Biology subjects

Glenny, E. M.

Publications and source records attributed to Glenny, E. M..

5 recordsLinked to original sources

bioRxiv2025

Obesity Impairs the Antitumor Activity of CAR-T Cells in Triple-Negative Breast Cancer

BackgroundWe have reported that chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR) are effective in a preclinical model of triple negative breast cancer (TNBC), and have initiated a Phase I study to assess safety and efficacy. However, heterogeneous antigen expression and immunosuppressive tumor microenvironments (TME) remain roadblocks for effective CAR-T cell therapy. In particular, obesity represents a negative prognostic factor in TNBC partly due to chronic inflammation and impaired adaptive immune responses. Hence, we sought to determine if obesity can affect the antitumor activity of B7-H3.CAR-T cells. MethodsWe used qPCR and western blotting to determine if cytokines associated with obesity affect B7-H3 expression in TNBC cell lines. Furthermore, we used shRNA to suppress B7-H3 expression in a syngeneic orthotopic E0771 tumor model and measured tumor growth in control and diet-induced obese (DIO) mice. Finally, we evaluated the antitumor effects of B7-H3.CAR-T cells in both control and DIO mice orthotopically engrafted with the E0771 tumor cell line. Immune profiling was conducted using flow cytometry. ResultsObesity-related inflammatory cytokines promote B7-H3 expression in human and murine TNBC cells in vitro and B7-H3 expression correlates with tumor aggressiveness in vivo. CAR-T cells obtained from control or DIO mice were equally cytotoxic in vitro but activated T cells and B7-H3.CAR-T cells obtained from DIO mice show transcriptomic changes (enriched Tox2, Prdm1, Batf) and impaired glycolytic capacity, respectively. Finally, we demonstrated that obesity impairs CAR-T cell antitumor effects and durability of response in vivo with a near complete loss of memory formation. ConclusionsHere we identified a correlation between B7-H3 expression, obesity, and rate of tumor growth in TNBC. Furthermore, we showed that obesity constrains both the ability of B7-H3.CAR-T cells to control tumor growth and to elicit durable immunological memory. Taken together, these data identify obesity as an underappreciated and potent modulator of CAR-T cell functionality. What is already knownB7-H3 protein is upregulated in many human malignancies including TNBC and is often associated with worsened outcomes. B7-H3.CAR-T cells show promise in preclinical models of TNBC and entered clinical translation. What this study addsThis study identifies a previously unknown correlation between obesity, B7-H3 expression, and rate of tumor growth in TNBC. Furthermore, our preclinical model of B7-H3.CAR-T cell therapy demonstrates that obesity negatively affects the antitumor activity of B7-H3.CAR-T cells in TNBC. How this study affects other research/practiceThis study highlights obesity as an understudied and critically important covariate for adoptive T-cell therapy and demonstrates important links between systemic metabolism and antigen expression. This work paves the way for future mechanistic and translational research into how obesity impacts CAR-T cell functionality.

cancer biology↗

bioRxiv2025

Obesity promotes conserved inflammatory and metabolic transcriptional programs in mouse and human colon tumors

BackgroundThe global prevalence of obesity, an established risk and progression factor for colon cancer, is high and rising. Unfortunately, the mechanisms underlying the obesity-colon cancer association are incompletely understood, and new molecular targets enabling more effective intervention strategies to break the obesity-colon cancer link are urgently needed. ObjectiveThis study integrated RNA sequencing data from mouse and human colon tumor samples, as well as human adipose samples, to rigorously establish obesity-associated transcriptomic signatures conserved between the two species. MethodsWe employed a mouse colon cancer model with colonoscopy-guided orthotopic transplantation of syngeneic Apc-null;KrasG12D/+;Trp53-null;Smad4-null;tdTomato colon tumor organoids. Epithelial cell adhesion molecule (EpCAM)-positive cells from murine tumors, and 193 human colon tumors and 188 human mesenteric adipose tissue samples from the ColoCare cohort underwent transcriptomic analyses. ResultsDiet-induced obesity reduced survival in the mouse model of colon cancer. Integrated transcriptomic analyses of EpCAM-positive murine tumor cells and bulk human tumors revealed obesity-driven enrichment of inflammation and metabolic pathways, including upregulation of genes involved in innate immune sensing (TLR2, MYD88, IRF4) and tumor microenvironment remodeling (MMP9, TGFB1, SERPINE1). Analysis of paired mesenteric visceral adipose tissue and tumor samples from the ColoCare cohort indicated that obesity amplifies inflammatory signaling pathways through unique adipose ligand-tumor receptor interactions. ConclusionsThese results establish obesity-associated adipose tissue dysregulation as a key inter-tissue modulator of biology, with concordant cross-species effects on tumor cell-intrinsic inflammatory and metabolic programs.

