Fight Aging!

Senescent cells accumulate with age in part because the immune system becomes less able to clear senescent cells in a timely manner. Researchers have much yet to discover regarding the details of this decline, but some of the existing discoveries seem analogous to the ways in which cancer cells can shield themselves from the immune system via altered surface features. Such discoveries pave the way for the development of ways to restore at least some of the lost competence of the aged immune system, encouraging it to better destroy senescent cells. Here, the focus is on natural killer cells, now well known to be involved in clearance of senescent cells and the target of a number of research programs in this context.

Induction of senescence by chemotherapeutic agents arrests cancer cells and activates immune surveillance responses to contribute to therapy outcomes. In this investigation, we searched for ways to enhance the natural killer (NK)-mediated elimination of senescent cells. We used a staggered screen approach, first identifying siRNAs potentiating the secretion of immunomodulatory cytokines to later test for their ability to enhance NK-mediated killing of senescent cells.

We identified that genetic or pharmacological inhibition of SMARCA4 enhanced senescent cell elimination by NK cells. SMARCA4 expression is elevated during senescence and its inhibition derepresses repetitive elements, inducing the senescence-associated secretory phenotype (SASP) via activation of cGAS/STING and MAVS/MDA5 pathways. Moreover, a PROTAC targeting SMARCA4 synergized with cisplatin to increase the infiltration of CD8 T cells and mature, activated NK cells in an immunocompetent model of ovarian cancer. Our results indicate that SMARCA4 inhibitors enhance NK-mediated surveillance of senescent cells and may represent senotherapeutic interventions for ovarian cancer.

Link: https://doi.org/10.1126/sciadv.adn2811