Abstract 4142: Obesity contributes to CD8+ T cell dysfunction before and after lung metastasis in a mouse model of ER+ breast cancer

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. Although immune cells like neutrophils and myeloid derived suppressor cells have been studied in breast cancer metastasis of the lung, little is known how T cell populations change before and after metastasis. 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. One group was set as a tumor-naïve control and the other was 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 tumor-naïve and metastatic lung tissue from obese and lean mice using flow cytometry. Lungs from naïve obese mice showed a significant increase of total CD45+ immune cells. CD8+ T cells from naive obese mice expressed higher levels of programmed cell death protein-1 (PD1), a marker of T cell dysfunction or T cell activation. Metastatic lungs also showed increases in CD45+ immune cells and PD-1+ expression on CD3+ cells and CD8+ cells. Overall, metastatic lungs showed higher levels of PD-1 expression than naïve lungs on more cell types, evidence of more immune dysfunction or activation. 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 markers for increased TCR signaling. This may indicate more T cell activation which leads to exhaustion in obese naïve mice. In metastatic lungs from obese mice, immune cells showed impaired interferon and tumor necrosis factor signaling. In addition, immune cells from metastatic lungs of obese mice also had upregulated expression of genes associated with senescence which may indicate a combination of both exhaustion and senescent phenotypes are present. This was not seen in immune cells from naïve samples, indicating that obesity leads to more chronic T cell dysfunction in metastatic lungs. Overall, even without pathogenic interference, obesity contributes to more T cell signaling and impaired CD8+ T cell activation that leads to higher T cell dysfunction once metastasis is present. Citation Format: Abbey E. Williams, Lisa M. Arendt. Obesity contributes to CD8+ T cell dysfunction before and after lung metastasis in a mouse model of ER+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4142.