Restoring the Immunogenicity of Head and Neck Cancer

项目总结 免疫检查点受体阻滞剂(ICB)最近已被批准用于治疗 转移性、无法切除或复发的头颈部鳞状细胞癌(HNC)。 多种引爆策略已进入试验阶段，旨在使HNC变冷，HNC约占85% 这些病例，变成了T细胞炎热肿瘤，扩大了患者的人才库，可以从中受益 免疫疗法。从机制上讲，许多启动策略激活先天免疫传感器来启动 癌细胞和髓系细胞产生I型干扰素(IFN-I)。干扰素-I的激活及其靶点 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 交叉启动效率。当前启动方法的一个中心聚合点是接头分子 位于内质网及其相关膜的干扰素基因刺激物(STING)。 铅冷肿瘤增敏治疗，如照射、抑制DNA损伤修复、诱导 DNA复制压力和STING激动剂都参与了STING途径，进一步验证了 在恢复癌症免疫原性方面的刺激性。然而，最近对刺痛激动剂的试验表明 实体瘤患者的耐药率高，即使与ICB联合应用也是如此。HNC的作用机制 对刺痛的抗药性知之甚少，几乎没有有效的策略来克服癌症。 对天生免疫感应的抵抗力。这项计划的长期目标是建立生化和 HNC免疫原性的代谢调节网络和改善HNC的预防和免疫治疗 释放先天免疫传感器上的检查点。在最初的资助期内，我们发现 驱动癌基因使刺痛通路失效并促进免疫耐受，我们已经设计了 第一代纳米颗粒为了改善刺痛激动剂的细胞内递送，我们已经简化了我们的 单细胞免疫分析管道呈现皮损内免疫图景作为时间的函数。 最近，我们发现了一个新的途径，通过激活干扰素-I来抑制HNC的启动。此次续订 项目将利用我们以前的成就和我们最近的发现，形成一个具有凝聚力的计划 阐述了HNC抗刺激性的机理，并优化了一种新的 在对游离刺激剂不敏感的宿主中产生用于先天免疫启动的纳米颗粒。支持 以此为目标，我们建立了HNC对刺痛的启动和响应可塑性的综合模型 刺激，包括致癌物诱导的模型、植入性模型和基因工程模型。 对刺痛刺激的抵抗使一系列冷癌启动策略失去了资格。这个重建项目 将揭示支撑先天免疫传感器适合性的关键分子机制，并优化 强大的纳米技术在对叮咬刺激不敏感的个体中克服癌症抵抗力。

PROJECT SUMMARY Immune checkpoint receptor blockade (ICB) has been approved recently for the treatment of metastatic, unresectable, or recurrent head and neck squamous cell carcinoma (HNC) in the first-line setting. Multiple priming strategies have entered into trials, aiming to turn cold HNCs, which account for about 85% of the cases, into T-cell inflamed hot tumors and expand the pool of patients who can benefit from immunotherapy. Mechanistically, many priming strategies activate innate immune sensors to launch the production of type-I interferons (IFN-I) by cancer cells and myeloid cells. The activation of IFN-I and its target genes promotes antigen-presenting cell (APC) and effector cell trafficking to the tumor bed and enhances APC cross-priming efficiency. A central converging point of the current priming approaches is an adaptor molecule located at the endoplasmic reticulum and its associated membranes, stimulator of interferon genes (STING). Lead cold tumor sensitization treatments, such as irradiation, inhibition of DNA damage repair, induction of DNA replication stress, and STING agonists all engage the STING pathway, further validating the promise of STING-priming in restoring the immunogenicity of cancers. However, recent trials of STING agonists showed a high resistance rate in patients with solid tumors, even in combination with ICB. The mechanism of HNC resistance to STING priming is poorly understood, and few strategies are available to overcome cancer resistance to innate immune sensing. The long-term goal of this program is to establish the biochemical and metabolic regulatory network of HNC immunogenicity and improve HNC prevention and immunotherapy by releasing the checkpoints on innate immune sensors. During the initial funding period, we have uncovered driver oncogenes that disable the STING pathway and promote immune tolerance, we have engineered the first-generation nanoparticles to improve the intracellular delivery of STING agonists, we have streamlined our single-cell immune analysis pipelines to render intra-lesional immune landscape as a function of time. Recently, we discovered a new pathway that suppresses HNC initiation through IFN-I activation. This renewal project will parlay our previous accomplishments and our recent discovery into a cohesive program that addresses the mechanisms of HNC resistance to STING stimulation and optimizes the engineering of a new generation of nanoparticles for innate immune priming in hosts insensitive to free STING agonists. To support this goal, we have established comprehensive modeling for HNC initiation and response plasticity to STING stimulation, including carcinogen-induced models, implantable models, and genetically engineered models. Resistance to STING stimulation disqualifies a spectrum of cold cancer priming strategies. This renewal project will uncover a pivotal molecular mechanism underpinning the fitness of innate immune sensors and optimize robust nanotechnology overcoming cancer resistance in individuals insensitive to STING stimulation.