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Selective STING stimulation in dendritic cells primes antitumor T cell responses
Science Immunology ( IF 24.8 ) Pub Date : 2023-01-13 , DOI: 10.1126/sciimmunol.abn6612
Bakhos Jneid 1 , Aurore Bochnakian 1, 2 , Caroline Hoffmann 3 , Fabien Delisle 1 , Emeline Djacoto 1 , Philémon Sirven 1 , Jordan Denizeau 1 , Christine Sedlik 1 , Yohan Gerber-Ferder 1 , Frédéric Fiore 4 , Ramazan Akyol 5 , Carine Brousse 5 , Robert Kramer 2 , Ian Walters 2 , Sylvain Carlioz 2 , Hélène Salmon 1 , Bernard Malissen 4 , Marc Dalod 5 , Eliane Piaggio 1 , Nicolas Manel 1
Affiliation  

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.

中文翻译:

树突状细胞中的选择性 STING 刺激引发抗肿瘤 T 细胞反应

识别肿瘤抗原的 T 细胞对于产生抗肿瘤免疫反应至关重要。免疫原性肿瘤中抗肿瘤 T 细胞的诱导依赖于 STING,STING 是环磷酸鸟苷-磷酸腺苷 (cGAMP) 和相关环二核苷酸 (CDN) 的细胞内先天免疫受体。然而,在非免疫原性肿瘤中利用 STING 激活的最佳方法仍不清楚。在这里,我们表明通过瘤内注射病毒样颗粒 (cGAMP-VLP) 递送 cGAMP 导致循环肿瘤特异性 T 细胞分化,减少肿瘤调节性 T 细胞 (T规则),以及与 PD1 阻断协同作用的抗肿瘤反应。相比之下,合成 CDN ADU-S100 的瘤内注射导致肿瘤坏死和全身 T 细胞活化,但同时耗尽了注射肿瘤的免疫细胞并诱导了循环肿瘤特异性 T 细胞的最小启动。cGAMP-VLP 的抗肿瘤作用需要 1 型常规树突状细胞 (cDC1),而 ADU-S100 从注射肿瘤中消除 cDC1。cGAMP-VLP 优先靶向树突状细胞中的 STING,剂量比 ADU-S100 小 1000 倍。当与 PD1 阻断或肿瘤 T 联合使用时,cGAMP-VLP 的皮下给药显示出协同作用注册-消耗抗体以引发全身性肿瘤特异性 T 细胞和抗肿瘤活性,从而在肿瘤 T 的情况下导致完全和持久的肿瘤根除注册消耗。这些发现表明,STING 刺激的细胞靶向塑造了抗肿瘤 T 细胞反应,并确定了增强 T 细胞靶向免疫疗法的治疗策略。
更新日期:2023-01-13
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