Abstract 1316: Immune cell dysfunction is enhanced in a mouse model of obesity-associated breast cancer lung metastasis

Abstract

Abstract Obesity is known to worsen the overall prognosis of breast cancer patients. Breast cancer patients with a body mass index (BMI) of ≥30 kg/m2 have an increased risk for metastatic disease compared to patients with a BMI in the normal range. Further studies are necessary to understand the mechanisms driving increased breast cancer metastasis in obese patients, particularly to the lung. Although immune cells like neutrophils and myeloid derived suppressor cells have been studied in breast cancer metastasis of the lung, little is known how adaptive immune cells function in metastatic niche of the lung in obesity. To investigate these gaps, we fed 3-week-old female FVB/N mice either a low-fat diet (LFD) or high-fat diet (HFD) for 16 weeks to induce obesity. We then injected estrogen receptor positive (ER+) TC2 cells into the mammary fat pad. Tumors grew to 0.5 cm in diameter then were surgically removed. Lung tissue was collected 8 weeks after tumor removal to examine progression of metastatic disease, and T cell populations were quantified in metastatic lung tissue from obese and lean mice using flow cytometry. Lungs from obese mice showed a significant increase of total immune cells (CD45) and a decrease in total T cells and natural killer cells (NK) compared with controls. CD3+ cells and CD8+ T cells from obese mice expressed higher levels of programmed cell death protein-1 (PD1), a marker of T cell dysfunction. These results suggest that T cells from the lungs of obese mice may have a greater level of T cell dysfunction than controls. To further investigate how obesity alters the function of T cells, CD45+ cells were sorted from lungs from lean and obese mice with and without metastasis, and gene expression was examined using the Nanostring nCounter Immune Exhaustion panel. Immune cells from the lungs of obese non-tumor-bearing mice showed increased expression of NK exhaustion markers and increased TCR signaling. In metastatic lungs from obese mice, immune cells also showed impaired interferon and tumor necrosis factor signaling and an increase in genes associated with exhaustion in NK cells. Further analysis showed upregulated expression of genes associated with senescence in immune cells from metastatic lungs of obese mice. These data suggest that obesity may increase dysfunctional states of T cells and NK cells, leading to enhanced metastatic growth of breast cancer cells. Citation Format: Abbey E. Williams, Lisa M. Arendt. Immune cell dysfunction is enhanced in a mouse model of obesity-associated breast cancer lung metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1316.