评价光动力治疗胶质母细胞瘤的免疫治疗方法。

IF 2.6
Yeo Song Kim, Byeong Geun Kang, Seung-Ho Yang, Sin-Soo Jeun, Soon A Park
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引用次数: 0

摘要

胶质母细胞瘤(GBM)是成人最常见和侵袭性的原发性脑肿瘤,其特点是预后差。尽管免疫检查点抑制剂(ICIs)如抗pd - l1抗体已在各种癌症中显示出临床成功,但它们在GBM中不会引起反应,因为它是一种低新抗原负荷和T细胞衰竭的冷肿瘤。光动力疗法(PDT)利用适当波长的光与光敏剂相结合,选择性地破坏肿瘤细胞,最近因其刺激抗肿瘤免疫反应的潜力而受到关注。在现有的光敏剂中,5-氨基乙酰丙酸(5-ALA)被临床用于GBM手术,以显示肿瘤边缘并改善切除结果。鉴于其批准的临床应用和手术兼容性,基于5- ala的PDT代表了整合到GBM治疗方案的有希望的策略。本研究旨在探讨基于5- ala的PDT是否可以增强抗pd - l1治疗GBM的疗效。在体外,我们评估了PD-L1在GL26和U87胶质瘤细胞系以及患者源性GBM细胞中的表达。PD-L1在部分肿瘤细胞中表达,而在其他肿瘤细胞中未观察到PD-L1的表达,说明胶质母细胞瘤中PD-L1的表达水平存在差异。在最初表现出低PD-L1表达的GL26细胞系中,5-ALA PDT处理显著增加了PD-L1的表达。这表明5-ALA PDT后抗pd - l1治疗的疗效可能会增强。在体内,利用GL26细胞建立异位(皮下)和原位GBM小鼠模型。小鼠接受5-ALA PDT、抗pd - l1或两者联合治疗,并评估肿瘤生长、免疫细胞浸润和总生存率。在异位(皮下)模型中,将GL26细胞植入两侧,将PDT应用于左侧,指定为原发肿瘤。未接受PDT的右侧被指定为远处肿瘤。在这个模型中,5-ALA PDT联合抗pd - l1治疗抑制了原发肿瘤和远处肿瘤的生长,尽管对远处肿瘤的影响没有统计学意义。联合用药组原发肿瘤中T细胞、B细胞、CD4 +、CD8 + T细胞浸润增加,原发肿瘤和右侧远端肿瘤中CD8 + T细胞浸润升高。在原位模型中,联合治疗显著提高了生存率。此外,在脑肿瘤浸润淋巴细胞(TILs)中观察到增强的T细胞、CD8 + T细胞和NKT细胞反应。联合用药组细胞凋亡最为明显。这些结果表明,在异位(皮下)和原位GBM模型中,5-ALA PDT增强抗肿瘤免疫反应并与抗pd - l1治疗协同作用。因此,这种联合策略不仅可以抑制局部和远处肿瘤的生长,还可以延长生存期,支持其作为GBM的新型免疫治疗方法的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Evaluating an immunotherapeutic approach to photodynamic therapy for glioblastoma.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, characterized by poor prognosis. Although immune checkpoint inhibitors (ICIs) such as anti-PD-L1 antibodies have demonstrated clinical success in various cancers, they do not elicit a response in GBM, as it is a cold tumor with low neoantigen load and T cell exhaustion. Photodynamic therapy (PDT) which uses light at an appropriate wavelength in combination with a photosensitizer to selectively destroy tumor cells, has recently gained attention for its potential to stimulate anti-tumor immune responses. Among available photosensitizers, 5-aminolevulinic acid (5-ALA) is clinically used in GBM surgery to visualize tumor margins and improve resection outcomes. Given its approved clinical use and surgical compatibility, 5-ALA-based PDT represents a promising strategy for integration into GBM treatment protocols. This study aimed to investigate whether 5-ALA-based PDT can enhance the efficacy of anti-PD-L1 therapy in GBM. In vitro, PD-L1 expression was evaluated in GL26 and U87 glioma cell lines as well as in patient-derived GBM cells. PD-L1 was expressed in some tumor cells while no PD-L1 expression was observed in others, indicating that the level of PD-L1 expression varies among glioblastomas. In the GL26 cell line, which initially exhibited low PD-L1 expression, treatment with 5-ALA PDT significantly increased PD-L1 expression. This suggests that the therapeutic efficacy of anti-PD-L1 treatment may be enhanced following 5-ALA PDT. In vivo, heterotopic (subcutaneous) and orthotopic GBM mouse models using the GL26 cells were established. Mice received 5-ALA PDT, anti-PD-L1, or a combination of both, and tumor growth, immune cell infiltration, and overall survival were evaluated. In the heterotopic (subcutaneous) model, GL26 cells was implanted into both flanks, with PDT applied to the left side, designated as the primary tumor. The right side, which did not receive PDT, was designated as the distant tumor. In this model, the combination of 5-ALA PDT and anti-PD-L1 treatment suppressed both primary and distant tumor growth, although the effect on distant tumors was not statistically significant. Additionally, in the combination group, infiltration of T cells, B cells, CD4⁺, CD8⁺ T cells increased in the primary tumors, and CD8⁺ T cells infiltration was elevated in primary and right-side distant tumors. In the orthotopic model, combination treatment significantly improved survival. Furthermore, enhanced T cells, CD8⁺ T cells and NKT cells responses were observed in brain tumor-infiltrating lymphocytes (TILs). Apoptosis was most pronounced in the combination group. These results suggest that 5-ALA PDT enhances the anti-tumor immune response and synergizes with anti-PD-L1 therapy in both heterotopic (subcutaneous) and orthotopic GBM models. Therefore, this combination strategy not only inhibits local and distant tumor growth but also prolongs survival, supporting its potential as a novel immunotherapeutic approach for GBM.

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