Abstract 6147: Immune population changes in mammary adipose tissue during the development of obesity and their influence on triple negative breast cancer progression
Authors: Liu Shimeng , Zhang Yi , Brown Myles 
Published: June 2022

Abstract
Obesity is associated with increased risk for many cancer types, including triple-negative breast cancer (TNBC). In addition to obesity’s role in TNBC pathogenesis, it is also recognized as a marker of poor prognosis for survival in pre- and post-menopausal women. However, the mechanism underlying how obesity leads to worsened TNBC progression remains unclear. In this study, we aim to characterize the immune population changes in mammary adipose during the development of obesity and their impact on TNBC progression. First, we utilized a diet-induced obesity mouse model to evaluate tumor growth under obese condition. Four weeks after E0771 (TNBC cell line) mammary fat pad injection, TNBC tumors volume were 1.6-fold larger in obese C57BL/6 mice compared to their lean counterparts. To profile the transcriptome changes induced by obesity, we performed single-cell RNA-Seq on mammary adipose stromal vascular fraction and TNBC allograft from lean and obese C57BL/6 female mice. In TNBC allografts, obesity upregulated genes enriched in the extracellular matrix and epithelial-mesenchymal transition pathways in cancer cells, creating a more aggressive phenotype. Consistent with the heavier TNBC tumor burden, lymphocyte infiltration decreased while myeloid population increased in TNBC allografts from obese mice, which indicated an immunosuppressed tumor microenvironment. Macrophage was the dominant population among Cd45+ cells in tumors, constituting 41.2% in lean and 51.2% in obese mice. An increase of adipose tissue macrophage (ATM) population (2.2-fold increase in obese vs lean adipose; 5.6-fold increase in tumor-bearing vs control adipose) was also observed in the obese or tumor-bearing mammary adipose stroma. Using Gene Set Enrichment Analysis (GSEA), we found that ATM adapted to the obese condition by upregulating fatty acid metabolism and adipogenesis hallmarks while downregulating IFNγ response, allograft rejection, and TNFα signal hallmarks. When encountering TNBC development, ATM downregulated similar proinflammatory pathways, while upregulated the hypoxia and glycolysis pathways. Through integrative analysis, we found that the complement pathway is the primary pathway upregulated in ATM under both obese and tumor growth conditions. Major components of the complement pathway, C1qa and C1qb, were significantly upregulated in ATM by TNBC and obesity. Interestingly, C1qa and C1qb were also upregulated in bone-marrow derived macrophage during M2 polarization and when co-culturing with E0771. Taken together, our data showed that the C1qahi/C1qbhi macrophage expanded in mammary adipose tissue during the development of obesity and TNBC, which created an immunosuppressed microenvironment to facilitate TNBC progression. This suggests that the complement pathway may serve as a potential immune therapy target for obese TNBC patients.
Citation Format: Shimeng Liu, Yi Zhang, Myles Brown. Immune population changes in mammary adipose tissue during the development of obesity and their influence on triple negative breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6147.