Inducing Tumor Neoantigens Through RNA Editing for Cancer Immunotherapy

项目摘要/摘要 免疫检查点抑制剂(ICIS)使癌症免疫治疗发生了革命性的变化，但仅在 患者和肿瘤类型的子集。缺乏T细胞渗透的肿瘤的成功治疗，称为 免疫冷冻性肿瘤仍然是癌症免疫治疗的主要障碍。肿瘤突变负担 与ICI疗效相关，这是因为有丰富的新抗原可由 ICI后的免疫系统。这项建议旨在提高多种肿瘤类型的能见度，并具有低 通过RNA编辑方法诱导新抗原表达而产生的突变负担。我们的 在一种高度侵袭性、免疫寒冷的小鼠黑色素瘤模型中的初步数据显示， RNA编辑和抗PD-1 ICI的组合比单独使用抗PD-1有显著的生存益处。我们 假设新抗原的诱导增强了T细胞对肿瘤的渗透并促进了表位 传播使得免疫系统除了识别诱导的肿瘤抗原外，还识别内源性肿瘤抗原 新抗原。我们将通过两个具体目标来检验这一假设。目标1将阐明其作用机制。 这种新的癌症免疫疗法通过对分离的肿瘤细胞的转录图谱进行分析，对肿瘤- 浸润性免疫细胞，以及远处肿瘤生长被抑制的非局部性效应的评估 在对原发肿瘤进行局部治疗后。目标2将确定此方法的普适性 其他免疫冷的小鼠癌症模型及其向人类癌症的转化 在多种患者来源的肿瘤有机化合物中的评估。这些目标的成功实现将提供 临床前验证，并进一步支持这一创新方法的发展。这一战略具有 使新抗原库多样化和扩大ICIS作为许多肿瘤类型的一线治疗的潜力， 改善癌症患者的临床结局。

PROJECT SUMMARY/ABSTRACT Immune checkpoint inhibitors (ICIs) have revolutionized cancer immunotherapy but remain effective in only a subset of patients and tumor types. The successful treatment of tumors that lack T cell infiltration, known as immunologically cold tumors, remains a major roadblock in cancer immunotherapy. Tumor mutational burden has been correlated with ICI efficacy due to the abundance of neoantigens that are recognizable by the immune system after ICI. This proposal aims to enhance the visibility of multiple tumor types with low mutational burden by inducing the expression of neoantigens through RNA editing approaches. Our preliminary data in a highly aggressive, immunologically cold model of murine melanoma show that the combination of RNA editing and anti-PD-1 ICI results in a significant survival benefit over anti-PD-1 alone. We hypothesize that the induction of neoantigens enhances T cell infiltration into the tumor and promotes epitope spreading such that the immune system recognizes endogenous tumor antigens in addition to induced neoantigens. We will test this hypothesis with two specific aims. Aim 1 will elucidate the mechanism of action of this novel cancer immunotherapy through transcriptomic profiling of isolated tumor cells, analysis of tumor- infiltrating immune cells, and evaluation of the abscopal effect whereby growth of a distant tumor is suppressed following localized treatment of the primary tumor. Aim 2 will determine the generalizability of this approach to additional immunologically cold murine cancer models as well as its translation to human cancers through evaluation in multiple patient-derived tumor organoids. The successful completion of these aims would provide preclinical validation and further support the advancement of this innovative approach. This strategy has the potential to diversify the neoantigen repertoire and expand ICIs as frontline therapies in many tumor types, improving clinical outcomes for cancer patients.