Develop a Therapeutic Nano-vaccine against Head and Neck Cancer

项目总结 免疫检查点受体(ICR)阻断的临床成功源于其恢复 耗尽的肿瘤浸润性淋巴细胞的效应功能。而是一种专门针对免疫细胞的效应器 在免疫原性低的感冒肿瘤中，治疗容易失败，其特点是不能充分诱导 肿瘤特异性T细胞免疫和对免疫原性细胞毒的抵抗。事实上，大约80%的口腔、头部和 颈部鳞状细胞癌(HNC)患者对ICR阻断没有反应。传统型 放化疗和外科治疗与吞咽等高发病率有关。 问题，口干，真菌感染，颌骨死亡，毁容，和“闭合性颌骨”。降级 治疗会导致疾病的进展。因此，迫切需要描述支持HNC的机制 免疫原性低下。我们的初步研究确定了肿瘤微环境中的I型干扰素信号 作为调节抗肿瘤免疫反应可塑性的关键途径。I型干扰素靶基因 促进抗原提呈细胞(APC)和效应细胞向肿瘤床的转运，并增强APC的交叉 引爆效率。为了减轻寒冷的HNC对免疫激活的负面影响，我们设计了一种 纳米疫苗系统，可有效增强I型干扰素信号和抗原传递。我们的原型 纳米疫苗导致肿瘤微环境中肿瘤特异性T细胞的12倍以上的扩张， 显著减轻肿瘤负担。根据我们的结果并回应FOA，最重要的是 该项目的假设是：I型干扰素信号对维持HNC的免疫原性至关重要，而我们的 纳米疫苗使寒冷的HNC对ICR封锁敏感。为了验证这一假设，我们设定了三个目标：**(1) 我们将描述I型干扰素信号在调节HNC免疫原性中的作用；**(2)我们将 确定HNC细胞用来抑制I型干扰素信号和促进对 关卡封锁；**(3)我们将优化I型干扰素诱导肿瘤特异性纳米疫苗系统，以 打破HNC免疫耐受。这些目标与《全面和平协议》完全一致。(1)我们会澄清 I型干扰素信号在调节抗肿瘤免疫可塑性中的作用(2)我们将开发一个安全的， 生物相容、高免疫原性和有效的纳米疫苗技术，精确和可预测地富集 肿瘤抗原特异性T细胞谱系。

PROJECT SUMMARY Clinical success of immune checkpoint receptor (ICR) blockade stems from its efficacy in restoring the effector function of exhausted tumor-infiltrating lymphocytes. But an exclusive effector immune cell-targeted treatment is prone to failure in hypoimmunogenic cold tumors, which are featured by insufficient elicitation of tumor-specific T-cell immunity and resistance to immunogenic cytotoxicity. Indeed, about 80% of Oral, Head & Neck Squamous Cell Carcinoma (HNC) patients do not respond to ICR blockade. Conventional chemoradiotherapy and surgical management are associated with high morbidity, such as swallowing problems, dry mouth, fungal infection, dead bone of the jaw, disfigurement, and “lock-jaw”. Deescalating treatment results in disease progression. Thus, it is urgent to characterize the mechanisms underpinning HNC hypoimmunogenicity. Our preliminary study identifies type I interferon signaling in the tumor microenvironment as a key pathway modulating the plasticity of anti-tumor immune response. Type I interferon target genes promote antigen-presenting cell (APC) and effector cell trafficking to the tumor bed, and enhance APC cross- priming efficiency. To mitigate the negative impact of cold HNC upon immune activation, we engineered a nano-vaccine system that potently enhances type I interferon signaling and antigen delivery. Our prototype nano-vaccine leads to an over 12-fold expansion of tumor-specific T cells in the tumor microenvironment, and significantly reduces tumor burden. Informed by our results and in response to the FOA, the overarching hypothesis of the project is: type I interferon signaling is essential to maintain HNC immunogenicity, and our nano-vaccine sensitizes cold HNC to ICR blockade. To test this hypothesis, three aims are put in place: **(1) we will characterize the role of type I interferon signaling in modulating HNC immunogenicity; **(2) we will determine the mechanisms HNC cells employ to dampen type I interferon signaling and promote resistance to checkpoint blockade; **(3) we will optimize a type I interferon-inducing tumor-specific nano-vaccine system to break HNC immune tolerance. These goals are in precise alignment with the FOA. (1) We will elucidate the role of type I interferon signaling in modulating the plasticity of anti-tumor immunity. (2) We will develop a safe, biocompatible, highly immunogenic and effective nano-vaccine technology to precisely and predictably enrich tumor antigen-specific T-cell repertoire.