Senescence-Associated Secretory Phenotype Determines Survival And Therapeutic Response In Cervical Cancer

Simple SummaryCervical cancer is the most common gynecological cancer caused by persistent infections with human papilloma viruses. Over time, this infection leads to secretion of inflammatory proteins in the cervix, which exacerbates the neoplastic and senescent changes to the cervical epithelial lining. We measured nineteen serum proteins in retrospectively collected samples from cervical cancer patients. We show here that 10 out of 19 proteins are associated with senescence phenotype in cervical cancer patients. This senescence associated protein signature influences how cervical cancer patients responds to therapy.Molecular biomarkers that can predict survival and therapeutic outcome are still lacking for cervical cancer. Here we measured a panel of 19 serum proteins in sera from 565 patients with stage II or III cervical cancer and identified 10 proteins that have an impact on disease specific survival (DSS) (Hazzard's ratio; HR = 1.51-2.1). Surprisingly, all ten proteins are implicated in senescence-associated secreted phenotype (SASP), a hallmark of cellular senescence. Machine learning using Ridge regression of these SASP proteins can robustly stratify patients with high SASP, which is associated with poor survival, and patients with low SASP associated with good survival (HR = 3.09-4.52). Furthermore, brachytherapy, an effective therapy for cervical cancer, greatly improves survival in SASP-high patients (HR = 3.3, p < 5 x 10(-5)) but has little impact on survival of SASP-low patients (HR = 1.5, p = 0.31). These results demonstrate that cellular senescence is a major determining factor for survival and therapeutic response in cervical cancer and suggest that senescence reduction therapy may be an efficacious strategy to improve the therapeutic outcome of cervical cancer.