Differential PML localization in tumor-associated macrophages reflects the inflammatory state and the prognosis of triple-negative breast cancer patients

Abstract Background Triple-negative breast cancer (TNBC) stands out as a particularly aggressive and metastatic subtype, defined by its absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. It's important to note that outcomes for TNBC patients vary widely, suggesting this classification encompasses various cancers with different histological, genomic, and immunological profiles, leading to distinct prognoses. Our prior research revealed that the tumor microenvironment, especially the expression and localization of promyelocytic leukemia protein (PML) within tumor-associated macrophages (TAMs), can influence patient outcomes by affecting the inflammatory environment. The beneficial prognostic role of increased tumor-infiltrating lymphocytes (TILs) in TNBC is also well-established. Methods This is a retrospective cohort study composed of a total of 20 female patients affected by TNBCS, divided into two groups according to the observed outcome in a 10-year follow-up: 10 TNBC patients showing complete remission of the disease and 10 TNBC patients experiencing tumor recurrence and death within the follow-up. The collected histological tumor samples were stained to evaluate TILs and TAMs presence and PML expression. Results We found that PML expression in tumor cells is inversely related to the presence of TILs and is associated with worse patient outcomes. Furthermore, we discovered that patients with disease recurrence exhibited a higher number of TAMs with predominantly nuclear-localized PML, unlike what was observed in patients with complete disease recovery. This accumulation of PML in the nucleus reduces its presence at ER-mitochondria contact sites, thereby impairing its interaction with the NLRP3 inflammasome and leading to increased IL-1β secretion. This promotes a pro-inflammatory tumor microenvironment, as seen in patients with adverse outcomes. Conclusions Our findings suggest that both PML expression in cancer cells and its localization in TAMs can serve as additional prognostic factors, alongside TIL abundance, indicating the potential of PML as a target for TNBC therapy.