cancer biology↗

bioRxiv2024

Purified diets containing high levels of soluble fiber and grain-based diets promote similar gastrointestinal morphometry yet distinct microbial communities

Grain-based diets (GBDs) are widely used in rodent studies but their utility is limited due to batch-to-batch variability resulting from inconsistent ingredients. Purified diets (PDs) are composed of only known and refined ingredients and offer a solution to the constraints of GBDs. However, unlike GBDs, PDs commonly used as control diets typically contain little to no soluble fiber. We therefore sought to identify a combination of fibers in PDs that best recapitulates the gastrointestinal morphometry and intestinal microbial composition of mice fed GBDs. Adult male mice (n=30) were randomly assigned to one of six diets--two GBDs and four PDs with varying insoluble and soluble fiber composition--for 28 days. 16S rRNA gene sequencing was used to compare microbial profiles across different gastrointestinal (GI) niches and diets. Gut microbiotas and cecal weights were distinct between mice fed the two GBDs, indicating that GBDs are unreliable controls in diet-based studies. Unexpectedly, intestinal microbial richness decreased as the amount of soluble fiber in the PDs increased and the addition of multiple soluble fibers did not rescue this effect. Mice fed PDs with high soluble fiber content ([≥] 75% of dietary fiber was soluble fiber) best recapitulated GI morphometry of mice fed GBDs, but intestinal microbial communities were distinct between PD- and GBD-fed mice. Although supplementing PDs with soluble fiber improved GI morphometry, further research to determine the optimal mixture of soluble and insoluble fibers is required to more closely mirror the intestinal microbial diversity observed in mice fed GBDs. ImportanceDietary fibers are essential for maintaining gut health. Insoluble fibers aid in fecal bulking and water retention while soluble fiber is a fermentative substrate for intestinal microbial communities. GBDs are commonly used in preclinical research but the variability in ingredients across batches impedes reproducibility. PDs, which are composed of highly refined ingredients, pose a potential solution but the most widely used low-fat control PDs contain no soluble fiber. This study intended to identify a PD with a combination of fibers that promotes murine gut health and microbial diversity. A PD with optimal fiber composition would aid in the standardization and reproducibility of studies investigating intestinal physiology and the gut microbiota.

microbiology↗

bioRxiv2024

Tirzepatide attenuates mammary tumor progression in diet-induced obese mice

Obesity, an established risk and progression factor for at least 13 cancer types, is highly prevalent globally, and effective strategies to mitigate the burden of obesity-related cancer are urgently needed. We investigated whether tirzepatide, a widely used incretin-mimetic drug that induces substantial weight loss, offers anticancer benefits. Across 3 tumor models, we demonstrate that chronic tirzepatide treatment reverses diet-induced increases in body weight and fat mass, systemic metabolic perturbations, and tumor growth. We also showed that the anticancer activity of tirzepatide does not involve direct effects on the neoplastic cells used, which lack incretin receptor expression. The anticancer actions of tirzepatide require the reversal of both the metabolic dysregulation and hyporesponsiveness of CD8+ tumor infiltrating lymphocytes evident in obesity. Our findings establish tirzepatide as a promising compound for intercepting obesity-related cancers.

cancer biology↗

bioRxiv2023

Calorie Restriction Outperforms Bariatric Surgery in a Murine Model of Obesity and Triple-Negative Breast Cancer

Obesity promotes triple-negative breast cancer (TNBC), and effective interventions are urgently needed to break the obesity-TNBC link. Epidemiologic studies indicate that bariatric surgery reduces TNBC risk, while evidence is limited or conflicted for weight loss via low-fat diet (LFD) or calorie restriction (CR). Using a murine model of obesity- driven TNBC, we compared the antitumor effects of vertical sleeve gastrectomy (VSG) with LFD, chronic CR, and intermittent CR. Each intervention generated weight and fat loss and suppressed tumor growth relative to obese mice (greatest suppression with CR). VSG and CR regimens exerted both similar and unique effects, as assessed using multi-omic approaches, in reversing obesity-associated transcriptional, epigenetic, secretome, and microbiota changes and restoring antitumor immunity. Thus, in a murine model of TNBC, bariatric surgery and CR each reverse obesity-driven tumor growth via shared and distinct antitumor mechanisms, and CR is superior to VSG in reversing obesitys procancer effects.

cancer biology↗