METHODS: The immunocompetent B acute lymphoblastic leukemia (B-ALL), lymphoma, and melanoma murine models were employed to investigate the characteristics of endogenous T cells within the TME following CD19 and hCAIX CAR-T cell therapy, respectively. Furthermore, we examined the role of VISTA controlled by interferon (IFN)-γ signaling in regulating endogenous T-cell activation and functionality in B-ALL mice.
RESULTS: We demonstrated that the administration of CD19 CAR-T or hCAIX CAR-T cell therapy elicited augmented immune responses of endogenous T cells within the TME of B-ALL, lymphoma, and melanoma mice, thereby substantiating the efficacy of CAR-T cell efficacy. However, in the TME lacking IFN-γ signaling, VISTA levels remained elevated, resulting in attenuated cytotoxicity of endogenous T cells and reduced B-ALL recipient survival. Mice treated with CD19 CAR-T cells exhibited increased proportions of endogenous memory T cells during prolonged remission, which possessed the tumor-responsive capabilities to protect against B-ALL re-challenge. Compared with wild-type (WT) CAR-T treated mice, the administration of IFN-γ-/- CAR-T to both WT and IFN-γ-/- recipients resulted in a reduction in the numbers of endogenous CD4+ and CD8+ effectors, while exhibiting increased populations of naïve-like CD4+ T and memory CD8+ T cells. VISTA expression consistently remained elevated in resting or memory CD4+ T cells, with distinct localization from programmed cell death protein-1 (PD-1) expressing T subsets. Blocking the VISTA signal enhanced dendritic cell-induced proliferation and cytokine production by syngeneic T cells.
CONCLUSIONS: Our findings confirm that endogenous T-cell activation and functionality are regulated by VISTA, which is associated with the therapeutic efficiency of CAR-T and provides a promising therapeutic strategy for relapse cases in CAR-T therapy.
方法:免疫活性B急性淋巴细胞白血病(B-ALL),淋巴瘤和黑色素瘤鼠模型被用来研究在CD19和hCAIXCAR-T细胞治疗后TME内内源性T细胞的特征,分别。此外,我们研究了由干扰素(IFN)-γ信号控制的VISTA在调节B-ALL小鼠内源性T细胞活化和功能中的作用.
结果:我们证明了CD19CAR-T或hCAIXCAR-T细胞疗法的给药在B-ALL的TME内引起内源性T细胞增强的免疫应答,淋巴瘤和黑色素瘤小鼠,从而证实了CAR-T细胞的功效。然而,在缺乏IFN-γ信号传导的TME中,VISTA水平仍然升高,导致内源性T细胞的细胞毒性减弱,并降低B-ALL受体的存活率。用CD19CAR-T细胞治疗的小鼠在长期缓解期间表现出内源性记忆T细胞的比例增加。具有预防B-ALL再攻击的肿瘤反应能力。与野生型(WT)CAR-T处理的小鼠相比,对WT和IFN-γ-/-受体施用IFN-γ-/-CAR-T导致内源性CD4+和CD8+效应子数量减少,同时表现出原始样CD4+T和记忆CD8+T细胞的数量增加。VISTA表达在静息或记忆CD4+T细胞中持续升高,与程序性细胞死亡蛋白-1(PD-1)表达T亚群不同的定位。阻断VISTA信号增强了树突状细胞诱导的增殖和同系T细胞产生的细胞因子。
结论:我们的发现证实内源性T细胞活化和功能受VISTA调节,这与CAR-T的治疗效率相关,并为CAR-T治疗中的复发病例提供了有希望的治疗策略。