STING negatively regulates allogeneic T-cell responses by constraining antigen-presenting cell function

Abstract

Stimulator of interferon genes (STING)-mediated innate immune activation plays a key role in tumor-and self-DNA elicited anti-tumor immunity and autoimmunity, respectively, yet the mechanism remains largely unclear. We utilized murine models of allogeneic hematopoietic cell transplantation (allo-HCT) to study the biology of STING in antigen-presenting cells (APCs) and T cells. STING expression in donor T cells was dispensable for their ability to induce graftversus-host disease (GVHD), a major complication of allo-HCT in the clinic. However, when STING-deficient mice were used as recipients, more severe GVHD was induced after allo-HCT.Using bone marrow (BM) chimeras where STING was absent in different compartments, we found that STING-deficiency on host hematopoietic cells was primarily responsible for exacerbating the disease. Furthermore, STING on host CD11c + cells played a dominant role in the regulation of allogeneic T-cell responses. Mechanistically, STING deficiency resulted in increased survival, activation and function of APCs, including macrophages and dendritic cells (DCs). Consistently, constitutive activation of STING attenuated the survival, activation and function of APCs isolated from STING V154M knock-in mice. In addition, STING-deficient APCs augmented donor T-cell expansion, chemokine receptor expression and migration into intestinal tissues, resulting in accelerated/exacerbated GVHD. Using pharmacologic approaches, we demonstrate that systemic administration of a STING agonist (c-di-GMP) to recipient mice before transplantation significantly reduced GVHD mortality. In conclusion, we reveal a novel role of STING in APC activity that dictates T-cell allogeneic responses and validate STING as a potential therapeutic target for controlling GVHD after allo-HCT.

The druggable transcription factor Fli-1 regulates T cell immunity and tolerance in graft-versus-host disease

“…Inhibition of topoisomerases by CPT, ETO, or TPT could induce apoptosis of activated T cells during the G 1 to S-phase transition ( 59 ), reduce the expression of MHC-II and costimulatory molecules on APCs ( 60 , 61 ), or activate the stimulator of IFN genes (STING) pathway ( 62 ) and other Fli-1–regulated inflammatory factors, such as CXCR3, IL-6, C16-ceramide, GM-CSF, and miR-17-92 ( 4 – 8 ). All of these pathways have been shown by us and others to critically contribute to GVHD pathogenesis ( 9 , 10 – 13 , 63 ).…”

Functional tumor cell-intrinsic STING, not host STING, drives local and systemic antitumor immunity and therapy efficacy following cryoablation

“…Lastly, it remains to be determined whether the observed effect of tumor cell-intrinsic STING contribution to local and systemic immunity converges on IFN-β, chemokines or other as-yet undiscovered effector molecules. Although IFN response is the most recognized signaling activity of STING and such IFN signaling is widely believed to be the major contributor to STING-mediated antiviral and antitumor responses, recent evidence suggests the existence of IFN-independent activities of STING in hematopoietic-derived cells including T cells, 18 20 21 as mice harboring the functionally deficient STING S365A/365A point mutant are still capable of exhibiting STING-related IFN-independent activities. Importantly, when analyzing chemokine and cytokine productions within TME, we found elevated IFN-β levels following cryoablation of RMS STING wt irrespective of host STING status, whereas INF-β levels remained at baseline in cryoablated STING -/- RMS TME even in wild-type mice.…”

“…16 17 STING is an essential protein for the innate immune defense against a wide array of microbial pathogens. STINGrelated contributions to homeostasis and disease pathogenesis have been described in innate myeloid immune cells, 18 as well as T, [19][20][21] non-hematopoietic stromal 22 and endothelial [23][24][25] cells. Detection of cytosolic dsDNA in the context of viral and bacterial infections, [26][27][28][29] aging and damaged cells, 30 or cancer, [31][32][33] is performed by the cytoplasmic DNA sensor, cGAS.…”

Spatial proteomics identifies a spectrum of immune dysregulation in acquired bone marrow failure syndromes

“…The end result is HSC depletion, either directly by IFN-γ increasing the sensitivity of HSCs to T-cell-mediated apoptosis ( 12 , 47 ) or indirectly by CCR5 increasing inflammatory macrophage persistence and the depletion of CD41+ HSCs ( 13 ). While STING classically regulates type 1 IFN responses to dsDNA pathogens and is expressed in most haematopoietic lineages, IFN-independent effects in T cells have been recently described, with STING KO mice exhibiting reduced T-cell death in response to STING agonists ( 48 ) and significant effects post-alloSCT, including increased proportions of macrophages and activated dendritic cells and increased CD8 T-cell proliferation and IFN-γ production ( 49 ). Additionally, analysis of mouse models of neutropenia has recently demonstrated that IFN-γ signalling in myeloid cells is associated with the functional decline of haematopoiesis ( 50 ).…”

“…In addition, CD44+ CD8 T cells have been shown to mediate anti-tumour responses without inducing GVHD ( 56 ), suggesting that downregulation in GGF patients may diminish graft vs. tumour responses. STING has also been examined for its impact on GVHD in both MHC-matched and mismatched mouse models, demonstrating that STING agonists may reduce or prevent GVHD ( 49 , 57 , 58 ). Our analysis is the first to our knowledge to examine STING expression in patient PB and BM samples, demonstrating an increased frequency of STING-positive cells across multiple PB lymphocyte subsets in patients post-alloSCT with STING downregulation in the BM of patients with PGF.…”