioRxiv2017

DNA-Demethylating Agents enhance cytolytic activity of CD8+ T Cells and anti-tumor immunity

Recent studies have shown that DNA methyltransferase inhibitors (DNMTi) can induce IRF7 activation and Type I/III interferon signaling through dsRNA-mediated viral mimicry in cancer cells. By performing a large pan-cancer analysis using TCGA data, we determined that IRF7 activation is associated with higher CD8+ T cell tumor infiltration and higher cytolytic activity across multiple cancer types. Accordingly, we demonstrate that DNMTi treatment results in increased CD8+ T cell tumor infiltration, enhanced cytolytic activity and CD8+ T cell dependent tumor growth inhibition. Finally, we show that DNMTi triggers a process marked by the induction of viral mimicry directly on CD8+ T cells, leading to activation of dsRNA sensing pathway, and up-regulation of T cell activation markers, effector cytokines, and Granzyme B. Taken together, our findings suggest that dsRNA sensing pathway activation in the immune compartment, through pharmacological DNA demethylation, is a viable strategy for boosting anti-tumor immune response.

cancer biology↗