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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.

Abstract Women with obesity who develop breast cancer have a worsened prognosis with diminished survival rates and increased rates of metastasis. Obesity is also associated with decreased breast cancer response to endocrine and chemotherapeutic treatments. Studies utilizing multiple in vivo models of obesity as well as human breast tumors have enhanced our understanding of how obesity alters the breast tumor microenvironment. Changes in the complement and function of adipocytes, adipose-derived stromal cells, immune cells, and endothelial cells and remodeling of the extracellular matrix all contribute to the rapid growth of breast tumors in the context of obesity. Interactions of these cells enhance secretion of cytokines and adipokines as well as local levels of estrogen within the breast tumor microenvironment that promote resistance to multiple therapies. In this review, we will discuss our current understanding of the impact of obesity on the breast tumor microenvironment, how obesity-induced changes in cellular interactions promote resistance to breast cancer treatments, and areas for development of treatment interventions for breast cancer patients with obesity.

Obesity is correlated with increased incidence of breast cancer metastasis, however, the mechanisms underlying how obesity promotes metastasis are unclear. In a diet-induced obese mouse model, obesity enhanced lung metastasis in both the presence and absence of primary mammary tumors and increased recruitment of myeloid lineage cells into the lungs. In the absence of tumors, obese mice demonstrated increased numbers of myeloid lineage cells and elevated collagen fibers within the lung stroma, reminiscent of premetastatic niches formed by primary tumors. Lung stromal cells isolated from obese tumor-naïve mice showed increased proliferation, contractility, and expression of extracellular matrix, inflammatory markers and transforming growth factor beta-1 (TGFβ1). Conditioned media from lung stromal cells from obese mice promoted myeloid lineage cell migration in vitro in response to colony-stimulating factor 2 (CSF2) expression and enhanced invasion of tumor cells. Together, these results suggest that prior to tumor formation, obesity alters the lung microenvironment, creating niches conducive to metastatic growth.

SUMMARYObesity is correlated with increased incidence of breast cancer metastasis, however the mechanisms underlying how obesity promotes metastasis are unclear. In a diet-induced obesity mouse model, obesity enhanced lung metastases in both the presence and absence of primary mammary tumors and increased recruitment of myeloid lineage cells into the lungs. In the absence of tumors, obese mice demonstrated increased numbers of myeloid lineage cells and elevated collagen fibers within the lung stroma, reminiscent of pre-metastatic niches formed by primary tumors. Lung stromal cells isolated from obese non-tumor-bearing mice showed increased proliferation, contractility, and expression of extracellular matrix, inflammatory markers, and TGFβ1. Conditioned media from lung stromal cells from obese mice promoted myeloid lineage cell migration in vitro in response to CSF2 expression and enhanced invasion of tumor cells. Together, these results suggest that prior to tumor formation, obesity alters the lung microenvironment, creating niches conducive for metastatic growth.

Recent epidemiological studies suggest that the risk factors of breast density and obesity together increase breast cancer risk in premenopausal women, and these women have a worsened prognosis following breast cancer diagnosis. Although the underlying causes of increased risk associated with dense breasts and obesity have individually been explored, little is known about how these underlying risk factors interact together to enhance breast cancer risk. To model breast density, we used heterozygous Col1a1tmjae mice, that have a mutation that limits collagen degradation, leading to increased mammary collagen deposition. Heterozygous (het) mice or wild type (wt) litter mates were fed either a control diet (CD) or a high fat diet (HFD) to induce obesity. We quantified F4/80-positive macrophages within mammary glands using immunohistochemistry. We observed significantly increased numbers of macrophages in mammary glands of CD/het, HFD/wt and HFD/het mice compared to CD/wt mice. We observed significantly enhanced picrosirius red stained collagen surrounding mammary ducts from CD/het, HFD/wt, and HFD/het mice compared to those from CD/wt mice. Notably, HFD/het mice had significantly more collagen surrounding ducts than in mammary glands from CD/het mice. These results may suggest that obesity enhances collagen deposition and macrophage-driven inflammation within dense breast tissue in the mammary glands of non-tumor-bearing mice. Citation Format: Abbey E. Williams, Abbey E. Williams, Erica Hoffman, Julia Warren, Suzanne Ponik, Lisa M. Arendt. Collagen density and obesity promote mammary gland inflammation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2574.