Understanding and overcoming Immunotherapy resistance in Pediatric High-Grade Glioma

点击翻译按钮获取中文摘要

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.