Rethinking Immunotherapy in Meningiomas.
Rethinking Immunotherapy in Meningiomas.
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DOI：
10.1093/neuonc/noab168
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发表时间：
2021-07
期刊：
影响因子：
15.9
通讯作者：
M. Terabe;Jing Wu
中科院分区：
文献类型：
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作者：
M. Terabe;Jing Wu
脑膜瘤是中枢神经系统(CNS)最常见的肿瘤，占中枢神经系统肿瘤的38%，占非恶性肿瘤的一半。1尽管约三分之二的脑膜瘤是良性的，被归类为WHO I级，但20%-30%的脑膜瘤是II级和III级，它们的肿瘤行为通常更具侵袭性。在一些III级脑膜瘤的病例中，特别是那些不能进行大体全切除的脑膜瘤，总体存活率可以勉强超过一年。2在目前的治疗方法下，I、II、III级肿瘤的总10年生存率分别为84%、53%和0%。1、3虽然I级脑膜瘤被认为是良性的，但并不是所有的肿瘤都可以进行大体全切除，这主要是由于肿瘤的位置或累及静脉窦或神经血管组织。3这些肿瘤经常导致衰弱的神经功能障碍，如共济失调、视力障碍、脑神经瘫痪和眼球突出。此外，这些典型的生长缓慢的脑膜瘤甚至可以有2-4毫米/年的线性增长率。3尽管三分之一的脑膜瘤没有增长，但大约四分之一的脑膜瘤可能会经历指数增长。4这些事实突出了脑膜瘤有效和个体化治疗的重要性。手术一直是症状性脑膜瘤的主要治疗方法。放射治疗适用于不能切除的脑膜瘤或那些即使在大体全切除后仍有可能复发的脑膜瘤。5不幸的是，一旦患者发展成对手术或放射治疗不再有效的进展性疾病，就没有有效的系统疗法可以提供给这些患者。在认识到未得到满足的临床需求时，已作出临床努力来开发新的治疗方法。虽然基于几个大规模基因组图谱的发现而进行的靶向治疗的临床试验已经开发出来，但6，7免疫治疗已经成为神经肿瘤学领域的一个新兴兴趣。如表1所示，大多数正在进行的脑膜瘤免疫治疗临床试验都集中在针对PD-1/PD-L1轴的研究上。在本期《神经肿瘤学》中，Yeung等人报道，靶向CSF1/CSF1R轴是恶性脑膜瘤的一种潜在治疗策略。开展脑膜瘤的临床前研究一直是极具挑战性的，这主要是因为缺乏同基因动物模型来概括脑膜瘤的生物学和免疫学。使用一种新的同基因小鼠Nf2突变脑膜瘤模型MGS1，Yeung和他的同事证明了针对CSF1/CSF1R轴的免疫治疗，而不是针对PD-1/PD-L1轴的免疫治疗，有可能为脑膜瘤患者带来临床益处。8作者表明，MGS1重现了人类脑膜瘤的免疫格局，大量弥漫着表达PD-L1的M2样巨噬细胞。然而，令人惊讶的是，即使与促进T细胞激活的抗4-1BB联合使用，抗PD-1治疗也没有为荷瘤小鼠提供生存益处。相反，阻断CSF1显著延长了荷瘤小鼠的存活时间。CSF1由髓系细胞和肿瘤细胞产生，而其受体CSF1R仅在髓系细胞上差异表达。因此，与先前在胶质母细胞瘤中观察到的相似，CSF1阻断通过减少M2样免疫抑制髓系细胞和增加促炎树突状细胞改变了肿瘤组织中髓系细胞的格局。9然而，它并没有减少髓系细胞的数量，这可能是由于…产生了髓系细胞生长因子。
As the most commonly occurring tumor in the central nervous system (CNS), meningiomas account for 38% of all CNS tumors and half of all nonmalignant tumors. 1 Although about two-thirds of meningiomas are benign and classified as WHO grade I, 20%–30% are grade II and III, which usually are more aggressive in their tumor behavior. In some cases of grade III meningiomas, particularly those cannot have a gross total resection, the overall survival rate can be barely over a year. 2 With the current therapeutic approaches, the overall 10-year survival of grade I, II, and III tumors are 84%, 53%, and 0%, respectively. 1, 3 Although grade I meningiomas are considered benign, not all tumors can have gross total resection, largely due to the location of the tumor or the involvement of the venous sinus or neurovascular tissue. 3 These tumors often cause debilitating neurological deficits, such as ataxia, visual impairment, cranial nerve palsies, and exophthalmos. In addition, these typically slow-growing meningiomas can even have a linear growth rate of 2-4 mm/year. 3 Although a third of all meningiomas show no growth, about one-fourth may experience exponential growth. 4 These facts highlight the importance of effective and individualized treatments in meningiomas. Surgery has been the primary therapeutic approach for symptomatic meningiomas. Radiation therapy is reserved for unresectable meningiomas or those likely to have disease recurrence even after the gross total resection. 5 Unfortunately, once patients develop a progressive disease that no longer responds to surgery or radiation therapy, there are no effective systemic therapies that can be offered to these patients. In recognizing the unmet clinical need, clinical efforts have been made to develop new therapies. While clinical trials of targeted therapies based on discoveries made by several large-scale genomic profiling have been developed, 6, 7 immunotherapy has been an emerging interest in the field of neuro-oncology. As summarized in Table 1, most of the ongoing immune therapy clinical trials in meningiomas are focused on targeting the PD-1/PD-L1 axis. In this issue of Neuro-Oncology, Yeung et al reported that targeting the CSF1/CSF1R axis is a potential treatment strategy for malignant meningiomas. 8It has been extremely challenging to develop preclinical studies in meningiomas, largely due to the lack of syngeneic animal models to recapitulate the biology and the immunology of meningiomas. Using a novel syngeneic mouse Nf2-mutant meningioma model MGS1, Yeung and colleagues demonstrated that immunotherapy targeting the CSF1/CSF1R axis, but not the PD-1/PD-L1 axis, has the potential to bring a clinical benefit to meningioma patients. 8 The authors showed that MGS1 recapitulates the immune landscape of human meningioma with heavy infiltration of M2-like macrophages that express PD-L1. However, surprisingly, anti-PD-1 treatment provided no survival benefit to tumor-bearing mice even when it was combined with anti-4-1BB, which facilitates T-cell activation, to take a push-pull approach. In contrast, blockade of CSF1 significantly prolonged the survival of tumor-bearing mice. CSF1 is produced by both myeloid cells and tumor cells, while its receptor, CSF1R is differentially expressed only on myeloid cells. Thus, similar to previous observations in glioblastoma, the CSF1 blockade shifted the landscape of myeloid cells in tumor tissues by reducing M2-like immunosuppressive myeloid cells and increasing proinflammatory dendritic cells. 9 However, it did not reduce the number of myeloid cells presumably be due to the production of myeloid cell growth factors …