Nuclear factor–ĸB (NF-ĸB) transcription factor is a family of essential regulators of the immune response and cell proliferation and transformation. A typical factor is a heterodimer made of either p50 or p52, which are limited processing products of either p105 or p100, respectively, and a member of the Rel family of proteins, typically p65. The transcriptional program of NF-ĸB is tightly regulated by the composition of the dimers. In our previous work, we demonstrated that the ubiquitin ligase KPC1 is involved in ubiquitination and proteasomal processing of p105 to generate p50. Its overexpression and the resulting high level of p50 stimulates transcription of a broad array of tumor suppressors. Here we demonstrate that additional mechanisms are involved in the p50-mediated tumor-suppressive effect. p50 down-regulates expression of a major immune checkpoint inhibitor, the programmed cell death-ligand 1 (PD-L1), both in cells and in tumors. Importantly, the suppression is abrogated by overexpression of p65. This highlights the importance of the cellular quantities of the two different subunits of NF-ĸB which determine the composition of the dimer. While the putative p50 homodimer is tumor-suppressive, the “canonical” p50p65 heterodimer is oncogenic. We found that an additional mechanism is involved in the tumor-suppressive phenomenon: p50 up-regulates expression of the proinflammatory chemokines CCL3, CCL4, and CCL5, which in turn recruit into the tumors active natural killer (NK) cells and macrophages. Overall, p50 acts as a strong tumor suppressor via multiple mechanisms, including overexpression of tumor suppressors and modulation of the tumor microenvironment by recruiting active immune cells.

核因子-ĸB (NF-ĸB) 转录因子是免疫反应以及细胞增殖和转化的重要调节因子家族。一个典型的因子是由 p50 或 p52 组成的异二聚体，它们分别是 p105 或 p100 的有限加工产物，并且是蛋白质 Rel 家族的成员，通常是 p65。NF-ĸB 的转录程序受到二聚体组成的严格调控。在我们之前的工作中，我们证明泛素连接酶 KPC1 参与 p105 的泛素化和蛋白酶体加工以生成 p50。它的过度表达和由此产生的高水平 p50 可刺激多种肿瘤抑制因子的转录。在这里，我们证明 p50 介导的肿瘤抑制作用涉及其他机制。p50 下调细胞和肿瘤中主要免疫检查点抑制剂——程序性细胞死亡配体 1 (PD-L1) 的表达。重要的是，p65 的过度表达会消除这种抑制。这凸显了 NF-ĸB 两个不同亚基的细胞数量的重要性，它们决定了二聚体的组成。虽然假定的 p50 同二聚体具有肿瘤抑制作用，但“典型的”p50p65 异二聚体具有致癌作用。我们发现肿瘤抑制现象还涉及另一种机制：p50 上调促炎趋化因子 CCL3、CCL4 和 CCL5 的表达，这些趋化因子反过来又招募到肿瘤活性自然杀伤 (NK) 细胞和巨噬细胞中。总体而言，p50 通过多种机制发挥强大的肿瘤抑制因子的作用，包括肿瘤抑制因子的过度表达和通过招募活性免疫细胞来调节肿瘤微环境。