The tumor suppressor kinase DAPK3 drives tumor-intrinsic immunity through the STING-IFNb pathway Phospho
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Orbitrap Fusion
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
David Gonzalez
PROVIDER: MSV000086706 | MassIVE | Fri Jan 15 13:09:00 GMT 2021
SECONDARY ACCESSION(S): PXD023637
REPOSITORIES: MassIVE
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Project description:Proteome analysis reveals that the tumor suppressor kinase DAPK3 drives tumor-intrinsic immunity through the STING-IFNb pathway Proteome
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Project description:PARP inhibitors (PARPi) have drastically changed the treatment landscape of advanced ovarian tumors with BRCA mutations. However, the impact of this class of inhibitors in patients with advanced BRCA-mutant breast cancer is relatively modest. Using a syngeneic genetically-engineered mouse model of breast tumor driven by Brca1 deficiency, we show that tumor-associated macrophages (TAMs) blunt PARPi efficacy both in vivo and in vitro. Mechanistically, BRCA1-deficient breast tumor cells induce pro-tumor polarization of TAMs, which in turn suppress PARPi-elicited DNA damage in tumor cells, leading to reduced production of dsDNA fragments and synthetic lethality, hence impairing STING-dependent anti-tumor immunity. STING agonists reprogram M2-like pro-tumor macrophages into an M1-like anti-tumor state in a macrophage STING-dependent manner. Systemic administration of a STING agonist breaches multiple layers of tumor cell-mediated suppression of immune cells, and synergizes with PARPi to suppress tumor growth. The therapeutic benefits of this combination require host STING and are mediated by a type I IFN response and CD8+ T cells, but do not rely on tumor cell-intrinsic STING. Our data illustrate the importance of targeting innate immune suppression to facilitate PARPi-mediated engagement of anti-tumor immunity in breast cancer.
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Project description:Type I interferon (IFN) response is the most recognized signaling activity of STING, and IFN signaling is commonly believed to be the major (if not the sole) contributor to STING-mediated anti-viral and anti-cancer responses. Here, we genetically mutated mouse Sting serine 365 residue that is critically required for initiating IFN signaling. Sting-S365A mutation in mice precisely ablated IFN-dependent while preserving IFN-independent activities of STING. To our surprise, StingS365A/S365A mice protected against HSV-1 infection remarkably well, similar to wild type mice, while Sting–/– mice succumbed to infection very quickly. This challenges the current prevailing view and suggests that STING controls HSV-1 infection through IFN-independent activities. Transcriptomic analysis of wild type, Sting–/– and StingS365A/S365A macrophages and T cells stimulated with Sting agonist DMXAA revealed widespread IFN-independent activities of STING in both cell types and identified many T cell effector functions that are activated by STING independently of IFN. In mouse tumor models, we found that T cells in the tumor experience substantial cell death that was in part mediated by STING. Adoptively transferred Sting–/– T cells were more resistant to cell death in the tumor leading to more effective tumor control compared to wild type and StingS365A/S365A T cells. Together, our data demonstrate that mammalian STING possesses widespread IFN-independent activities that are functionally important for restricting Type I interferon (IFN) response is the most recognized signaling activity of STING, and IFN signaling is commonly believed to be the major (if not the sole) contributor to STING-mediated anti-viral and anti-cancer responses. Here, we genetically mutated mouse Sting serine 365 residue that is critically required for initiating IFN signaling. Sting-S365A mutation in mice precisely ablated IFN-dependent while preserving IFN-independent activities of STING. To our surprise, StingS365A/S365A mice protected against HSV-1 infection remarkably well, similar to wild type mice, while Sting–/– mice succumbed to infection very quickly. This challenges the current prevailing view and suggests that STING controls HSV-1 infection through IFN-independent activities. Transcriptomic analysis of wild type, Sting–/– and StingS365A/S365A macrophages and T cells stimulated with Sting agonist DMXAA revealed widespread IFN-independent activities of STING in both cell types and identified many T cell effector functions that are activated by STING independently of IFN. In mouse tumor models, we found that T cells in the tumor experience substantial cell death that was in part mediated by STING. Adoptively transferred Sting–/– T cells were more resistant to cell death in the tumor leading to more effective tumor control compared to wild type and StingS365A/S365A T cells. Together, our data demonstrate that mammalian STING possesses widespread IFN-independent activities that are functionally important for restricting HSV-1 infection, tumor immune evasion and likely also adaptive T cell immunity.
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