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Cancer immunotherapy is accompanied by distinct metabolic patterns in primary and secondary lymphoid organs observed by non-invasive in vivo 18F-FDG-PET.
Theranostics ( IF 12.4 ) Pub Date : 2020-01-01 , DOI: 10.7150/thno.35989
Johannes Schwenck 1, 2, 3 , Barbara Schörg 2 , Francesco Fiz 1, 4 , Dominik Sonanini 2, 5 , Andrea Forschner 6 , Thomas Eigentler 6 , Benjamin Weide 6 , Manuela Martella 7 , Irene Gonzalez-Menendez 3, 7 , Cristina Campi 8 , Gianmario Sambuceti 9 , Ferdinand Seith 10 , Leticia Quintanilla-Martinez 3, 7 , Claus Garbe 6 , Christina Pfannenberg 10 , Martin Röcken 3, 6, 11 , Christian la Fougere 1, 3, 11 , Bernd J Pichler 2, 3, 11 , Manfred Kneilling 2, 3, 6
Affiliation  

Purpose: Cancer immunotherapy depends on a systemic immune response, but the basic underlying mechanisms are still largely unknown. Despite the very successful and widespread use of checkpoint inhibitors in the clinic, the majority of cancer patients do not benefit from this type of treatment. In this translational study, we investigated whether noninvasive in vivo positron emission tomography (PET) imaging using 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) is capable of detecting immunotherapy-associated metabolic changes in the primary and secondary lymphoid organs and whether this detection enables the prediction of a successful anti-cancer immune response.

Methods: RIP1-Tag2 mice with progressed endogenous insular cell carcinomas underwent a combined cancer immunotherapy consisting of CD4+ T cells plus monoclonal antibodies (mAbs) against programmed death ligand-1 (PD-L1) and lymphocyte activation gene-3 (LAG-3) or a sham treatment after radiation-mediated immune cell depletion. A second cohort of RIP1-Tag2 mice underwent exclusive checkpoint inhibitor therapy (CIT) using anti-PD-L1/LAG-3 mAbs or sham treatment without initial immune cell depletion to mimic the clinical situation.

All mice were monitored by 18F-FDG-PET combined with anatomical magnetic resonance imaging (MRI). In addition, we retrospectively analyzed PET / computed tomography (CT) scans (PET/CT) regarding 18F-FDG uptake of CIT-treated metastatic melanoma patients in the spleen (n=23) and bone marrow (BM; n=20) as well as blood parameters (n=17-21).

Results: RIP1-Tag2 mice with advanced insular cell carcinomas treated with combination immunotherapy exhibited significantly increased 18F-FDG uptake in the spleen compared to sham-treated mice. Histopathology of the spleens from treated mice revealed atrophy of the white pulp with fewer germinal centers and an expanded red pulp with hyperplasia of neutrophils than those of sham-treated mice. Immunohistochemistry and flow cytometry analyses of the spleens revealed a lower number of T cells and a higher number of neutrophils compared to those in the spleens of sham-treated mice. Flow cytometry of the BM showed enhanced activation of T cells following the treatment schemes that included checkpoint inhibitors. The ratio of 18F-FDG uptake at baseline to the uptake at follow-up in the spleens of exclusively CIT-treated RIP1-Tag2 mice was significantly enhanced, but the ratio was not enhanced in the spleens of the sham-treated littermates. Flow cytometry analysis confirmed a reduced number of T cells in the spleens of exclusively CIT-treated mice compared to that of sham-treated mice. A retrospective analysis of clinical 18F-FDG-PET/CT scans revealed enhanced 18F-FDG uptake in the spleens of some successfully CIT-treated patients with metastatic melanoma, but there were no significant differences between responders and non-responders. The analysis of the BM in clinical 18F-FDG-PET/CT scans with a computational segmentation tool revealed significantly higher baseline 18F-FDG uptake in patients who responded to CIT than in non-responders, and this relationship was independent of bone metastasis, even in the baseline scan.

