Dendritic Cells but Not Macrophages Sense Tumor Mitochondrial DNA for Cross-priming through Signal Regulatory Protein a Signaling

Xu M, Pu Y, Han D, Shi Y, Cao X, Liang H, Chen X, Li X, Deng L, Chen Z, Weichselbaum R, Fu Y

Immunity 2017 Aug 15;47(2):363-373.e5

Speaker: Man-Ling Chu (朱曼菱)                       Time: 13:10~14:00, Jan. 10, 2018

Commentator: Dr. Hong-Tai Tzeng (曾鴻泰)       Place: Room 601

Abstract:

  Cytosolic DNA sensing is important for tumor immunity. However, tumor cells express CD47 to prevent immune cells from sensing DNA for immune evasion. Many evidences indicate that abundant CD47 has correlated with poor survival in several types of cancers. CD47 is a transmembrane protein known as a “ don’t eat me ”signal that interacts with signal regulatory protein α (SIRPα) expressed on macrophages and dendritic cells (DCs). The blocking of CD47- SIRPα interaction as a therapeutic target has been demonstrated in various preclinical models. Although macrophages had more powerful phagocytosis ability than DCs did, the therapeutic effect of increase of DNA sensing by CD47 blockade depended on DCs but not on macrophages. Mechanistically, activation of DADPH oxidase NOX2 in DCs after CD47 blockade inhibited the acidification of phagosomes and reduced the degradation of tumor mitochondrial DNA (mtDNA). In contrast, mtDNA was degraded in short time after phagocytosed in macrophages. As a result, tumor mtDNA was selectively increased inside the cytosol of DCs in response to CD47 blockade. mtDNA was recognized by cyclic-GMP-AMP synthase (cGAS) and stimulated type I interferon (IFN) production. In addition, cGAS-STING-IRF3 pathway induced by tumor mtDNA was also required for cross-priming in DCs which is important in adaptive immunity. In conclusion, after anti-CD47-mediated phagocytosis, DCs utilize cGAS pathway sensing mtDNA and play an important  role in bridging the innate response and adaptive response.

  In this study, the author observed that the effect of anti-CD47 treatment on tumor therapy attributes not only to the reduction of “don’t eat me” but also to the activation of mtDNA-mediated host cGAS-STING pathway inside DCs. The combination of anti-CD47treatment with ‘‘eat me signaling’’ enhancers, such as genotoxic agents, including radiotherapy and chemotherapy as well as targeted therapies, could be a potential therapeutic strategy to synergistically enhance phagocytosis and trigger mtDNA sensing to improve the adaptive immune response.

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