Obesity Is Associated With Immunometabolic Changes in Adi-Pose Tissue That May Drive Treatment Resistance in Breast Cancer: Immune-Metabolic Reprogramming and Novel Therapeutic Strategies

Abstract

White adipose tissue (WAT) has evolved to slowly mobilise energy stores in the form of lipids and a dynamic endocrine and immunologically active organ that regulates energy homeostasis. Breast WAT is involved not only in the biosynthesis of important molecular mediators but is also reported to be linked to the metastatic potential of breast tumours. The role of adiposity and consequently the role of systemic inflammation in immune responses and resistance to anti-cancer treatment in breast cancer (BC) patients is however still not clear. This review aims to evaluate the emerging evidence on the crosstalk between adiposity and the immune-tumour microenvironment in BC, its progression and treatment resistance. Adiposity, and by extension subclinical inflammation, are associated with metabolic dysfunction and changes in the immune-tumour microenvironment in BC. In oestrogen receptor positive (ER+) breast tumours, it is proposed that these changes are mediated via a paracrine interaction between macrophages and preadipocytes leading to elevated aromatase expression and secretion of pro-inflammatory cytokines and adipokines in the breast tissue in patients who are obese or overweight. In HER2+ breast tumours, WAT inflammation has been reported to induce trastuzumab resistance via activation of MAPK or PI3K signalling pathways. Furthermore, adipose tissue in patients with obesity is associated with upregulation of immune checkpoints on T-cells that is partially mediated via immunomodulatory effects of leptin and has been paradoxically associated with improved responses to immunotherapy in several cancers. In conclusion, evidence suggests that body composition and metabolic status are associated with patient outcomes. In order to optimise patient stratification and personalisation of treatment prospective studies are required to evaluate the role of body composition and metabolic parameters in metabolic immune reprogramming with and without immunotherapy in patients with BC.