Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Adv Healthc Mater. 2023 Sep;12(24):e2300688. doi: 10.1002/adhm.202300688. Epub 2023 Apr 21.
Stimulator of interferon genes (STING) signaling is a promising target in cancer immunotherapy, with many ongoing clinical studies in combination with immune checkpoint blockade (ICB). Existing STING-based therapies largely focus on activating CD8 T cell or NK cell-mediated cytotoxicity, while the role of CD4 T cells in STING signaling has yet to be extensively studied in vivo. Here, a distinct CD4-mediated, protein-based combination therapy of STING and ICB as an in situ vaccine, is reported. The treatment eliminates subcutaneous MC38 and YUMM1.7 tumors in 70-100% of mice and protected all cured mice against rechallenge. Mechanistic studies reveal a robust T 1 polarization and suppression of T of CD4 T cells, followed by an effective collaboration of CD4 T, CD8 T, and NK cells to eliminate tumors. Finally, the potential to overcome host STING deficiency by significantly decreasing MC38 tumor burden in STING KO mice is demonstrated, addressing the translational challenge for the 19% of human population with loss-of-function STING variants.
干扰素基因刺激物 (STING) 信号转导是癌症免疫治疗的一个有前途的靶点，许多正在进行的临床研究都将其与免疫检查点阻断 (ICB) 联合使用。现有的基于 STING 的疗法主要集中在激活 CD8 T 细胞或 NK 细胞介导的细胞毒性，而 CD4 T 细胞在 STING 信号转导中的作用在体内尚未得到广泛研究。在这里，报告了一种独特的基于 CD4 的 STING 和 ICB 蛋白联合治疗作为原位疫苗。该治疗方法可消除皮下 MC38 和 YUMM1.7 肿瘤，在 70-100%的小鼠中有效，并保护所有治愈的小鼠免受再挑战。机制研究表明，该疗法可引起强烈的 T1 极化和 CD4 T 细胞的抑制，随后 CD4 T、CD8 T 和 NK 细胞有效协作以消除肿瘤。最后，通过显著降低 STING KO 小鼠中 MC38 肿瘤负担来克服宿主 STING 缺陷的潜力得到了证明，解决了 19%具有功能丧失性 STING 变体的人类人群的转化挑战。
