Identifying novel strategies to promote NK cell-mediated clearance of senescent cells
File(s)
Author(s)
Reen, Virinder
Type
Thesis
Abstract
Cellular senescence is a stress-induced stable growth arrest programme that is accompanied by distinct phenotypic alterations including the production of a bioactive secretome, termed the senescence-associated secretory phenotype (SASP). Transient senescence induction can suppress cancer development, limit fibrosis, and promote wound repair. SASP-mediated activation of the host immune response triggers the clearance of senescent cells contributing to those phenotypes. However, with age and impaired immunity, senescence clearance is subdued, and lingering senescent cells paradoxically contribute to tumour progression and age-related disorders. Interventions that directly eliminate senescent cells such as senolytic compounds have shown to prolong survival and improve healthspan, but there are concerns regarding the safety and efficacy of these treatments. Consequently, strategies that target the SASP to reignite an anti-senescence immune response may provide an alternative therapeutic solution. Here, we carried out large-scale RNAi screens in search for perturbations that enhance an immunomodulatory SASP expression in oncogene-induced senescent cells. Based on our candidates, we screened for genes regulating natural killer (NK) cell effector function. We identified 9 targets whose knockdown preferentially sensitised senescent cells to NK cell-mediated elimination, without interfering with the viability of growing cells. Upon pharmacological inhibition of two of those targets, SMARCA4 and POLR1B, we observed a significant reinforcement of NK-mediated killing of cells that have undergone oncogene- or chemotherapy-induced senescence. Overall, our results indicate that the genetic or pharmacological inhibition of SMARCA4 and POLR1B enhanced NK cell surveillance of senescent cells and may represent novel senotherapeutic interventions for various senescence-associated diseases including cancer and fibrosis.
Version
Open Access
Date Issued
2022-09-15
Date Awarded
01/03/2023
License URL
Advisor
Gil, Jesús
Sponsor
Imperial College London
Publisher Department
Institute of Clinical Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)