IL15 修饰使 CAR T 细胞能够成为针对 GBM 中肿瘤细胞和髓源抑制细胞的双重靶向治疗药物。
IL15 modification enables CAR T cells to act as a dual targeting agent against tumor cells and myeloid-derived suppressor cells in GBM.
机构信息
Department of Neurological Surgery, Northwestern University, Chicago, Illinois, USA.
Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
出版信息
J Immunother Cancer. 2023 Feb;11(2). doi: 10.1136/jitc-2022-006239.
INTRODUCTION
The immunosuppressive tumor microenvironment (TME) is a major barrier to the efficacy of chimeric antigen receptor T cells (CAR-T cells) in glioblastoma (GBM). Transgenic expression of IL15 is one attractive strategy to modulate the TME. However, at present, it is unclear if IL15 could be used to directly target myeloid-derived suppressor cells (MDSCs), a major cellular component of the GBM TME. Here, we explored if MDSC express IL15Rα and the feasibility of exploiting its expression as an immunotherapeutic target.
METHODS
RNA-seq, RT-qPCR, and flow cytometry were used to determine IL15Rα expression in paired peripheral and tumor-infiltrating immune cells of GBM patients and two syngeneic murine GBM models. We generated murine T cells expressing IL13Rα2-CARs and secretory IL15 (CAR.IL15s) or IL13Rα2-CARs in which IL15 was fused to the CAR to serve as an IL15Rα-targeting moiety (CAR.IL15f), and characterized their effector function in vitro and in syngeneic IL13Rα2+glioma models.
RESULTS
IL15Rα was preferentially expressed in myeloid, B, and dendritic cells in patients' and syngeneic GBMs. In vitro, CAR.IL15s and CAR.IL15f T cells depleted MDSC and decreased their secretion of immunosuppressive molecules with CAR.IL15f T cells being more efficacious. Similarly, CAR.IL15f T cells significantly improved the survival of mice in two GBM models. TME analysis showed that treatment with CAR.IL15f T cells resulted in higher frequencies of CD8+T cells, NK, and B cells, but a decrease in CD11b+cells in tumors compared with therapy with CAR T cells.
CONCLUSIONS
We demonstrate that MDSC of the glioma TME express IL15Ra and that these cells can be targeted with secretory IL15 or an IL15Rα-targeting moiety incorporated into the CAR. Thus, IL15-modified CAR T cells act as a dual targeting agent against tumor cells and MDSC in GBM, warranting their future evaluation in early-phase clinical studies.
简介
免疫抑制性肿瘤微环境（TME）是嵌合抗原受体 T 细胞（CAR-T 细胞）在胶质母细胞瘤（GBM）中疗效的主要障碍。转基因表达 IL15 是一种调节 TME 的有吸引力的策略。然而，目前尚不清楚 IL15 是否可直接靶向髓系来源的抑制性细胞（MDSC），这是 GBM TME 的主要细胞成分。在这里，我们探讨了 MDSC 是否表达 IL15Rα，以及利用其表达作为免疫治疗靶点的可行性。
方法
使用 RNA-seq、RT-qPCR 和流式细胞术来确定 GBM 患者配对的外周和肿瘤浸润免疫细胞以及两种同源鼠 GBM 模型中 IL15Rα 的表达。我们生成了表达 IL13Rα2-CAR 和分泌型 IL15（CAR.IL15s）或 IL13Rα2-CAR 的鼠 T 细胞，其中 IL15 与 CAR 融合，作为 IL15Rα 靶向部分（CAR.IL15f），并在体外和同源性 IL13Rα2+胶质母细胞瘤模型中对其效应功能进行了表征。
结果
IL15Rα 在患者和同源性 GBM 中的髓样细胞、B 细胞和树突状细胞中优先表达。在体外，CAR.IL15s 和 CAR.IL15f T 细胞耗尽了 MDSC，并减少了其免疫抑制分子的分泌，而 CAR.IL15f T 细胞更有效。同样，CAR.IL15f T 细胞显著改善了两种 GBM 模型中小鼠的存活率。TME 分析表明，与 CAR T 细胞治疗相比，CAR.IL15f T 细胞治疗导致肿瘤中 CD8+T 细胞、NK 和 B 细胞的频率升高，但 CD11b+细胞减少。
结论
我们证明了胶质母细胞瘤 TME 中的 MDSC 表达 IL15Ra，并且可以使用分泌型 IL15 或与 CAR 融合的 IL15Rα 靶向部分来靶向这些细胞。因此，IL15 修饰的 CAR-T 细胞在 GBM 中充当针对肿瘤细胞和 MDSC 的双重靶向剂，值得在早期临床研究中进一步评估。
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