p21 produces a bioactive secretome that places stressed cells under immunosurveillance

Immune cells identify and destroy damaged cells to prevent them from causing cancer or other pathologies by mechanisms that remain poorly understood. Here, we report that the cell-cycle inhibitor p21 places cells under immunosurveillance to establish a biological timer mechanism that controls cell fate. p21 activates retinoblastoma protein (Rb)-dependent transcription at select gene promoters to generate a complex bioactive secretome, termed p21-activated secretory phenotype (PASP). The PASP includes the chemokine CXCL14, which promptly attracts macrophages. These macrophages disengage if cells normalize p21 within 4 days, but if p21 induction persists, they polarize toward an M1 phenotype and lymphocytes mount a cytotoxic T cell response to eliminate target cells, including preneoplastic cells. Thus, p21 concurrently induces proliferative arrest and immunosurveillance of cells under duress.

Automated summary

The cell-cycle inhibitor p21 activates Rb-dependent transcription to generate a complex bioactive secretome, known as PASP, which includes chemokine CXCL14 that attracts macrophages. Macrophages disengage if cells normalize p21 within 4 days, but persisting p21 induction leads to M1 polarization and cytotoxic T cell response for eliminating target cells, including preneoplastic cells. Thus, p21 concurrently induces proliferative arrest and immunosurveillance of cells under duress.