PDF(Pubmed)
Abstract：
BACKGROUND: Despite continuous improvements in the new target and construction of chimeric antigen receptor (CAR)-T, relapse remains a significant challenge following CAR-T therapy. Tumor microenvironment (TME) strongly correlates with the efficacy of CAR-T therapy. V-domain Ig suppressor of T-cell activation (VISTA), which exerts a multifaceted and controversial role in regulating the TME, acts not only as a ligand on antigen-presenting cells but also functions as a receptor on T cells. However, the characteristics and underlying mechanisms governing endogenous T-cell activation by VISTA, which are pivotal for reshaping the TME, remain incompletely elucidated.
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.
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.
摘要：
背景：尽管在新靶标和嵌合抗原受体（CAR）-T的构建方面不断改进，CAR-T治疗后复发仍是一项重大挑战.肿瘤微环境(TME)与CAR-T疗法的疗效密切相关。T细胞激活的V域Ig抑制因子（VISTA），在调节TME方面发挥着多方面和有争议的作用，不仅在抗原呈递细胞上充当配体，而且在T细胞上充当受体。然而,VISTA控制内源性T细胞激活的特征和潜在机制，这是重塑TME的关键，仍未完全阐明。
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。
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。
