Work

1143 Obesity promotes interferon-driven regulatory T-cell activation and CD8 T-cell exhaustion in triple-negative breast cancer

Year: 2026

Type: conference-abstract

Abstract: Background Obesity is a prevalent metabolic condition associated with increased mortality and inferior clinical outcomes in triple-negative breast cancer (TNBC). Obesity-related chronic inflammation has been implicated in systemic immune dysregulation, but how obesity reshapes antitumor immunity within the TNBC tumor microenvironment remains poorly understood. We used spatial single-cell transcriptomics to investigate obesity-associated immune alterations within the tumor neighborhood in TNBC.Methods Thirty-nine TNBC tumors from Mayo Clinic patients including 23 obese (BMI ≥30 kg/m 2) and 16 normal (BMI 18–25 kg/m2) were analyzed. The tumor neighborhood was defined as all cells located within 50 mm of the nearest tumor cells. CosMxTM Spatial Molecular Imager spatial transcriptomic profiling was used to characterize immune cell composition, neighborhood interactions, and cell-type-specific transcriptional programs. Ingenuity pathway analysis was performed across immune populations within the tumor neighborhood, with particular focus on T-cell subsets. Pathways were considered significantly activated when they met statistical significance after Benjamini-Hochberg adjustment, p-value < 0.05, and had an absolute Z-score ≥ 1.5. Analysis was approved by the Institutional Review Board.Results While there was no significant difference in the number of CD8 and CD4 T cells in both tumor and stromal niches, obesity was associated with broad activation of interferon-related pathways across T-cell populations within the TNBC tumor neighborhood. These effects were most pronounced in regulatory T-cells and CD8 T-cells. Compared with tumors from patients with normal BMI, regulatory T-cells from obese TNBC tumors showed increased T-cell receptor signaling (Z-score = 2.74, p-value = 8.68E-10), interferon-a/b signaling (Z-score = 2.00, p-value = 9.04E-12), interferon- g signaling (Z-score = 1.70, p-value = 3.73E-11), and MHC class I antigen processing and presentation (Z-score = 2.18, p-value = 2.72E-3). CD8 T-cells from obese TNBC tumors demonstrated activation of interferon-a/b signaling (Z-score = 2.67, p-value = 3.04E-13), T-cell exhaustion signaling (Z-score = 2.33, p-value = 3.92E-14), MHC class I antigen processing and presentation (Z-score = 2.84, p-value = 8.62E-3), JAK1/JAK2/TYK2-mediated signaling (Z-score = 1.63, p-value = 4.77E-12), and DDX58/IFIH-1-mediated induction of interferon α/β (Z-score = 1.64, p-value = 1.16E-9). Together, these findings identify interferon signaling as a shared obesity-associated immune feature linked to both regulatory T-cell activation and CD8 T-cell dysfunction in TNBC tumor neighborhoods.Conclusions Obesity is associated with a chronic interferon-driven immune state in the TNBC tumor neighborhood, characterized by activated regulatory T-cells and exhausted CD8 T-cells. These findings suggest obesity-associated inflammation may contribute to immune dysfunction rather than effective antitumor immunity. Obesity-associated T-cell exhaustion may represent one mechanism of impaired immune-mediated tumor control in TNBC. Understanding how host metabolic status shapes spatial immunity programs may inform future biomarker development and immunotherapeutic strategies for TNBC.Acknowledgements This study was supported in part by Mayo Clinic Breast SPORE grant P50 CA116201 from the National Institutes of HealthEthics Approval The study was approved by the Mayo Clinic Institutional Review Board. The IRB approval ID is 18-008231. Participants gave informed consent before taking part in the study.

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.1143