Conclusions: Thus, we are presenting the first translational study of solid tumors focusing on the metabolic patterns of primary and secondary lymphoid organs induced by the systemic immune response after CIT. We demonstrate that the widely available 18F-FDG-PET modality is an applicable translational tool that has high potential to stratify patients at an early time point.



中文翻译:

癌症免疫疗法伴随着通过非侵入性体内18F-FDG-PET观察到的初级和次级淋巴器官的独特代谢模式。

目的:癌症免疫疗法取决于全身免疫反应,但基本的基本机制仍不清楚。尽管在临床上非常成功且广泛地使用了检查点抑制剂,但大多数癌症患者仍无法从这种治疗中受益。在这项转化研究中,我们调查了使用2- [ 18 F]氟-2-脱氧-D-葡萄糖(18 F-FDG)进行的非侵入性体内正电子发射断层扫描(PET)成像是否能够检测免疫疗法相关的新陈代谢变化。主要和次要淋巴器官,以及这种检测是否能够预测成功的抗癌免疫反应。

方法:对患有进展性内源性岛状细胞癌的RIP1-Tag2小鼠进行联合癌症免疫治疗,包括CD4 + T细胞加上针对程序性死亡配体-1(PD-L1)和淋巴细胞活化基因-3(LAG-3)的单克隆抗体(mAb) )或辐射介导的免疫细胞耗竭后进行假治疗。第二批RIP1-Tag2小鼠接受抗PD-L1 / LAG-3 mAb抗体或假治疗的排他性检查点抑制剂治疗(CIT),且初始免疫细胞不消耗,无法模拟临床情况。

通过18 F-FDG-PET结合解剖磁共振成像(MRI)监测所有小鼠。此外,我们回顾性分析了经CIT治疗的转移性黑色素瘤患者在脾脏(n = 23)和骨髓(BM; n = 20)中对18 F-FDG摄取的PET /计算机断层扫描(CT)扫描(PET / CT)。以及血液参数(n = 17-21)。

结果:与假治疗的小鼠相比,经联合免疫疗法治疗的患有晚期岛状细胞癌的RIP1-Tag2小鼠脾脏中的18 F-FDG摄取显着增加。与经假手术处理的小鼠相比,经处理的小鼠的脾脏的组织病理学显示具有较少生发中心的白色牙髓萎缩和中性粒细胞增生的扩大的红色牙髓。脾脏的免疫组织化学和流式细胞仪分析显示,与经假手术处理的小鼠脾脏相比,脾脏中的T细胞数量较少,嗜中性粒细胞数量较多。BM的流式细胞仪显示,按照包括检查点抑制剂在内的治疗方案,T细胞的活化增强。比例18完全接受CIT治疗的RIP1-Tag2小鼠脾脏中基线F-FDG的摄取与随访时的摄取显着提高,但深水处理的同窝仔小鼠的脾脏中F-FDG的摄取率并未提高。流式细胞术分析证实,与假手术处理的小鼠相比,仅CIT处理的小鼠的脾脏中T细胞数量减少。临床18 F-FDG-PET / CT扫描的回顾性分析显示,在一些成功CIT治疗的转移性黑色素瘤患者的脾脏中,18 F-FDG的摄取增加,但应答者与非应答者之间无显着差异。使用计算分割工具对临床18 F-FDG-PET / CT扫描中的BM进行分析后发现,基线18明显较高对CIT有反应的患者的F-FDG摄取要比无反应的患者高,并且这种关系与骨转移无关,即使在基线扫描中也是如此。

结论:因此,我们提出了实体瘤的第一个转化研究,重点是CIT后全身免疫反应诱导的原发性和继发性淋巴器官的代谢模式。我们证明,广泛可用的18 F-FDG-PET方式是一种适用的翻译工具,具有在早期将患者分层的巨大潜力。

更新日期:2020-01-01
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