OBJECTIVES Clinical response to antibody-based immunotherapies targeting checkpoint inhibitors is critically dependent on the tumor immune microenvironment (TIME). However, the precise impact of the TIME on adoptive cellular immunotherapy remains unexplored. Here we have conducted a long-term follow-up analysis of patients with recurrent glioblastoma multiforme (GBM) who were treated with autologous CMV-specific T-cell therapy to delineate the potential impact of the TIME on their clinical response. METHODS Multiplexed immunohistochemical analysis of CD3, PD-L1 and Sox-2 in GBM tissue biopsies obtained before autologous T-cell therapy was carried out and correlated with long-term survival of GBM patients adoptively treated with T-cell therapy. RESULTS Tumor microenvironment analyses revealed that the pre-treatment cellular composition of the tumor tissue may influence the subsequent response to adoptive T-cell therapy. GBM patients who showed prolonged overall survival following T-cell therapy had a significantly lower number of tumor-infiltrating CD3+ T cells in recurrent tumors than that in patients with short-term survival. Furthermore, long-term surviving patients showed low or undetectable PD-L1 expression in tumor cells in recurrent GBM biopsies. CONCLUSION We hypothesise that lack of PD-L1-mediated immunosuppression in the TIME may allow efficient immune control following adoptive T-cell therapy. Future studies combining anti-PD-L1 or genetically modified T cells with PD-1 receptor knockdown could be considered to improve clinical responses in patients who have high PD-L1 expression in their tumors.

中文翻译：

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治疗前多形性胶质母细胞瘤微环境对自体 CMV 特异性 T 细胞治疗的临床反应的影响。

目标针对检查点抑制剂的基于抗体的免疫疗法的临床反应严重依赖于肿瘤免疫微环境 (TIME)。然而，TIME 对过继性细胞免疫疗法的确切影响仍未探索。在这里，我们对接受自体 CMV 特异性 T 细胞治疗的复发性多形性胶质母细胞瘤 (GBM) 患者进行了长期随访分析，以描述 TIME 对其临床反应的潜在影响。方法 对自体 T 细胞治疗前获得的 GBM 组织活检中的 CD3、PD-L1 和 Sox-2 进行多重免疫组织化学分析，并与接受 T 细胞治疗的 GBM 患者的长期生存率相关。结果 肿瘤微环境分析表明，肿瘤组织的预处理细胞组成可能会影响随后对过继性 T 细胞治疗的反应。T 细胞治疗后总生存期延长的 GBM 患者在复发性肿瘤中的肿瘤浸润 CD3+ T 细胞数量明显低于短期生存期患者。此外，长期存活的患者在复发性 GBM 活检中的肿瘤细胞中显示出低或检测不到的 PD-L1 表达。结论 我们假设在 TIME 缺乏 PD-L1 介导的免疫抑制可能允许在过继性 T 细胞治疗后进行有效的免疫控制。