TAp73 represses NF-κB–mediated recruitment of tumor-associated macrophages in breast cancer

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 10; pp. 1 - 10
• Main Authors: Wolfsberger, Johanna, Sakil, Habib A. M., Zhou, Leilei, van Bree, Niek, Baldisseri, Elena, de Souza Ferreira, Sabrina, Zubillaga, Veronica, Stantic, Marina, Fritz, Nicolas, Hartman, Johan, Rolny, Charlotte, Wilhelm, Margareta T.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 09.03.2021
• Subjects: Accumulation; Angiogenesis; Biological Sciences; Breast cancer; Breast carcinoma; CD163 antigen; Correlation; Immune system; Infiltration; Inflammation; Macrophages; Mannose; Medicin och hälsovetenskap; Metastases; Monocyte chemoattractant protein 1; Monocytes; NF-κB protein; Phenotypes; Receptors; Scavenger receptors; Tumor microenvironment; Tumor suppressor genes; Tumors; NF-κB; breast cancer; p73; tumor-associated macrophages
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2017089118

Infiltration of tumor-promoting immune cells is a strong driver of tumor progression. Especially the accumulation of macrophages in the tumor microenvironment is known to facilitate tumor growth and to correlate with poor prognosis in many tumor types. TAp73, a member of the p53/p63/p73 family, acts as a tumor suppressor and has been shown to suppress tumor angiogenesis. However, what role TAp73 has in regulating immune cell infiltration is unknown. Here, we report that low levels of TAp73 correlate with an increased NF-κB–regulated inflammatory signature in breast cancer. Furthermore, we show that loss of TAp73 results in NF-κB hyperactivation and secretion of Ccl2, a known NF-κB target and chemoattractant for monocytes and macrophages. Importantly, TAp73-deficient tumors display an increased accumulation of protumoral macrophages that express the mannose receptor (CD206) and scavenger receptor A (CD204) compared to controls. The relevance of TAp73 expression in human breast carcinoma was further accentuated by revealing that TAp73 expression correlates negatively with the accumulation of protumoral CD163⁺ macrophages in breast cancer patient samples. Taken together, our findings suggest that TAp73 regulates macrophage accumulation and phenotype in breast cancer through inhibition of the NF-κB pathway.