Biology subjects

Coleman, M. F.

Publications and source records attributed to Coleman, M. F..

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

Urinary Signatures Predict Calorie Restriction-Mediated Weight Loss in Obese Diversity Outbred Mice

Predictive analytics encompassing metabolomic profiles are increasingly being used to forecast responders to dietary interventions. Advances using this approach are particularly needed to personalize and enhance the effectiveness of dietary weight loss interventions. Using obese Diversity Outbred (DO) mice that model genetic and phenotypic heterogeneity of human populations, we aimed to identify urinary metabolite signatures predictive of responsiveness to calorie restriction (CR)-mediated weight loss. DO mice (150 males, 150 females) were fed a high-fat diet for 12 weeks to induce obesity, then urine was collected and an 8-week CR regimen (30% decrease in energy intake) initiated. At study completion, mice were rank-ordered according to their percent body weight change, with mice in the extreme quartiles deemed CR responders (n=67) versus nonresponders (n=67). Targeted semi-quantitative metabolomics identified elevated glutamic acid and hydroxyproline as key urinary metabolites that distinguish CR responders from CR nonresponders, independent of sex. Three urinary metabolites (glutamic acid, hydroxyproline, and putrescine) distinguished male CR responders from nonresponders. Six metabolites (glutamic acid, hydroxyproline, dopamine, histamine, lysine, and spermine) distinguished female CR responders from nonresponders. Multivariate receiver operating characteristic analyses integrated the common metabolites and sex-specific metabolites to reveal moderate (males) to robust (females, males plus females) prediction models of CR-mediated weight loss. Further, pathway analysis identified several metabolic pathways, including arginine and proline metabolism, and alanine, aspartate, and glutamate biosynthesis, that distinguished CR responders from nonresponders and could be indicative of metabolic reprogramming to enhance insulin sensitivity and energy metabolism.

physiology↗

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↗

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↗

bioRxiv2022

Hypoxia-mediated suppression of pyruvate carboxylase drives tumor microenvironment immunosuppression

Metabolic reprogramming and immune evasion are established hallmarks of the tumor microenvironment (TME). Growing evidence supports tumor metabolic dysregulation as an important mediator of tumor immune evasion. High TME levels of lactate potently suppress antitumor immunity. Pyruvate carboxylase (PC), the enzyme responsible for the anaplerotic conversion of pyruvate to oxaloacetate, is essential for lung metastasis in breast cancer. Moreover, PC may be dispensable in some cells within the TME, and loss of PC expression is associated with immunosuppression. Here we test whether PC suppression alters tumor metabolism and immunosuppression. Using multiple animal models of breast cancer, we identify a dimorphic role for PC expression in mammary cancer cells. Specifically, PC supports metastatic colonization of the lungs, while suppression of PC promotes primary tumor growth and suppresses histological and transcriptomic markers of antitumor immunity. We demonstrate that PC is potently suppressed by hypoxia, and that PC is frequently suppressed in solid tumors, particularly those with higher levels of hypoxia. Using metabolomics, high-resolution respirometry, and extracellular flux analysis, we show that PC-suppressed cells produce more lactate and undergo less oxidative phosphorylation than controls. Finally, we identify lactate metabolism as a targetable dependency of PC-suppressed cells, which is sufficient to restore T cell populations to the TME of PC-suppressed tumors. Taken together, these data demonstrate that elevated lactate following PC suppression by hypoxia may be a key mechanism through which primary tumors limit antitumor immunity. Thus, these data highlight that PC-directed tumor metabolism is a nexus of tumor progression and antitumor immunity.

cancer biology↗