STING suppresses the reactivation of dormant metastasis

ABSTRACT: Metastatic relapse frequently develops from disseminated cancer cells that remain dormant in distant organs after the apparently successful treatment of a primary tumor. Disseminated cancer cells fluctuate between immune evasive quiescent and cell cycle reentry states, which exposes them to elimination by the immune system. Little is known about the molecules that determine immune-mediated clearing of awakened metastatic cells and how this process could be therapeutically activated to eliminate residual disseminated disease in patients. Here, we use models of indolent metastasis to identify cancer cell-intrinsic determinants of immune reactivity during cancer cell exit from dormancy. Through in vivo genetic screens of tumor-intrinsic immune regulators, we identified the STING (stimulator of interferon genes) pathway as a suppressor of metastatic outbreak in dormant models of human and mouse lung adenocarcinoma metastasis. STING levels and signaling activity rise in metastatic progenitors that reenter the cell cycle and are dampened by STING enhancer hypermethylation in breakthrough metastases or enhancer chromatin repression in cells reentering dormancy in response to TGF-β. STING expression in cancer cells from spontaneous metastases suppresses their outgrowth in a NK cell- and CD8+ T cell-dependent manner. Systemic treatment of mice with pharmacologic STING agonists eliminates indolent metastatic cells and prevents spontaneous metastasis, both effects requiring cancer cell STING function. Thus, STING signaling represents a checkpoint against the progression of dormant metastasis and suggests a therapeutically actionable strategy for the prevention of disease relapse. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for histone modification markers H3K4me1, H3K4me3, H3K27ac in human lung cancer cells at different stages of metastasis and in cells treated with TGF-β or not.

ORGANISM(S): Homo sapiens

PROVIDER: GSE210946 | GEO | 2023/01/30

REPOSITORIES: GEO