Cell-free Tumor Microparticle Vaccines Stimulate Dendritic Cells via cGAS/STING Signaling

Abstract

Tumor antigens and innate signals are vital considerations in developing new therapeutic or prophylactic antitumor vaccines. The role or requirement of intact tumor cells in the development of an effective tumor vaccine remains incompletely understood. This study reveals the mechanism by which tumor cell-derived microparticles (T-MP) can act as a cell-free tumor vaccine. Vaccinations with T-MPs give rise to prophylactic effects against the challenge of various tumor cell types, while T-MP-loaded dendritic cells (DC) also exhibit therapeutic effects in various tumor models. Such antitumor effects of T-MPs are perhaps attributable to their ability to generate immune signaling and to represent tumor antigens. Mechanically, T-MPs effectively transfer DNA fragments to DCs, leading to type I IFN production through the cGAS/STING-mediated DNA-sensing pathway. In turn, type I IFN promotes DC maturation and presentation of tumor antigens to T cells for antitumor immunity. These findings highlight a novel tumor cell-free vaccine strategy with potential clinical applications.

Tumor cell-derived microparticles polarize M2 tumor-associated macrophages for tumor progression

“…48,49,51 Our previous study showed that T-MPs contain both nuclear and mitochondrial DNA fragments and effectively activate dendritic cells through cGAS/STING pathway. 27 In the present study, we further demonstrated that T-MPs activate the cGAS/STING pathway in macrophages. The key signal transducer downstream of STING is TBK1, a central IKK family member of serine/threonine kinase essential for IFN induction.…”

“…Recently, we identified that T-MPs included mitochondrial and nuclear DNA fragments that activated the cGAS/STING signaling pathway in dendritic cells. 27 We thus examined the involvement of TBK1, because activated STING can recruit TBK1 and TBK1 has been reported as one of the upstream signal molecules of STAT6. 28 As expected, the phosphorylation of TBK1 was enhanced in T-MP-treated M0 macrophages, and more importantly, knocking down TBK1 resulted in decreases in the phosphorylation of STAT6 and the expression of arginase 1 (Fig.…”

Tumor cell-derived microparticles: a new form of cancer vaccine

“…This type I IFN is responsible for T-MP-induced DC maturation via upregulation of CD80, CD86, and MHCII. 5 In our study, we found that DCs rarely took up apoptotic tumor cells but highly effectively took up T-MPs, probably due to the appropriate size of T-MPs. Following taking up T-MPs, DCs underwent maturation, presented tumor antigen peptides, and stimulated T cell development toward Th1 effector cells.…”

“…T-MPs harbor abundant DNA fragments of both genomic and mitochondrial origins, which are capable of activating type I IFN pathway inside DC. 5 Type I interferon recently is highlighted to play a crucial role in the induction of protective antitumor immunity. 6 IFN-a is recognized as a powerful inducer of the activation of DCs and IFN-a-conditioned DCs represent promising DC candidates for the development of therapeutic cancer vaccines.…”

Exosome-mediated immune regulation and its clinical application

“…Interestingly, it has been reported that tumor cell exosome-engulfed DCs produce immune competent exosomes for effective induction of anti-tumor immunity [39,40] . This seems to be related to the Type-I IFN secretion mediated by cGAS (cyclic GMP-AMP synthase)/STING (Stimulation of IFN gene) pathway in DCs by exosomal DNAs [41] .…”