Unleashing T-cell anti-tumor response through repair of altered RNA splicing and antigen mimicry recognition

项目摘要 尽管免疫疗法在几种癌症中取得了成功，但实体瘤中的免疫原性仍然是一个问题。 主要问题，指出需要重新发明免疫方法和技术。检查点 免疫疗法在患有相同癌症的患者中没有显示出相同的反应， 突变负荷、DNA损伤或检查点蛋白的表达可以准确预测免疫治疗 反应此外，癌症疫苗的进展受到缺乏癌症特异性和免疫原性的限制。 高免疫原性抗原、抗原递送技术和指导治疗的生物标志物。基于这些 由于目前癌症免疫疗法的局限性，我们需要发现非传统的和未经鉴定的 调节侵袭性癌症中抗肿瘤活性的机制。所提出的方案旨在揭示 T细胞中有缺陷的RNA剪接和抗菌记忆如何决定抗肿瘤免疫的命运。通过 研究这些机制，我们将有证据开发新的和有效的 具有可穿透递送和肿瘤特异性的免疫疗法。长期目标是开发检查点 免疫疗法和癌症疫苗，克服免疫无知，逃避和抑制， 肿瘤的该项目的目的是了解基因表达和抗原的内在机制， 抑制或促进T细胞对肿瘤细胞活性并形成检查点的识别 免疫疗法和癌症疫苗来释放T细胞的全部细胞毒性活性。在节目一中，我们将潜入 我们的初步数据表明，特定的RNA剪接 肿瘤浸润性T细胞的改变影响它们的成熟和功能。在这里，我们将评估 这些剪接缺陷，并测试通过我们的专利纠正剪接改变的治疗潜力， 临床前模型中的寡疗法。在程序2中，我们建立在胚胎转录的发现上， 作为细菌毒力因子的程序，在与最严重患者相关的实体瘤中打开 结果。我们将确定获得性抗细菌免疫在癌症进展中的作用，并测试一种新的 基于这种生物标志物的表达的癌症疫苗作为重新点燃抗肿瘤活性的方法。 这些程序旨在测试生物学机制，这些机制在生物学的背景下还没有被认识到。 免疫肿瘤学作为治疗靶点，并可能产生靶向患者和肿瘤的新型免疫疗法 具体特点。

PROJECT SUMMARY Despite the success of immunotherapies across several cancers, immunogenicity in solid tumors remains a major problem, pointing to the need to re-invent immunotherapeutic approaches and technologies. Checkpoint immunotherapies do not show the same response across patients with the same cancer, and neither mutational burden, DNA damage or expression of checkpoint proteins can accurately predict immunotherapy response. In addition, the progress on cancer vaccines has been limited by the lack of cancer specific and highly immunogenic antigens, antigen-delivery technology, and biomarkers to guide treatment. Based on these limitations in current cancer immunotherapies, we need to discover unconventional and unidentified mechanisms that regulate anti-tumor activity in aggressive cancers. The Programs presented seek to reveal how defective RNA splicing and anti- bacterial memory in T-cells determine the fate of anti-tumor immunity. By studying these mechanisms, we will have evidence for the development of novel and effective immunotherapies with penetrable delivery and tumor specificity. The long-term goal is to develop checkpoint immunotherapies and cancer vaccines that overcome immune ignorance, escape, and suppression in solid tumors. The project objective is to understand the intrinsic mechanisms of gene expression and antigen recognition that either inhibit or promote T-cell activity against tumor cells and develop checkpoint immunotherapies and cancer vaccines to unleash the full cytotoxic activity of T cells. In Program 1, we will dive deeper into the transcriptome of T-cells, where our preliminary data suggests that specific RNA splicing alterations in tumor infiltrating T-cells impact their maturation and function. Here we will evaluate the function of these splicing defects and test the therapeutic potential of correcting splicing alterations via our patented oligotherapy in pre-clinical models. In Program 2, we build on our discovery of an embryonic transcription program that acts as a bacterial virulence factor and is turned on in solid tumors associated with worst patient outcome. We will determine the role of acquired anti-bacterial immunity in cancer progression and test a novel cancer vaccine based on the expression of this biomarker as an approach to re-ignite anti-tumor activity. These programs are designed to test biological mechanisms that have not been appreciated in the context of immuno-oncology as therapeutic targets and could yield novel immunotherapies targeted at patient and tumor specific features.