Understanding and Overcoming Immunotherapy Resistance in Pediatric High-Grade Glioma

摘要： 儿童脑肿瘤是儿童癌症相关死亡的主要原因1。儿童的总生存率 淋巴细胞白血病在5年时超过90% 2。与此形成鲜明对比的是，儿童的总体生存率 高级别胶质瘤（pHGG）在5年时小于20%。在过去的几年里， 阐明儿童脑肿瘤的起源和基因组景观的十年3.尽管有这些进步， pHGG大多数是不可治愈的，因为目前的治疗很少提供比目前更大的生存益处。 标准治疗局部放疗少数患有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， 神经系统疾病和继发性肿瘤的高发病率4 -6。这些副作用进一步突出了 有必要开发新的治疗方式，理想情况下具有最小的毒性，同时保持显著的 pHGG患儿的预后结果。免疫检查点抑制（ICI）导致了前所未有的 在许多癌症类型中的缓解率，包括晚期转移阶段的癌症，如黑色素瘤， 非小细胞肺癌7-9.不幸的是，ICI在很大程度上未能在pHGG中产生益处， 除了患有体质性错配修复（MMR）缺陷综合征（CMMRD）的患者10-13。 基于文献中有限的数据和我们的初步观察，我们假设双等位基因种系 pHGG中的MMR突变导致ICI反应增强，而体细胞MMR突变则不会。我们进一步 假设间质MMR突变通过逆转免疫抑制因子而驱动ICI应答增强， 肿瘤微环境中称为肿瘤相关巨噬细胞（TAM）的先天免疫细胞表型 （TME）。TAM是TME中最丰富的非肿瘤细胞浸润，表达最高水平的 PD-L114，15，效应T细胞上程序性细胞死亡-1受体（PD-1）的配体。为了验证我们的假设， 我们开发了生殖系和体细胞MMR突变pHGG的遗传模型，并建议使用这些模型来 将它们的表达谱与来自CMMRD和非CMMRD患者的人pHGG样品进行比较。我们将 我也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。这种高风险高回报应用的临床益处是双重的。第一、 它将确定pHGG中双等位基因MMR突变与免疫治疗之间是否存在因果关系， 反应如果这种联系存在，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，以及随后如何靶向这些机制。其次，CMMRD肿瘤具有耐药性 由于包括替莫唑胺在内的几种常见的化疗药物需要 足够的错配修复以发挥其细胞毒性作用。因此，CMMRD肿瘤患者需要新的 治疗策略，我们的研究将从机制上确定ICI是否能增强抗- 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.