Summary
♦️Phagocytes are generally capable of en- gulfing and eliminating apoptotic cells without initiating the CGAS-STING path- ways that are triggered by cytosolic dou- ble-stranded DNA.
♦️ How phagocytes are therefore able to detect DNA-damaged cells that are potentially precancerous or virally infected is not well understood. Park et al. report that DNA-damaged cells initiate a cGAS-STING-driven gene program, which spurs the production of immunogenic products including CCL5 and STING-inducible endosomal vesicles (SIEVEs) containing autophagy-associ- ated proteins associated with cytosolic DNA.
♦️After these target cells are phago- cytosed, these products trigger the phagocyte’s own cGAS-STING system. Mutations that silence CGAS-STING may therefore be one way that DNA-damaged and transformed cells escape detection by the immune system. -Seth Thomas Scanlon.
Abstract;
♦️Antigen-presenting cells (APCs) are readily activated after phagocytosing in- fected or DNA-damaged cells but not normal apoptotic cells for reasons that are not well understood.
♦️Here, we demonstrate that after DNA damage events, cytosolic dsDNA species trigger intrinsic STING signaling and the pro- duction of key immunogenic proteins, including CCL5, which renders such cells capable of APC activation upon phago- cytosis.
♦️These events involve the genera- tion of immunogenic STING-inducible endosomal vesicles (SIEVEs) additionally comprising critical autophagy-associated proteins associated with cytosolic DNA species.
♦️After phagocytosis, extrinsic CGAS-STING signaling is triggered via engulfed, immunogenic transactivating DNA vesicles resulting in APC stimula- tion. These results help explain how APCs are predominantly activated by DNA-damaged or infected cells in con- trast with normal apoptotic cells and suggest that reconstitution of STING sig- naling or key inducible genes in CGAS- STING-defective malignancies could substantially augment cancer immunotherapies.