STING and transplantation: can targeting this pathway improve outcomes?

Abstract

Stimulator of interferon genes (STING) is an innate immune sensor of cytoplasmic dsDNA originating from microorganisms and host cells. STING plays an important role in the regulation of murine graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and may be similarly activated during other transplantation modalities. In this review, we discuss STING in allo-HSCT and its prospective involvement in autologous HSCT (auto-HSCT) and solid organ transplantation (SOT), highlighting its unique role in nonhematopoietic, hematopoietic, and malignant cell types.

Graphical abstract

Figure 1.

The STING pathway in NH and HCs: prospective contribution to transplant outcome. (A) Left: As a result of transplantation-related damage, dsDNA from host cells (eg, dendritic cells, epithelial cells) or viruses induce cyclic dinucleotide (CDN) production by cGAS which bind to and activate STING. Bacterial CDNs can also activate STING directly. Downstream of STING signaling, activation of IRF3 and NF-κB induce the production of cytokines, which regulate immune activation and reparative processes such as epithelial regeneration. Right: STING activation in the NH or hematopoietic compartments during SOT could increase T-cell responses against donor grafts. STING activation in the NH compartment during allo-HSCT increases aGVHD in MHC-matched transplant recipients; however, expression of STING in this compartment decreases aGVHD in MHC-mismatched transplant recipients. The potential role of STING in auto-HSCT is unclear. Promotion of epithelial repair in the GI tract and/or increased anti-pathogen T-cell responses could diminish recipient transplant-related mortality (TRM). Alternatively, increased cytokine production as a result of conditioning could elevate recipient TRM. (B) STING-targeted agents (see Table 1) can be combined with tumor vaccination and checkpoint blockade to promote tumor-specific responses without exacerbating GVHD. Application of this strategy could be combined with prophylactic GVHD regimens involving posttransplant cyclophosphamide to reduce potential exacerbation of donor antihost alloreactivity in addition to direct cytotoxic effects on the tumor. EBV, Epstein-Barr virus.