Selective STING stimulation in dendritic cells primes antitumor T cell responses

T cells that recognize tumor antigens are crucial for mounting antitumor immune responses. Induction of an-titumor 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 (Tregs), 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-VIP showed synergy when combined with PD1 blockade or a tumor Tre9 depleting antibody to elicit systemic tumor-specific T cells and antitumor activity, leading to complete and durable tumor eradication in the case of tumor Tres depletion. These findings show that cell targeting of STING stimu-lation shapes the antitumor T cell response and identify a therapeutic strategy to enhance T cell -targeted immunotherapy.

Automated summary

Activation of STING in immunogenic tumors can induce antitumor T cell response, but it remains unclear how to apply it in nonimmunogenic tumors. This study showed that intratumoral delivery of cGAMP-VLP activated T cells and reduced tumor regulatory T cells, synergizing with PD1 blockade. However, intratumoral administration of the synthetic CDN ADU-S100 caused tumor necrosis and systemic T cell activation, but depleted immune cells and minimally primed circulating tumor-specific T cells. Thus, cell targeting of STING stimulation shapes the antitumor T cell response and provides a strategy to enhance T cell-targeted immunotherapy.