Abstract 3822: Chromosomal instability shapes the tumor microenvironment through a chronic ER-stress response

Abstract Chromosomal instability (CIN) is a cancer hallmark associated with cancer metastasis and immune evasion. Yet, it is unclear how CIN modulates the tumor-microenvironment (TME). Here we show that CIN results in a protumor TME with enrichment of immune-suppressive macrophages, a granulocytic infiltrate, and exhausted T cells. Using ContactTracing, a newly developed computational tool to infer conditionally dependent cell-cell interactions from single cell RNA sequence data, we identify tumor ligands induced by the ER stress response in cancer cells as central mediators of immune suppression. Mechanistically, CIN-dependent chronic activation of the cytosolic DNA sensing cGAS-STING pathway promotes ER-stress-dependent transcription. Suppression of CIN or depletion of cancer cell STING reduces ER-stress and restores CIN-induced changes on the TME. Correspondingly, chronic STING activation in human breast cancer patients is associated with reduced tumor infiltrating lymphocytes and increased metastasis. Remarkably, pharmacologic inhibition of chronically active STING or depletion of downstream ER stress signaling suppresses metastasis in syngeneic models of melanoma, breast, and colorectal cancers, thereby demonstrating a viable therapeutic strategy for chromosomally unstable cancers. Citation Format: Jun Li, Melissa Hubisz, Ethan Earlie, Mercedes A. Duran, Emanuele Lettera, Su M. Phyu, Amit D. Amin, Matthew Deyell, Erina Kamiya, Karolina Budre, Julie-Ann Cavallo, Christopher Garris, Hannah Wen, Benjamin Izar, Eileen Parkes, Ashley Laughney, Samuel Bakhoum. Chromosomal instability shapes the tumor microenvironment through a chronic ER-stress response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3822.