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.

肿瘤促进免疫细胞的浸润是肿瘤进展的强大驱动力。众所周知，巨噬细胞在肿瘤微环境中的积累会促进肿瘤生长并与许多肿瘤类型的不良预后相关。TAp73 是 p53/p63/p73 家族的成员，可作为肿瘤抑制因子，并已被证明可抑制肿瘤血管生成。然而，TAp73 在调节免疫细胞浸润中的作用尚不清楚。在这里，我们报告了低水平的 TAp73 与乳腺癌中增加的 NF-κB 调节的炎症特征相关。此外，我们表明 TAp73 的缺失导致 NF-κB 过度活化和 Ccl2 的分泌，Ccl2 是一种已知的 NF-κB 靶标和单核细胞和巨噬细胞的趋化剂。重要的，与对照组相比，TAp73 缺陷肿瘤表现出表达甘露糖受体 (CD206) 和清道夫受体 A (CD204) 的原肿瘤巨噬细胞的积累增加。通过揭示 TAp73 表达与原肿瘤 CD163 的积累呈负相关，进一步强调了人乳腺癌中 TAp73 表达的相关性⁺乳腺癌患者样本中的巨噬细胞。总之，我们的研究结果表明 TAp73 通过抑制 NF-κB 途径调节巨噬细胞积累和乳腺癌表型。