Nivolumab Reaches Brain Lesions in Patients with Recurrent Glioblastoma and Induces T-cell Activity and Upregulation of Checkpoint Pathways.

IF 8.1 1区 医学 Q1 IMMUNOLOGY
Signe K Skadborg, Simone Maarup, Arianna Draghi, Annie Borch, Sille Hendriksen, Filip Mundt, Vilde Pedersen, Matthias Mann, Ib J Christensen, Jane Skjøth-Ramussen, Christina W Yde, Bjarne W Kristensen, Hans S Poulsen, Benedikte Hasselbalch, Inge M Svane, Ulrik Lassen, Sine R Hadrup
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引用次数: 0

Abstract

Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis. Although immunotherapy is being explored as a potential treatment option for patients with GBM, it is unclear whether systemic immunotherapy can reach and modify the tumor microenvironment in the brain. We evaluated immune characteristics in patients receiving the anti-PD-1 immune checkpoint inhibitor nivolumab 1 week prior to surgery, compared with control patients receiving salvage resection without prior nivolumab treatment. We observed saturating levels of nivolumab bound to intratumorally and tissue-resident T cells in the brain, implicating saturating levels of nivolumab reaching brain tumors. Following nivolumab treatment, significant changes in T-cell activation and proliferation were observed in the tumor-resident T-cell population, and peripheral T cells upregulated chemokine receptors related to brain homing. A strong nivolumab-driven upregulation in compensatory checkpoint inhibition molecules, i.e., TIGIT, LAG-3, TIM-3, and CTLA-4, was observed, potentially counteracting the treatment effect. Finally, tumor-reactive tumor-infiltrating lymphocytes (TIL) were found in a subset of nivolumab-treated patients with prolonged survival, and neoantigen-reactive T cells were identified in both TILs and blood. This indicates a systemic response toward GBM in a subset of patients, which was further boosted by nivolumab, with T-cell responses toward tumor-derived neoantigens. Our study demonstrates that nivolumab does reach the GBM tumor lesion and enhances antitumor T-cell responses both intratumorally and systemically. However, various anti-inflammatory mechanisms mitigate the clinical efficacy of the anti-PD-1 treatment.

Nivolumab可到达复发性胶质母细胞瘤患者的脑部病灶,诱导T细胞活性和检查点通路的上调。
胶质母细胞瘤(GBM)是一种侵袭性脑肿瘤,预后不良。尽管免疫疗法正被探索作为GBM患者的一种潜在治疗选择,但全身性免疫疗法是否能到达并改变脑部肿瘤微环境尚不清楚。我们对手术前一周接受抗 PD1 免疫检查点抑制剂 Nivolumab 治疗的患者的免疫特征进行了评估,并与未接受 Nivolumab 治疗的接受挽救性切除术的对照组患者进行了比较。我们观察到 Nivolumab 与脑内肿瘤内和组织驻留 T 细胞结合的饱和水平,这意味着到达脑肿瘤的 Nivolumab 达到饱和水平。Nivolumab治疗后,在肿瘤常驻T细胞群中观察到T细胞活化和增殖发生了显著变化,外周T细胞上调了与脑归属相关的趋化因子受体。观察到Nivolumab驱动的补偿性检查点抑制分子TIGIT、LAG-3、TIM-3和CTLA-4上调,这可能会抵消治疗效果。最后,在Nivolumab治疗后生存期延长的患者中发现了肿瘤反应性肿瘤浸润淋巴细胞(TILs),并在TILs和血液中发现了新抗原反应性T细胞。这表明在一部分患者中出现了针对GBM的全身反应,Nivolumab进一步增强了这种反应,并出现了针对肿瘤衍生新抗原的T细胞反应。我们的研究表明,Nivolumab 确实能到达 GBM 肿瘤病灶,并增强肿瘤内和全身的抗肿瘤 T 细胞反应。然而,各种抗炎机制削弱了抗 PD1 治疗的临床疗效。
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来源期刊
Cancer immunology research
Cancer immunology research ONCOLOGY-IMMUNOLOGY
CiteScore
15.60
自引率
1.00%
发文量
260
期刊介绍: Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes. Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.
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