Abstract PS16-17: Pml mediates tumor-associated macrophages to promote breast tumor progression

Abstract

Abstract Introduction: Tumor-associated macrophages (TAMs) are major immunosuppressive cells that accumulate in tumor microenvironment (TME), and are associated with poor outcome in breast cancer patients. Although TAMs have been directly implicated in tumor cell proliferation, motility, invasiveness and chemoresistance, the underlying mechanisms by which TAMs promote tumor progression remains poorly elucidated. Methods: MCF-7 cells were cultured alone or co-cultured with human monocyte-derived macrophages (MDMs) or polarized TAMs (pol-TAMs). Genome-scale RNA-seq analysis from these samples showed that promyelocytic leukemia (PML) gene was significantly upregulated in pol-TAMs co-culture samples (P=0.0250). The upregulation of PML was further verified by qRT-PCR and immunohistochemistry (IHC) in tissue microarray (TMA, BR6161, US Biomax) containing 294 cases of primary breast tumor tissues, 19 cases of adjacent normal tissue and 9 cases of normal tissue, with duplicate cores per case of cancer, and single core per case of adjacent normal and normal tissue. To evaluate the infiltration of CD 68+ TAMs and its association with the upregulation of PML, IHC in the same TMA samples was performed. Kaplan-Meier survival plots were generated to assess effect on patient prognosis. Results: Global transcriptome analysis revealed that co-culture with pol-TAMs significantly upregulated PML expression in MCF-7 cells, which was confirmed by qRT-PCR. Further, the protein level of PML was detected by IHC in TMA tissue samples. As expected, both the maximal immunoreactivity and the percentage of stronger immunoreactivity of PML were higher in breast tumor than those in benign tissue (P<0.0001). The positive correlation between TAMs infiltration and PML expression in breast tumor tissue was further confirmed by IHC in the same TMA (P<0.0001, R2=0.2074). When compared among breast carcinoma tissue, a higher percentage of stronger immunoreactivity of PML was observed in lymph node metastasis cases (P=0.0369). Further, high PML expression resulted in worse relapse-free survival (RFS), overall survival (OS), distant metastasis-free survival (DMFS) and palliative performance scale (PPS) survival curve (logrank P =9.3e-11, 0.0012, 0.00012 and 0.00065 respectively). Conclusion: Promyelocytic leukemia (PML) gene is upregulated in a subset of breast tumor and has been identified as breast cancer oncogene. Here, we demonstrate that PML expression in tumor cells is induced by TAMs, and is enriched in lymph node metastasis. High PML expression also exhibited worse prognosis in patient outcome, consistent with lymph node metastasis cases. Thus, PML upregulation mediates TAMs activity to promote breast cancer progression, suggesting PML as a potential therapeutic target in breast malignancies. Citation Format: Meijun Long, Meena Kusi, Renbin Liu. Pml mediates tumor-associated macrophages to promote breast tumor progression [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-17.