Understanding and Overcoming Immunotherapy Resistance in Pediatric High-Grade Glioma

摘要： 儿童脑瘤是儿童癌症相关死亡的主要原因1。儿科患者的总体存活率 淋巴细胞性白血病在5年内超过90%2。与之形成鲜明对比的是，儿童白血病的总体存活率 高级别胶质瘤(PHGG)在5年时不到20%。在过去的几年里，已经取得了显著的进步 十年来一直在阐明儿童脑瘤的起源和基因组图谱3.尽管有这些进展， PHGG大多是无法治愈的，因为目前的治疗方法很少能提供比目前更大的生存益处。 标准护理，焦点辐射。少数患有PHGG的幸存者往往会留下毁灭性的副作用， 包括内分泌疾病，精神和神经认知障碍，发育障碍， 神经系统疾病，以及继发性肿瘤的高发4-6。这些副作用进一步突显了 开发新的治疗方式的必要性，理想情况下毒性最小，同时保持显著的 PHGG儿童的预后。免疫检查点抑制(ICI)导致了前所未有的 许多癌症类型的应答率，包括晚期转移期癌症，如黑色素瘤和 非小细胞肺癌7-9例。不幸的是，ICI在很大程度上未能在PHGG中产生好处， 患有体质错配修复(MMR)缺陷综合征(CMMRD)的患者除外10-13。 根据有限的文献数据和我们的初步观察，我们假设双等位基因生殖系 PHGG的MMR突变导致ICI反应增强，而体细胞MMR突变不会。我们进一步 假设基质MMR突变通过逆转免疫抑制来驱动增强的ICI反应 肿瘤微环境中肿瘤相关巨噬细胞(TAMs)的表型 (TME)。TAMs是TME中含量最丰富的非肿瘤性细胞浸润性细胞，表达最高水平的 PD-L114，15，效应性T细胞上程序性细胞死亡-1受体(PD-1)的配体。为了检验我们的假设， 我们建立了胚系和体细胞MMR突变体pHGG的遗传模型，并建议使用这些模型来 将它们的表达谱与CMMRD和非CMMRD患者的人PHGG样本进行比较。我们会 也可以使用这些模型来确定生殖系双等位基因MMR突变和 对抗PD-L1治疗的反应。这种高风险、高回报的应用程序的临床益处是双重的。第一, 它将确定PHGG的双等位基因MMR突变与免疫治疗之间是否存在因果联系 回应。如果存在这种联系，它将有助于我们理解对检查点抑制剂的主要耐药性 在患有PHGG的儿童中，以及随后如何针对这种机制。其次，CMMRD肿瘤是耐药的 对于传统疗法，因为包括替莫唑胺在内的几种常见化疗药物需要 充分的错配修复以发挥其细胞毒作用。因此患有CMMRD肿瘤的患者需要新的 治疗策略，我们的研究将机械地确定ICI是否会引起增强的抗- 这些肿瘤中的肿瘤反应。

Abstract: Pediatric brain tumors are the leading cause of childhood cancer-related death1. The overall survival for pediatric lymphoblastic leukemia is over 90% at 5 years 2. In stark contrast, the overall survival of children with pediatric high-grade gliomas (pHGG) is less than 20% at 5-years. Remarkable progress has been made over the last decade in elucidating the origin and genomic landscape of childhood brain tumors 3. Despite these advances, pHGGs are mostly incurable, as current therapies rarely provide a greater survival benefit over the current standard of care, focal radiation. The few survivors with pHGG are often left with devastating side effects, including endocrine morbidity, psychiatric and neurocognitive impairments, developmental disorders, neurological disease, and a high incidence of secondary tumors4-6. These side effects further highlight the necessity of developing novel treatment modalities, ideally with minimal toxicity while maintaining significant prognostic outcomes for children with pHGG. Immune checkpoint inhibition (ICI) resulted in an unprecedented response rate in many cancer types, including cancers in advanced metastatic stages such as melanoma and non-small cell lung cancer 7-9. Unfortunately, ICI has largely failed to produce benefits in pHGG, with the exception of patients harboring constitutional mismatch repair (MMR) deficiency syndrome (CMMRD) 10-13. Based on limited data from literature and our preliminary observations, we hypothesize that biallelic germline MMR mutations in pHGG result in enhanced ICI response while somatic MMR mutations do not. We further hypothesize that stromal MMR mutations drive enhanced ICI response by reversing the immunosuppressive phenotype of innate immune cell called tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). TAMs are the most-abundant non-neoplastic cell infiltrates in the TME and express the highest levels of PD-L114,15, a ligand for the programmed cell death-1 receptor (PD-1) on effector T-cells. To test our hypothesis, we developed genetic models of germline and somatic MMR mutant pHGG and propose to use these models to compare their expression profiles to human pHGG samples from CMMRD and non-CMMRD patients. We will also use these models to determine whether there is a casual link between germline biallelic MMR mutation and response to anti-PD-L1 therapy. The clinical benefits of this high-risk high-reward application are two-fold. First, it will establish whether there is a causal link between biallelic MMR mutation in pHGG and immunotherapy response. If the link exists it will contribute to our understanding of the primary resistance to checkpoint inhibitors in children with pHGG and subsequently, how to target such mechanisms. Second, CMMRD tumors are resistant to conventional therapies, since several common chemotherapeutic agents, including temozolomide, require adequate mismatch repair to exert their cytotoxic effects. Patients with CMMRD tumors thus require novel therapeutic strategies, and our studies will mechanistically establish whether or not ICI elicits an enhanced anti- tumor response in these tumors.