Jneid et al. showed that intratumoral delivery of cyclic-GAMP in virus-like particles (cGAMP-VLP) stimulated antitumor T cell response, delayed tumor growth, and synergized with PD-1 blockade at low cGAMP doses. cGAMP-VLP preferentially targeted dendritic cells, and the antitumor effects of cGAMP-VLP required type 1 conventional dendritic cells (cDC1), whereas synthetic STING agonist ADU-S100 eliminated cDC1, but led to tumor necrosis with systemic, but not tumor-specific T cell activation. Subcutaneous cGAMP-VLP administration synergized with ICB to elicit systemic tumor-specific T cells and complete and durable tumor eradication with Treg depletion.
Contributed by Shishir Pant
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.
Author Info: (1) Institut Curie, PSL Research University, INSERM U932, Paris, France. (2) Institut Curie, PSL Research University, INSERM U932, Paris, France. Stimunity, Paris, France. (3) Inst
Author Info: (1) Institut Curie, PSL Research University, INSERM U932, Paris, France. (2) Institut Curie, PSL Research University, INSERM U932, Paris, France. Stimunity, Paris, France. (3) Institut Curie, INSERM U932 Immunity and Cancer, Department of Surgical Oncology, PSL University, Paris, France. (4) Institut Curie, PSL Research University, INSERM U932, Paris, France. (5) Institut Curie, PSL Research University, INSERM U932, Paris, France. (6) Institut Curie, PSL Research University, INSERM U932, Paris, France. (7) Institut Curie, PSL Research University, INSERM U932, Paris, France. (8) Institut Curie, PSL Research University, INSERM U932, Paris, France. (9) Institut Curie, PSL Research University, INSERM U932, Paris, France. (10) Centre d'Immunophénomique (CIPHE), Aix Marseille Université, INSERM, CNRS, 13288 Marseille, France. (11) Aix-Marseille University, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Turing Center for Living Systems, Marseille, France. (12) Aix-Marseille University, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Turing Center for Living Systems, Marseille, France. (13) Stimunity, Paris, France. (14) Stimunity, Paris, France. (15) Stimunity, Paris, France. (16) Institut Curie, PSL Research University, INSERM U932, Paris, France. (17) Centre d'Immunophénomique (CIPHE), Aix Marseille Université, INSERM, CNRS, 13288 Marseille, France. (18) Aix-Marseille University, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Turing Center for Living Systems, Marseille, France. (19) Institut Curie, PSL Research University, INSERM U932, Paris, France. (20) Institut Curie, PSL Research University, INSERM U932, Paris, France.
