PhD Student University of Macau Macao, Macao, Macau
Abstract: Growing evidence had demonstrated important immunomodulatory functions of p53 (encoded by TP53), in addition to its other well-known roles in tumor suppression. Tumor cells with different p53 statuses often manifest complicated immune evasion capability relevant to various mechanisms. Here, we found that osteosarcoma cell lines with p53 loss had lower natural killer (NK) sensitivity than those with wild type p53, which was restored following ectopic expression of TP53 in the cells. Then, we elucidated the correlation of p53 and NK sensitivity in human osteosarcoma. Via single cell RNA-seq analysis, we identified mesenchymal stem cells (MSCs) as a source-of-origin for osteosarcoma, in which cells with high scores of p53 functions had more signal communications with NK cells than cells with low scores. Then, we modeled the preneoplastic stage of osteosarcoma using TP53-/- MSCs constructed through TP53 knockout. TP53-/- MSCs showed lower NK sensitivity than the wild-type control and TP53-/- MSC-derived osteocytes displayed osteosarcoma-like characteristics. The reduction in NK sensitivity was associated with NF-κB-IFNβ-mediated upregulation of NK-inhibitory ligands, mainly type-Ia human leukocyte antigens (HLA-Ia). Consistently, clinical data mining also demonstrated the correlation of p53 functions negatively with the HLA-Ia level and type I IFN signaling. Thus, these findings suggest that NK resistance increases in p53-deficient MSCs and osteosarcoma cells via NF-κB-IFNβ-mediated upregulation of HLA-Ia, revealing a novel role of p53 during tumorigenesis.
Funding Source: Macau Science and Technology Development Fund grants [0002-2021-AKP, 0071-2022-A2], University of Macau Research Committee funds [MYRG2022-00044-FHS], China National Natural Science Foundation [32270842].
