Recurrent Tumor-Specific Alternately Processed Transcripts as a Source of Neoantigens for NF1-associated Malignant Peripheral Nerve Sheath Tumor Immunoprevention

复发性肿瘤特异性交替加工转录本作为 NF1 相关恶性周围神经鞘肿瘤免疫预防的新抗原来源

• 批准号: 10023258
• 负责人: DAVID ANDREW LARGAESPADA
• 金额: $ 76.16万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-25 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10023258
• 关键词: Alleles; Amino Acid Sequence; Benign; CDKN2A gene; Cause of Death; Cell Line; Chimera organism; Code; Codon Nucleotides; Dangerousness; Data; Development; Drug usage; Excision; Exons; Frameshift Mutation; Genes; Genetic Transcription; Grant; Human; Immune Targeting; Immune response; Immune system; Immunization; Immunoprecipitation; Introns; Knowledge; Lead; Malignant - descriptor; Malignant Neoplasms; Mass Spectrum Analysis; Modeling; Mus; Mutation; NF1 gene; Neoplasm Metastasis; Nerve; Neurofibromatosis 1; Neurofibrosarcoma; Operative Surgical Procedures; Patients; Peptide Vaccines; Peptides; Peripheral Nerve Sheath Neoplasm; Pharmaceutical Preparations; Pharmacotherapy; Phase; Plexiform Neurofibroma; Predisposition; Prevention; Preventive vaccine; Process; Production; Public Health; RNA Splicing; Radiation therapy; Recurrence; Recurrent tumor; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Ribosomes; Schwann Cells; Site; Soft tissue sarcoma; Source; Surgical margins; Survival Rate; Syndrome; Terminator Codon; Transcript; Translating; Tumor Cell Line; Tumor Tissue; Vaccinated; Vaccination; Vaccines; Variant; chemoradiation; chemotherapy; dermal neurofibroma; design; lifetime risk; loss of function mutation; mouse model; neoantigens; neurofibroma; novel; premalignant; premature; prevent; prophylactic; transcriptome; transcriptome sequencing; tumor

Abstract/Summary Neurofibromatosis type 1 (NF1) syndrome is an autosomal dominant tumor predisposition syndrome that is caused by loss-of-function mutations of NF1 gene encoding neurofibromin. Among patients with NF1, loss of the non-mutant allele of NF1 in a rare Schwann cell or precursor, along with other ill-defined factors, leads to benign dermal or plexiform neurofibromas. The main cause of death among NF1 patients is the malignant peripheral nerve sheath tumor (MPNST), a highly aggressive soft tissue sarcoma that most likely develops from plexiform neurofibroma, in particular the so-called “atypical” plexiform neurofibroma. Approximately half of MPNSTs are NF1-associated, and NF1 patients have 10-15% lifetime risk of developing this terrible cancer. MPNSTs metastasize early and are often resistant to radiotherapy and chemotherapy. The main treatment for MPNSTs is surgical resection but, despite radical excision with wide surgical margins, followed by chemoradiation, 5-year survival rates are poor due to metastases as well as local recurrence. NF1 patients could greatly benefit from prophylactic vaccination that would prevent the malignant transformation of benign plexiform neurofibromas into “atypical” plexiform neurofibromas and to MPNSTs. We aim to determine if the mutations that govern the development of “atypical” plexiform neurofibroma (NF1 loss followed by CDKN2A loss) and MPSNT (NF1, CDKN2A, and SUZ12 loss) lead to the expression of recurrent alternately processed transcripts, such as transcriptionally-induced chimeras, that could express neoantigens and be used as targets for prophylactic vaccines. Such transcripts can be translated to produce novel peptides downstream of frameshift mutations caused by coding exon read-through into introns, mis-splicing from a coding exon to a non-canonical splice acceptors or splice acceptors in other genes. In most cases, a premature termination codon (PTC) will be rapidly encountered by the ribosome translating such transcripts. Therefore, we furthermore hypothesize that these alternately processed transcripts can express what we call “cryptic” neoantigens when treated with drugs that suppress utilization of premature codons such as Ataluren or gentamycin. In such a way, we could administer a prophylactic vaccine and induce conditionally active immune response that would eliminate nascent tumors only when drug treatment is used.

摘要/总结 1 型神经纤维瘤病 (NF1) 综合征是一种常染色体显性肿瘤易感综合征， 由编码神经纤维蛋白的 NF1 基因功能丧失突变引起。 罕见雪旺细胞或前体中 NF1 的非突变等位基因，以及其他不确定的因素，导致 良性真皮或丛状神经纤维瘤是 NF1 患者死亡的主要原因。 周围神经鞘瘤（MPNST），一种高度侵袭性的软组织肉瘤，最有可能发生 来自丛状神经纤维瘤，特别是所谓的“非典型”丛状神经纤维瘤。 MPNST 与 NF1 相关，NF1 患者终生有 10-15% 的风险患上这种可怕的癌症。 MPNST 转移较早，通常对放疗和化疗具有抵抗力。 MPNST 是手术切除，但尽管根治性切除具有广泛的手术切缘，但随后 放化疗期间，由于 NF1 患者发生转移和局部复发，5 年生存率较低。 预防性疫苗接种可以极大地受益于预防良性病变的恶性转化 我们的目标是确定是否将丛状神经纤维瘤转化为“非典型”丛状神经纤维瘤和 MPNST。 控制“非典型”丛状神经纤维瘤发展的突变（NF1 缺失，随后 CDKN2A 丢失）和 MPSNT（NF1、CDKN2A 和 SUZ12 丢失）导致反复交替加工的表达 转录物，例如转录诱导的嵌合体，可以表达新抗原并用作靶标 对于预防性疫苗，此类转录物可以被翻译以产生新的下游肽。 由编码外显子读入内含子、从编码外显子错误拼接到内含子引起的移码突变 在大多数情况下，非规范剪接受体或其他基因中的剪接受体会提前终止。 翻译此类转录本的核糖体将快速遇到密码子（PTC）。 此外，这些交替处理的转录本可以表达我们所说的“神秘” 使用抑制过早密码子利用的药物（例如 Ataluren 或）治疗时会产生新抗原 通过这种方式，我们可以注射预防性疫苗并诱导条件性主动免疫。 只有使用药物治疗才能消除新生肿瘤的反应。