Inducing Tumor Neoantigens Through RNA Editing for Cancer Immunotherapy

项目总结/摘要 免疫检查点抑制剂（ICI）已经彻底改变了癌症免疫疗法，但仅在癌症患者中有效。 患者和肿瘤类型的子集。缺乏T细胞浸润的肿瘤的成功治疗， 免疫冷肿瘤仍然是癌症免疫治疗的主要障碍。肿瘤突变负荷 与ICI功效相关，这是由于可被免疫组织化学识别的新抗原的丰度。 ICI后的免疫系统。该提案旨在提高低风险的多种肿瘤类型的可见性。 通过RNA编辑方法诱导新抗原的表达来减轻突变负担。我们 在高度侵袭性、免疫学冷的鼠黑色素瘤模型中的初步数据显示， RNA编辑和抗PD-1 ICI的组合导致比单独的抗PD-1显著的存活益处。我们 假设新抗原的诱导增强了T细胞向肿瘤中的浸润并促进了表位 扩散，使得免疫系统除了诱导肿瘤抗原外，还识别内源性肿瘤抗原。 新抗原我们将以两个具体目标来检验这一假设。目的1将阐明作用机制 通过对分离的肿瘤细胞进行转录组学分析，对肿瘤细胞进行分析， 浸润性免疫细胞，并评估远端效应，从而抑制远端肿瘤的生长 在原发性肿瘤的局部治疗之后。目标2将确定这种方法的普遍性， 另外的免疫学上冷的鼠癌症模型以及其通过以下途径转化为人类癌症： 在多种患者来源的肿瘤类器官中进行评价。这些目标的成功实现将提供 临床前验证，并进一步支持这种创新方法的发展。这一战略具有 有可能使新抗原库多样化，并扩大ICI作为许多肿瘤类型的一线治疗， 改善癌症患者的临床结果。

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.