Dynamics of Immune Responses Unit, Equipe Labellisée Ligue Contre le Cancer, Institut Pasteur, INSERM U1223, 75015 Paris, France.
University Paris Diderot, Sorbonne Paris Cité, Paris, France.
Sci Immunol. 2021 Mar 26;6(57). doi: 10.1126/sciimmunol.abd4344.
Chimeric antigen receptor (CAR) T cell therapy relies on the activity of a large pool of tumor-targeting cytotoxic effectors. Whether CAR T cells act autonomously or require interactions with the tumor microenvironment (TME) remains incompletely understood. Here, we report an essential cross-talk between CAR T cell subsets and the TME for tumor control in an immunocompetent mouse B cell lymphoma model of anti-CD19 CAR T cell therapy. Using single-cell RNA sequencing, we revealed substantial modification of the TME during CAR T cell therapy. Interferon-γ (IFN-γ) produced by CAR T cells not only enhanced endogenous T and natural killer cell activity but was also essential for sustaining CAR T cell cytotoxicity, as revealed by intravital imaging. CAR T cell-derived IFN-γ facilitated host interleukin-12 production that supported host immune and CAR T cell responses. Compared with CD8 CAR T cells, CD4 CAR T cells were more efficient at host immune activation but less capable of direct tumor killing. In summary, CAR T cells do not act independently in vivo but rely instead on cytokine-mediated cross-talk with the TME for optimal activity. Invigorating CAR T cell interplay with the host represents an attractive strategy to prevent relapses after therapy.
嵌合抗原受体 (CAR) T 细胞疗法依赖于大量靶向肿瘤的细胞毒性效应器的活性。CAR T 细胞是自主发挥作用还是需要与肿瘤微环境 (TME) 相互作用，目前仍不完全清楚。在这里，我们报告了在抗 CD19 CAR T 细胞治疗的免疫活性小鼠 B 细胞淋巴瘤模型中，CAR T 细胞亚群与 TME 之间进行肿瘤控制的重要串扰。通过单细胞 RNA 测序，我们揭示了在 CAR T 细胞治疗过程中 TME 的实质性修饰。CAR T 细胞产生的干扰素-γ (IFN-γ) 不仅增强了内源性 T 细胞和自然杀伤细胞的活性，而且对于维持 CAR T 细胞的细胞毒性也是必不可少的，这一点通过活体成像得到了揭示。CAR T 细胞衍生的 IFN-γ 促进了宿主白细胞介素-12 的产生，从而支持了宿主免疫和 CAR T 细胞反应。与 CD8 CAR T 细胞相比，CD4 CAR T 细胞在宿主免疫激活方面更有效，但直接杀伤肿瘤的能力较弱。总之，CAR T 细胞在体内并非独立发挥作用，而是依赖于细胞因子介导的与 TME 的串扰来实现最佳活性。增强 CAR T 细胞与宿主的相互作用是预防治疗后复发的一种有吸引力的策略。
