Abstract 2038: A non-canonical, cell-autonomous STING function protects breast cancer cells from intrinsic and genotoxic-induced DNA instability

Abstract

Abstract Several studies have recently indicated the activation of the immune system against tumor cells as well as the targeting of cancer cell DNA damage repair mechanisms as effective strategies to target tumor growth. STING is a well-known DNA sensor of innate immunity mostly characterized as a transmembrane protein of various cytoplasmic organelles that senses cytosolic DNA as a danger signal and triggers inflammatory responses. A current cancer immunotherapy strategy relies on the use of STING agonists to boost the patient's immune system through a cytokine-mediated recruitment of immune cells that infiltrate and kill tumor cells. However, the role of the STING pathway in cancer is far to be fully understood as there is otherwise accumulating evidence that activation of the cGAS-STING pathway can have a deleterious outcome. We recently showed that genotoxic treatment of breast cancer PDXs and cell lines triggered the STING pathway. Genetic inhibition of this pathway in MCF7 cells increased genotoxic treatment efficacy by promoting cell death and delaying cell colony regrowth, indicating that STING pathway intrinsically promotes cell resistance to treatment. In this study, we show that STING silencing decreased cell viability in a panel of classical or PDX-derived breast cancer cell lines irrespective of their ER status and of the genotoxic treatment received. Cell fractionation indicates that part of the STING pool intrinsically resides in the nucleus of various malignant and non-malignant cells. Fluorescence and electron microscopy show that STING partly resides at the inner membrane of the nucleus, and mass-spectrometry analysis revealed that STING interacts with core proteins of the non-homologous end joining (NHEJ) DNA damage repair (DDR) complex. STING promotes NEHJ-related protein assembly with chromatin, and its silencing decreases DDR and cell viability, while STING overexpression protects cancer cells from genotoxic treatment. STING involvement in DDR is independent of the classical STING-TBK1-IFN inflammatory response, thus identifying a new functional pathway for STING. STING nuclear localization was confirmed in a panel of breast cancer patient-derived xenografts and in surgical samples from breast cancer patients that received neoadjuvant chemotherapy. Evaluation of the impact of STING expression on patient outcome via the Kaplan Meier plotter show that overall STING expression level is positively correlated with favorable outcome in breast cancer patients, however high STING expression in breast and ovarian cancer patients treated with adjuvant chemotherapy is associated with poor prognosis. These findings place STING at the crossroad of DDR and immune surveillance, two major pathways for tumorigenesis and tumor survival. Citation Format: Laura Cheradame, Ida Chiara Guerrera, Julie Gaston, Alain Schmitt, Vincent Jung, Marion Pouillard, Nina Radosevic-Robin, Mauro Modesti, Jean-Gabriel Judde, Vincent Goffin, Stefano Cairo. A non-canonical, cell-autonomous STING function protects breast cancer cells from intrinsic and genotoxic-induced DNA instability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2038.