Department of Radiation Oncology, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198-7521, USA.
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
J Neurooncol. 2022 Aug;159(1):163-175. doi: 10.1007/s11060-022-04053-0. Epub 2022 Jun 26.
Glioblastoma (GBM) is the most lethal primary brain tumor in adult patients. The disease progression, response to chemotherapy and radiotherapy at initial diagnosis, and prognosis are profoundly associated with the tumor microenvironment, especially the features of tumor-infiltrating immune cells (TII). Recurrent GBM is even more challenging to manage. Differences in the immune environment between newly diagnosed and recurrent GBM and an association with tumor prognosis are not well defined.
To address this knowledge gap, we analyzed the clinical data and tissue specimens from 24 GBM patients (13 at initial diagnosis and 11 at recurrence). The expression levels of multiple immunobiological markers in patients' GBM at initial diagnosis versus at recurrence were compared, including five patients with both specimens available (paired). The distribution patterns of TII were evaluated in both the intratumoral and perivascular regions.
We found that tumors from recurrent GBM have significantly more tumor-infiltrating lymphocytes (TILs) and macrophages and higher PD-L1 and PD-1 expression than tumors at primary diagnosis and benign brain specimens from epilepsy surgery. The pattern changes of the TILs and macrophages of the five paired specimens were consistent with the unpaired patients, while the CD8 to CD4 ratio remained constant from diagnosis to recurrence in the paired tissues. The levels of TILs, macrophages, PD-1 or PD-L1+ cells at initial diagnosis did not correlate with OS. TILs, macrophages, and PD-1+ cells were increased in recurrent tumors both in intratumoral and perivascular areas, with higher distribution levels in intratumoral than perivascular regions. Higher CD4 or CD8 infiltration at recurrence was associated with a worse prognosis, respectively.
Our study elucidated that TIL and TAM tend to accumulate in perivascular region and are more abundant in recurrent GBM than newly diagnosed GBM.
胶质母细胞瘤（GBM）是成人患者中最致命的原发性脑肿瘤。疾病进展、初始诊断时对化疗和放疗的反应以及预后与肿瘤微环境密切相关，尤其是肿瘤浸润免疫细胞（TII）的特征。复发性 GBM 更难治疗。新诊断和复发性 GBM 之间免疫环境的差异及其与肿瘤预后的关系尚未明确。
为了弥补这一知识空白，我们分析了 24 名 GBM 患者（13 名初诊和 11 名复发）的临床数据和组织标本。比较了患者 GBM 初诊与复发时多种免疫生物学标志物的表达水平，其中 5 名患者有两份标本（配对）。评估了 TII 在肿瘤内和血管周围区域的分布模式。
我们发现，与初诊时的肿瘤和良性脑标本相比，复发性 GBM 肿瘤中浸润的淋巴细胞（TIL）和巨噬细胞明显更多，PD-L1 和 PD-1 的表达水平更高。5 份配对标本的 TIL 和巨噬细胞形态变化与非配对患者一致，而配对组织中 CD8 与 CD4 的比值从诊断到复发保持不变。初诊时 TIL、巨噬细胞、PD-1 或 PD-L1+细胞的水平与 OS 无关。TIL、巨噬细胞和 PD-1+细胞在复发肿瘤中无论是在肿瘤内还是血管周围区域均增加，肿瘤内的分布水平高于血管周围区域。复发时更高的 CD4 或 CD8 浸润与更差的预后相关。
本研究阐明了 TIL 和 TAM 倾向于在血管周围区域聚集，并且在复发性 GBM 中比初诊时更为丰富。
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