SMARCA4 regulates the NK-mediated killing of senescent cells.

Virinder Reen, Mariantonietta D'Ambrosio, Pia Pernille Søgaard, Katie Tyson, Bryony J Leeke, Isabelle Clément, Isabel C A Dye, Joaquim Pombo, Adam Kuba, Yemin Lan, Joanna Burr, Ida C Bomann, Maria Kalyva, Jodie Birch, Sanjay Khadayate, George Young, Diane Provencher, Anne-Marie Mes-Masson, Santiago Vernia, Nicholas McGranahan, Hugh J M Brady, Francis Rodier, Raffaella Nativio, Michelle Percharde, Iain A McNeish, Jesús Gil

MRC Laboratory of Medical Sciences (LMS), Du Cane Road, London W12 0NN, UK.MRC Laboratory of Medical Sciences (LMS), Du Cane Road, London W12 0NN, UK. · pubmed

Paper

Abstract

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 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 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.

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Research summary

The paper investigates the role of SMARCA4 in enhancing NK-mediated elimination of senescent cells, which is directly related to the mechanisms of cellular senescence and immune response in the context of aging. While it presents solid research findings, the impact is limited as it primarily focuses on a specific cancer model rather than addressing broader mechanisms of aging or longevity. The findings may contribute to the understanding of senotherapeutic strategies, but they do not fundamentally alter the landscape of aging research.

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