Immunophenotyping of Newly Diagnosed and Recurrent Glioblastoma Defines Distinct Immune Exhaustion Profiles in Peripheral and Tumor-infiltrating Lymphocytes
Immunophenotyping of Newly Diagnosed and Recurrent Glioblastoma Defines Distinct Immune Exhaustion Profiles in Peripheral and Tumor-infiltrating Lymphocytes
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DOI：
10.1158/1078-0432.ccr-17-2617
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发表时间：
2018-09-01
影响因子：
11.5
通讯作者：
Lamszus, Katrin
中科院分区：
文献类型：
--
作者：
Mohme, Malte;Schliffke, Simon;Lamszus, Katrin
目的：胶质母细胞瘤（GBM）的免疫治疗策略正在临床试验中进行研究。然而，我们对GBM浸润性T细胞（肿瘤浸润性淋巴细胞; TIL）的免疫表型和疾病进展过程中的变化的理解是有限的。迫切需要更深入的了解才能在治疗上克服肿瘤诱导的免疫衰竭。实验设计：我们使用流式细胞术和细胞因子测定来分析GBM患者的TIL和外周血淋巴细胞（PBL），将新诊断或复发的GEM与长期生存者进行比较（美国）和健康捐赠者。TCR测序进行配对样本的新诊断和复发GBM。结果：我们确定了一个明确的免疫签名耗尽和克隆限制性肿瘤浸润的GEM患者。CD 8 + TIL耗竭定义为PD-1（+）、CD 39（+）、Tim-3（+）、CD 45 RO（+）、HLA-DR+标记物表达的发生率增加，以及效应/过渡记忆分化表型的表现，而KLRG 1和CD 57的代表性不足。原发性和复发性肿瘤的免疫特征相似;然而，在复发性肿瘤的TIL中观察到有限的TCR库供体性和更活化的记忆表型。此外，血室中对PHA刺激的细胞因子应答降低表明GBM患者的外周T细胞应答功能障碍。LTS表现出明显的免疫特征，有大量的幼稚和较少耗尽的CD 8（+）T细胞。结论：TIL和PBL表现出截然不同的免疫特征，TIL中存在明显的耗尽特征。虽然原发性和复发性GEM的耗竭概况是相当的，但TCR测序显示复发性GBM中的收缩的库，伴随着复发性肿瘤中活化的记忆T细胞的频率增加。(C)2018年AACR。
Purpose: Immunotherapeutic treatment strategies for glioblastoma (GBM) are under investigation in clinical trials. However, our understanding of the immune phenotype of GBM-infiltratingT cells (tumor-infiltrating lymphocytes; TILs) and changes during disease progression is limited. Deeper insight is urgently needed to therapeutically overcome tumor-induced immune exhaustion.Experimental Design: We used flow cytometry and cytokine assays to profile TILs and peripheral blood lymphocytes (PBLs) from patients with GBM, comparing newly diagnosed or recurrent GEM to long-term survivors (US) and healthy donors. TCR sequencing was performed on paired samples of newly diagnosed and recurrent GBM.Results: We identified a dear immune signature of exhaustion and clonal restriction in the TILs of patients with GEM. Exhaustion of CD8+ TILs was defined by an increased prevalence of PD-1(+), CD39(+), Tim-3(+), CD45RO(+), HLA-DR+ marker expression, and exhibition of an effector-/transitional memory differentiation phenotype, whereas KLRG1 and CD57 were underrepresented. Immune signatures were similar in primary and recurrent tumors; however, restricted TCR repertoire donality and a more activated memory phenotype were observed in TILs from recurrent tumors. Moreover, a reduced cytokine response to PHA stimulation in the blood compartment indicates a dysfunctional peripheral T-cell response in patients with GBM. LTS displayed a distinct profile, with abundant naive and less exhausted CD8(+) T cells.Conclusions: TILs and PBLs exhibit contrasting immune profiles, with a distinct exhaustion signature present in TILs. While the exhaustion profiles of primary and recurrent GEM are comparable, TCR sequencing demonstrated a contracted repertoire in recurrent GBM, concomitant with an increased frequency of activated memory T cells in recurrent tumors. (C) 2018 AACR.