Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.
J Exp Med. 2021 Feb 1;218(2). doi: 10.1084/jem.20200844.
CAR T therapy targeting solid tumors is restrained by limited infiltration and persistence of those cells in the tumor microenvironment (TME). Here, we developed approaches to enhance the activity of CAR T cells using an orthotopic model of locally advanced breast cancer. CAR T cells generated from Th/Tc17 cells given with the STING agonists DMXAA or cGAMP greatly enhanced tumor control, which was associated with enhanced CAR T cell persistence in the TME. Using single-cell RNA sequencing, we demonstrate that DMXAA promoted CAR T cell trafficking and persistence, supported by the generation of a chemokine milieu that promoted CAR T cell recruitment and modulation of the immunosuppressive TME through alterations in the balance of immune-stimulatory and suppressive myeloid cells. However, sustained tumor regression was accomplished only with the addition of anti-PD-1 and anti-GR-1 mAb to Th/Tc17 CAR T cell therapy given with STING agonists. This study provides new approaches to enhance adoptive T cell therapy in solid tumors.
针对实体瘤的嵌合抗原受体 T 细胞（CAR T）疗法受到这些细胞在肿瘤微环境（TME）中有限浸润和持久性的限制。在这里，我们开发了使用局部晚期乳腺癌的原位模型来增强 CAR T 细胞活性的方法。用 STING 激动剂 DMXAA 或 cGAMP 联合给予 Th/Tc17 细胞产生的 CAR T 细胞大大增强了肿瘤控制，这与 CAR T 细胞在 TME 中的持久性增强有关。通过单细胞 RNA 测序，我们证明 DMXAA 促进了 CAR T 细胞的迁移和持久性，这是通过产生趋化因子微环境来支持的，该环境通过改变免疫刺激性和抑制性髓样细胞的平衡来促进 CAR T 细胞的募集和调节免疫抑制性 TME。然而，只有在用 STING 激动剂联合给予 Th/Tc17 CAR T 细胞治疗时添加抗 PD-1 和抗 GR-1 mAb，才能实现持续的肿瘤消退。本研究为增强实体瘤中的过继性 T 细胞疗法提供了新的方法。
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