Selective STING stimulation in dendritic cells primes antitumor T cell responses

Abstract

T cells that recognize tumor antigens are crucial for mounting antitumor immune responses. Induction of antitumor T cells in immunogenic tumors depends on STING, the intracellular innate immune receptor for cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) and related cyclic dinucleotides (CDNs). However, the optimal way to leverage STING activation in nonimmunogenic tumors is still unclear. Here, we show that cGAMP delivery by intratumoral injection of virus-like particles (cGAMP-VLP) led to differentiation of circulating tumor-specific T cells, decreased tumor regulatory T cells (T regs ), and antitumoral responses that synergized with PD1 blockade. By contrast, intratumoral injection of the synthetic CDN ADU-S100 led to tumor necrosis and systemic T cell activation but simultaneously depleted immune cells from injected tumors and induced minimal priming of circulating tumor-specific T cells. The antitumor effects of cGAMP-VLP required type 1 conventional dendritic cells (cDC1), whereas ADU-S100 eliminated cDC1 from injected tumors. cGAMP-VLP preferentially targeted STING in dendritic cells at a 1000-fold smaller dose than ADU-S100. Subcutaneous administration of cGAMP-VLP showed synergy when combined with PD1 blockade or a tumor T reg -depleting antibody to elicit systemic tumor-specific T cells and antitumor activity, leading to complete and durable tumor eradication in the case of tumor T reg depletion. These findings show that cell targeting of STING stimulation shapes the antitumor T cell response and identify a therapeutic strategy to enhance T cell–targeted immunotherapy.

STING licensing of type I dendritic cells potentiates antitumor immunity

“…3L). This cDC1 requirement is corroborated by a recent study using cGAMP-loaded virus-like nanoparticles (37). Our data further demonstrate that STING signaling within cDC1s is important because PolySTING efficacy is abolished in XCR1 cre STING fl/fl mice (Fig.…”

Mannosylated STING Agonist Drugamers for Dendritic Cell-Mediated Cancer Immunotherapy

“…This is consistent with reports that STING activation and/or its resultant IFN response stimulates CD8 + DC responses. 27,48,49 There were no differences in CD103 + DC populations between treatment groups (Figure S20). The quality of infiltrating T-cells was also examined through an analysis of PD-1 and TCF-1 expression (gating scheme in Figure S21).…”

“…28−32 STING activation in DCs strongly induces DC maturation, 33 and activation in cDC1 was crucial to the function of an intratumoral viral vector STING delivery platform. 27 We hypothesize that a STING delivery platform targeting tumoral APCs can induce potent antitumor responses with minimal toxicity. A Clec9a + DC-targeted STING delivery platform showcased this possibility.…”

“…24 As tumor cells can downregulate STING, 25 agonist delivery to tumor cells can be either ineffective or counterproductive through this mechanism. Conversely, overactivation of STING can result in unproductive nonimmunogenic cell ablation, 26,27 rendering patients vulnerable to relapse or metastasis. In light of this, targeted STING delivery to intratumoral APCs such as dendritic cells (DCs) may induce antitumor immunity without the aforementioned shortcomings.…”

Harnessing the cooperation between DNA‐PK and cGAS in cancer therapies

“…[48][49][50] This can be overcome by combining chemotherapy or STING agonists with checkpoint inhibitors, which is a promising therapeutic strategy to promote tumour regression. [51,52] The cGAS-STING pathway and its pro-tumoural roles…”