Marx Sascha, Wilken Fabian, Miebach Lea, Ispirjan Mikael, Kinnen Frederik, Paul Sebastian, Bien-Möller Sandra, Freund Eric, Baldauf Jörg, Fleck Steffen, Siebert Nikolai, Lode Holger, Stahl Andreas, Rauch Bernhard H, Singer Stephan, Ritter Christoph, Schroeder Henry W S, Bekeschus Sander
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA.
Department of Neurosurgery, Greifswald University Medical Center, Ferdinand-Sauerbruch-Str., 17475 Greifswald, Germany.
Cancers (Basel). 2022 Nov 23;14(23):5751. doi: 10.3390/cancers14235751.
Glioblastoma is the most common and lethal primary brain malignancy that almost inevitably recurs as therapy-refractory cancer. While the success of immune checkpoint blockade (ICB) revealed the immense potential of immune-targeted therapies in several types of cancers outside the central nervous system, it failed to show objective responses in glioblastoma patients as of now. The ability of glioblastoma cells to drive multiple modes of T cell dysfunction while exhibiting low-quality neoepitopes, low-mutational load, and poor antigen priming limits anti-tumor immunity and efficacy of antigen-unspecific immunotherapies such as ICB. An in-depth understanding of the GBM immune landscape is essential to delineate and reprogram such immunosuppressive circuits during disease progression. In this view, the present study aimed to characterize the peripheral and intratumoral immune compartments of 35 glioblastoma patients compared to age- and sex-matched healthy control probands, particularly focusing on exhaustion signatures on myeloid and T cell subsets. Compared to healthy control participants, different immune signatures were already found in the peripheral circulation, partially related to the steroid medication the patients received. Intratumoral CD4+ and CD8+ TEM cells (CD62L/CD45RO) revealed a high expression of PD1, which was also increased on intratumoral, pro-tumorigenic macrophages/microglia. Histopathological analysis further identified high PSGL-1 expression levels of the latter, which has recently been linked to increased metastasis in melanoma and colon cancer via P-selectin-mediated platelet activation. Overall, the present study comprises immunophenotyping of a patient cohort to give implications for eligible immunotherapeutic targets in neurooncology in the future.
胶质母细胞瘤是最常见且致命的原发性脑恶性肿瘤，几乎不可避免地会复发成为难治性癌症。虽然免疫检查点阻断（ICB）疗法在中枢神经系统以外的几种癌症中显示出免疫靶向治疗的巨大潜力，但截至目前，它在胶质母细胞瘤患者中并未显示出客观疗效。胶质母细胞瘤细胞能够驱动多种T细胞功能障碍模式，同时表现出低质量的新抗原表位、低突变负荷和较差的抗原启动能力，这限制了抗肿瘤免疫以及ICB等非特异性免疫疗法的疗效。深入了解胶质母细胞瘤的免疫格局对于在疾病进展过程中描绘和重新编程这种免疫抑制回路至关重要。从这个角度来看，本研究旨在对35例胶质母细胞瘤患者的外周和肿瘤内免疫区室进行特征分析，并与年龄和性别匹配的健康对照者进行比较，特别关注髓系和T细胞亚群上的耗竭特征。与健康对照参与者相比，在外周循环中已经发现了不同的免疫特征，部分与患者接受的类固醇药物有关。肿瘤内的CD4+和CD8+ TEM细胞（CD62L/CD45RO）显示出PD1的高表达，在肿瘤内促肿瘤的巨噬细胞/小胶质细胞上也有所增加。组织病理学分析进一步确定了后者的PSGL-1高表达水平，最近它通过P-选择素介导的血小板活化与黑色素瘤和结肠癌转移增加有关。总体而言，本研究对一组患者进行了免疫表型分析，为未来神经肿瘤学中合适的免疫治疗靶点提供了启示。
